Author: "Bialkowska K." - Searchworks@Jio Institute Digital Library Search Results

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1. Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women

Author: Dorling, L., Carvalho, S., Allen, J., Gonzalez-Neira, A., Luccarini, C., Wahlstrom, C., Pooley, K.A., Parsons, M.T., Fortuno, C., Wang, Q., Bolla, M.K., Dennis, J., Keeman, R., Alonso, M.R., Alvarez, N., Herraez, B., Fernandez, V., Nunez-Torres, R., Osorio, A., Valcich, J., Li, M., Torngren, T., Harrington, P.A., Baynes, C., Conroy, D.M., Decker, B., Fachal, L., Mavaddat, N., Ahearn, T., Aittomaki, K., Antonenkova, N.N., Arnold, N., Arveux, P., Ausems, M.G.E.M., Auvinen, P., Becher, H., Beckmann, M.W., Behrens, S., Bermisheva, M., Bialkowska, K., Blomqvist, C., Bogdanova, N.V., Bogdanova-Markov, N., Bojesen, S.E., Bonanni, B., Borresen-Dale, A.L., Brauch, H., Bremer, M., Briceno, I., Bruning, T., Burwinkel, B., Cameron, D.A., Camp, N.J., Campbell, A., Carracedo, A., Castelao, J.E., Cessna, M.H., Chanock, S.J., Christiansen, H., Collee, J.M., Cordina-Duverger, E., Cornelissen, S., Czene, K., Dork, T., Ekici, A.B., Engel, C., Eriksson, M., Fasching, P.A., Figueroa, J., Flyger, H., Forsti, A., Gabrielson, M., Gago-Dominguez, M., Georgoulias, V., Gil, F., Giles, G.G., Glendon, G., Garcia, E.B.G., Alnaes, G.I.G., Guenel, P., Hadjisavvas, A., Haeberle, L., Hahnen, E., Hall, P., Hamann, U., Harkness, E.F., Hartikainen, J.M., Hartman, M., He, W., Heemskerk-Gerritsen, B.A.M., Hillemanns, P., Hogervorst, F.B.L., Hollestelle, A., Ho, W.K., Hooning, M.J., Howell, A., Humphreys, K., Idris, F., Jakubowska, A., Jung, A., Kapoor, P.M., Kerin, M.J., Khusnutdinova, E., Kim, S.W., Ko, Y.D., Kosma, V.M., Kristensen, V.N., Kyriacou, K., Lakeman, I.M.M., Lee, J.W., Lee, M.H., Li, J.M., Lindblom, A., W.Y. lo, Loizidou, M.A., Lophatananon, A., Lubinski, J., MacInnis, R.J., Madsen, M.J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Maurer, T., Mavroudis, D., McLean, C., Meindl, A., Mensenkamp, A.R., Michailidou, K., Miller, N., Taib, N.A.M., Muir, K., Mulligan, A.M., Nevanlinna, H., Newman, W.G., Nordestgaard, B.G., Ng, P.S., Oosterwijk, J.C., Park, S.K., Park-Simon, T.W., Perez, J.I.A., Peterlongo, P., Porteous, D.J., Prajzendanc, K., Prokofyeva, D., Radice, P., Rashid, M.U., Rhenius, V., Rookus, M.A., Rudiger, T., Saloustros, E., Sawyer, E.J., Schmutzler, R.K., Schneeweiss, A., Schurmann, P., Shah, M., Sohn, C., Southey, M.C., Surowy, H., Suvanto, M., Thanasitthichai, S., Tomlinson, I., Torres, D., Truong, T., Tzardi, M., Valova, Y., Asperen, C.J. van, Dam, R.M. van, Ouweland, A.M.W. van den, Kolk, L.E. van der, Veen, E.M. van, Wendt, C., Williams, J.A., Yang, X.H.R., Yoon, S.Y., Zamora, M.P., Evans, D.G., Hoya, M. de la, Simard, J., Antoniou, A.C., Borg, A., Andrulis, I.L., Chang-Claude, J., Garcia-Closas, M., Chenevix-Trench, G., Milne, R.L., Pharoah, P.D.P., Schmidt, M.K., Spurdle, A.B., Vreeswijk, M.P.G., Benitez, J., Dunning, A.M., Kvist, A., Teo, S.H., Devilee, P., Easton, D.F., Breast Canc Assoc Consortium, Erasmus MC other, Medical Oncology, Clinical Genetics, Keeman, Renske [0000-0002-5452-9933], Decker, Brennan [0000-0003-4516-7421], Eriksson, Mikael [0000-0001-8135-4270], Martinez, Maria Elena [0000-0002-6728-1834], Surowy, Harald [0000-0002-3595-9188], Pharoah, Paul DP [0000-0001-8494-732X], Apollo - University of Cambridge Repository, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), and Klinische Genetica
Subjects: Adult, Risk, Oncology, medicine.medical_specialty, Adolescent, PALB2, Genetic counseling, Genes, BRCA2, Mutation, Missense, Genes, BRCA1, Estrogen receptor, Breast Neoplasms, 030204 cardiovascular system & hematology, OVARIAN-CANCER, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, skin and connective tissue diseases, CHEK2, Aged, Genetic testing, Genetic association, Aged, 80 and over, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], medicine.diagnostic_test, MUTATIONS, business.industry, Age Factors, Genetic Variation, Sequence Analysis, DNA, General Medicine, Odds ratio, Middle Aged, BRCA1, medicine.disease, 3. Good health, Logistic Models, Female, business
Abstract: BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes,evidence of an association with breast cancer is weak, underlying risk estimatesare imprecise, and reliable subtype-specific risk estimates are lacking.METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing onsamples from 60,466 women with breast cancer and 53,461 controls. In separateanalyses for protein-truncating variants and rare missense variants in these genes,we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluatedmissense-variant associations according to domain and classification of pathogenicity.RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2)were associated with a risk of breast cancer overall with a P value of less than0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D,and TP53) were associated with a risk of breast cancer overall with a P value ofless than 0.05 and a Bayesian false-discovery probability of less than 0.05. Forprotein-truncating variants in 19 of the remaining 25 genes, the upper limit ofthe 95% confidence interval of the odds ratio for breast cancer overall was lessthan 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios werehigher for estrogen receptor (ER)–positive disease than for ER-negative disease;for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, andRAD51D, odds ratios were higher for ER-negative disease than for ER-positivedisease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 wereassociated with a risk of breast cancer overall with a P value of less than 0.001.For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a riskof breast cancer overall, with the risk being similar to that of protein-truncatingvariants.CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimatesof the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)
Published: 2021

2. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers (Nature Communications, (2021), 12, 1, (1078), 10.1038/s41467-020-20496-3).

Author: Coignard J., Lush M., Beesley J., O'Mara T.A., Dennis J., Tyrer J.P., Barnes D.R., McGuffog L., Leslie G., Bolla M.K., Agata S., Ahearn T., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Arnold N., Aronson K.J., Arun B.K., Augustinsson A., Azzollini J., Barrowdale D., Baynes C., Becher H., Bermisheva M., Bernstein L., Bialkowska K., Blomqvist C., Bojesen S.E., Bonanni B., Borg A., Brauch H., Brenner H., Burwinkel B., Buys S.S., Caldes T., Caligo M.A., Campa D., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Chung W.K., Claes K.B.M., Clarke C.L., Bertrand O., Caputo S., Dupre A., Le Mentec M., Belotti M., Birot A.-M., Buecher B., Fourme E., Gauthier-Villars M., Golmard L., Houdayer C., Moncoutier V., de Pauw A., Saule C., Sinilnikova O., Mazoyer S., Damiola F., Barjhoux L., Verny-Pierre C., Leone M., Boutry-Kryza N., Calender A., Giraud S., Caron O., Guillaud-Bataille M., Bressac-de-Paillerets B., Bignon Y.-J., Uhrhammer N., Lasset C., Bonadona V., Berthet P., Vaur D., Castera L., Popovici C., Sobol H., Bourdon V., Noguchi T., Remenieras A., Nogues C., Coupier I., Pujol P., Dumont A., Revillion F., Adenis C., Muller D., Barouk-Simonet E., Bonnet F., Bubien V., Sevenet N., Longy M., Toulas C., Guimbaud R., Gladieff L., Feillel V., Leroux D., Dreyfus H., Rebischung C., Peysselon M., Coron F., Faivre L., Baurand A., Jacquot C., Bertolone G., Lizard S., Prieur F., Lebrun M., Kientz C., Ferrer S.F., Mari V., Venat-Bouvet L., Delnatte C., Bezieau S., Mortemousque I., Coulet F., Colas C., Soubrier F., Warcoin M., Sokolowska J., Bronner M., Collonge-Rame M.-A., Damette A., Gesta P., Lallaoui H., Chiesa J., Molina-Gomes D., Ingster O., Gregory H., Miedzybrodzka Z., Morrison P.J., Ong K.-R., Donaldson A., Rogers M.T., Kennedy M.J., Porteous M.E., Brewer C., Davidson R., Izatt L., Brady A., Barwell J., Adlard J., Foo C., Lalloo F., Side L.E., Eason J., Henderson A., Walker L., Eeles R.A., Cook J., Snape K., Eccles D., Murray A., McCann E., Conroy D.M., Czene K., Daly M.B., Devilee P., Diez O., Ding Y.C., Domchek S.M., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Eliassen A.H., Engel C., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Barberan V., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Gehrig A., Georgoulias V., Giles G.G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hart S.N., He W., Hogervorst F.B.L., Hollestelle A., Hopper J.L., Horcasitas D.J., Hulick P.J., Hunter D.J., Imyanitov E.N., Fox S., Campbell I., Spurdle A., Webb P., de Fazio A., Tassell M., Kirk J., Lindeman G., Price M., Southey M., Milne R., Deb S., Bowtell D., van der Hout A.H., van den Ouweland A.M.W., Mensenkamp A.R., van Deurzen C.H.M., Kets C.M., Seynaeve C., van Asperen C.J., Aalfs C.M., Gomez Garcia E.B., van Leeuwen F.E., de Bock G.H., Meijers-Heijboer H.E.J., Obdeijn I.M., Collee J.M., Gille J.J.P., Oosterwijk J.C., Wijnen J.T., van der Kolk L.E., Hooning M.J., Ausems M.G.E.M., Mourits M.J.E., Blok M.J., Rookus M.A., Adank M.A., van der Luijt R.B., van Cronenburg T.C.T.E.F., van der Pol C.C., Russell N.S., Siesling S., Overbeek L., Wijnands R., de Lange J.L., Clarke C., Graham D., Sachchithananthan M., Marsh D., Scott R., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Simpson P., Jager A., Jakubowska A., James P.A., Jensen U.B., John E.M., Jones M.E., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khusnutdinova E., Kiiski J.I., Ko Y.-D., Kosma V.-M., Kraft P., Kurian A.W., Laitman Y., Lambrechts D., Le Marchand L., Lester J., Lesueur F., Lindstrom T., Lopez-Fernandez A., Loud J.T., Luccarini C., Mannermaa A., Manoukian S., Margolin S., Martens J.W.M., Mebirouk N., Meindl A., Miller A., Milne R.L., Montagna M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nielsen F.C., O'Brien K.M., Olopade O.I., Olson J.E., Olsson H., Osorio A., Ottini L., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peshkin B., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Polley E.C., Poppe B., Presneau N., Pujana M.A., Punie K., Radice P., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Robson M., Romero A., Rossing M., Saloustros E., Sandler D.P., Santella R., Scheuner M.T., Schmidt M.K., Schmidt G., Scott C., Sharma P., Soucy P., Southey M.C., Spinelli J.J., Steinsnyder Z., Stone J., Stoppa-Lyonnet D., Swerdlow A., Tamimi R.M., Tapper W.J., Taylor J.A., Terry M.B., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Torres D., Trainer A.H., Truong T., Tung N., Vachon C.M., Vega A., Vijai J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wolk A., Yadav S., Yang X.R., Yannoukakos D., Zheng W., Ziogas A., Zorn K.K., Park S.K., Thomassen M., Offit K., Schmutzler R.K., Couch F.J., Simard J., Chenevix-Trench G., Easton D.F., Andrieu N., Antoniou A.C., Coignard J., Lush M., Beesley J., O'Mara T.A., Dennis J., Tyrer J.P., Barnes D.R., McGuffog L., Leslie G., Bolla M.K., Agata S., Ahearn T., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Arnold N., Aronson K.J., Arun B.K., Augustinsson A., Azzollini J., Barrowdale D., Baynes C., Becher H., Bermisheva M., Bernstein L., Bialkowska K., Blomqvist C., Bojesen S.E., Bonanni B., Borg A., Brauch H., Brenner H., Burwinkel B., Buys S.S., Caldes T., Caligo M.A., Campa D., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Chung W.K., Claes K.B.M., Clarke C.L., Bertrand O., Caputo S., Dupre A., Le Mentec M., Belotti M., Birot A.-M., Buecher B., Fourme E., Gauthier-Villars M., Golmard L., Houdayer C., Moncoutier V., de Pauw A., Saule C., Sinilnikova O., Mazoyer S., Damiola F., Barjhoux L., Verny-Pierre C., Leone M., Boutry-Kryza N., Calender A., Giraud S., Caron O., Guillaud-Bataille M., Bressac-de-Paillerets B., Bignon Y.-J., Uhrhammer N., Lasset C., Bonadona V., Berthet P., Vaur D., Castera L., Popovici C., Sobol H., Bourdon V., Noguchi T., Remenieras A., Nogues C., Coupier I., Pujol P., Dumont A., Revillion F., Adenis C., Muller D., Barouk-Simonet E., Bonnet F., Bubien V., Sevenet N., Longy M., Toulas C., Guimbaud R., Gladieff L., Feillel V., Leroux D., Dreyfus H., Rebischung C., Peysselon M., Coron F., Faivre L., Baurand A., Jacquot C., Bertolone G., Lizard S., Prieur F., Lebrun M., Kientz C., Ferrer S.F., Mari V., Venat-Bouvet L., Delnatte C., Bezieau S., Mortemousque I., Coulet F., Colas C., Soubrier F., Warcoin M., Sokolowska J., Bronner M., Collonge-Rame M.-A., Damette A., Gesta P., Lallaoui H., Chiesa J., Molina-Gomes D., Ingster O., Gregory H., Miedzybrodzka Z., Morrison P.J., Ong K.-R., Donaldson A., Rogers M.T., Kennedy M.J., Porteous M.E., Brewer C., Davidson R., Izatt L., Brady A., Barwell J., Adlard J., Foo C., Lalloo F., Side L.E., Eason J., Henderson A., Walker L., Eeles R.A., Cook J., Snape K., Eccles D., Murray A., McCann E., Conroy D.M., Czene K., Daly M.B., Devilee P., Diez O., Ding Y.C., Domchek S.M., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Eliassen A.H., Engel C., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Barberan V., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Gehrig A., Georgoulias V., Giles G.G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hart S.N., He W., Hogervorst F.B.L., Hollestelle A., Hopper J.L., Horcasitas D.J., Hulick P.J., Hunter D.J., Imyanitov E.N., Fox S., Campbell I., Spurdle A., Webb P., de Fazio A., Tassell M., Kirk J., Lindeman G., Price M., Southey M., Milne R., Deb S., Bowtell D., van der Hout A.H., van den Ouweland A.M.W., Mensenkamp A.R., van Deurzen C.H.M., Kets C.M., Seynaeve C., van Asperen C.J., Aalfs C.M., Gomez Garcia E.B., van Leeuwen F.E., de Bock G.H., Meijers-Heijboer H.E.J., Obdeijn I.M., Collee J.M., Gille J.J.P., Oosterwijk J.C., Wijnen J.T., van der Kolk L.E., Hooning M.J., Ausems M.G.E.M., Mourits M.J.E., Blok M.J., Rookus M.A., Adank M.A., van der Luijt R.B., van Cronenburg T.C.T.E.F., van der Pol C.C., Russell N.S., Siesling S., Overbeek L., Wijnands R., de Lange J.L., Clarke C., Graham D., Sachchithananthan M., Marsh D., Scott R., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Simpson P., Jager A., Jakubowska A., James P.A., Jensen U.B., John E.M., Jones M.E., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khusnutdinova E., Kiiski J.I., Ko Y.-D., Kosma V.-M., Kraft P., Kurian A.W., Laitman Y., Lambrechts D., Le Marchand L., Lester J., Lesueur F., Lindstrom T., Lopez-Fernandez A., Loud J.T., Luccarini C., Mannermaa A., Manoukian S., Margolin S., Martens J.W.M., Mebirouk N., Meindl A., Miller A., Milne R.L., Montagna M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nielsen F.C., O'Brien K.M., Olopade O.I., Olson J.E., Olsson H., Osorio A., Ottini L., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peshkin B., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Polley E.C., Poppe B., Presneau N., Pujana M.A., Punie K., Radice P., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Robson M., Romero A., Rossing M., Saloustros E., Sandler D.P., Santella R., Scheuner M.T., Schmidt M.K., Schmidt G., Scott C., Sharma P., Soucy P., Southey M.C., Spinelli J.J., Steinsnyder Z., Stone J., Stoppa-Lyonnet D., Swerdlow A., Tamimi R.M., Tapper W.J., Taylor J.A., Terry M.B., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Torres D., Trainer A.H., Truong T., Tung N., Vachon C.M., Vega A., Vijai J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wolk A., Yadav S., Yang X.R., Yannoukakos D., Zheng W., Ziogas A., Zorn K.K., Park S.K., Thomassen M., Offit K., Schmutzler R.K., Couch F.J., Simard J., Chenevix-Trench G., Easton D.F., Andrieu N., and Antoniou A.C.
Abstract: The original version of this Article contained an error in the spelling of the author Heiko Becher, which was incorrectly given as Heko Becher. This has now been corrected in both the PDF and HTML versions of the Article.Copyright © 2021, The Author(s).
Published: 2021

3. Breast cancer risk genes - Association analysis in more than 113,000 women.

Author: Cornelissen S., Michailidou K., Miller N., Taib N.A.M., Muir K., Mulligan A.M., Nevanlinna H., Newman W.G., Nordestgaard B.G., Ng P.-S., Oosterwijk J.C., Park S.K., Park-Simon T.-W., Perez J.I.A., Peterlongo P., Porteous D.J., Prajzendanc K., Prokofyeva D., Radice P., Rashid M.U., Rhenius V., Rookus M.A., Rudiger T., Saloustros E., Sawyer E.J., Schmutzler R.K., Schneeweiss A., Schurmann P., Shah M., Sohn C., Southey M.C., Surowy H., Suvanto M., Thanasitthichai S., Tomlinson I., Torres D., Truong T., Tzardi M., Valova Y., van Asperen C.J., van Dam R.M., van den Ouweland A.M.W., van der Kolk L.E., van Veen E.M., Wendt C., Williams J.A., Yang X.R., Yoon S.-Y., Zamora M.P., Evans D.G., de la Hoya M., Simard J., Antoniou A.C., Borg A., Andrulis I.L., Chang-Claude J., Garcia-Closas M., Chenevix-Trench G., Milne R.L., Pharoah P.D.P., Schmidt M.K., Spurdle A.B., Vreeswijk M.P.G., Benitez J., Dunning A.M., Kvist A., Teo S.H., Devilee P., Easton D.F., Dorling L., Carvalho S., Allen J., Gonzalez-Neira A., Luccarini C., Wahlstrom C., Pooley K.A., Parsons M.T., Fortuno C., Wang Q., Bolla M.K., Dennis J., Keeman R., Alonso M.R., Alvarez N., Herraez B., Fernandez V., Nunez-Torres R., Osorio A., Valcich J., Li M., Torngren T., Harrington P.A., Baynes C., Conroy D.M., Decker B., Fachal L., Mavaddat N., Ahearn T., Aittomaki K., Antonenkova N.N., Arnold N., Arveux P., Ausems M.G.E.M., Auvinen P., Becher H., Beckmann M.W., Behrens S., Bermisheva M., Bialkowska K., Blomqvist C., Bogdanova N.V., Bogdanova-Markov N., Bojesen S.E., Bonanni B., Borresen-Dale A.-L., Brauch H., Bremer M., Briceno I., Bruning T., Burwinkel B., Cameron D.A., Camp N.J., Campbell A., Carracedo A., Castelao J.E., Cessna M.H., Chanock S.J., Christiansen H., Collee J.M., Cordina-Duverger E., Czene K., Dork T., Ekici A.B., Engel C., Eriksson M., Fasching P.A., Figueroa J., Flyger H., Forsti A., Gabrielson M., Gago-Dominguez M., Georgoulias V., Gil F., Giles G.G., Glendon G., Gomez Garcia E.B., Grenaker Alnaes G.I., Guenel P., Hadjisavvas A., Haeberle L., Hahnen E., Hall P., Hamann U., Harkness E.F., Hartikainen J.M., Hartman M., He W., Heemskerk-Gerritsen B.A.M., Hillemanns P., Hogervorst F.B.L., Hollestelle A., Ho W.K., Hooning M.J., Howell A., Humphreys K., Idris F., Jakubowska A., Jung A., Kapoor P.M., Kerin M.J., Khusnutdinova E., Kim S.-W., Ko Y.-D., Kosma V.-M., Kristensen V.N., Kyriacou K., Lakeman I.M.M., Lee J.W., Lee M.H., Li J., Lindblom A., Lo W.-Y., Loizidou M.A., Lophatananon A., Lubinski J., MacInnis R.J., Madsen M.J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Maurer T., Mavroudis D., McLean C., Meindl A., Mensenkamp A.R., Cornelissen S., Michailidou K., Miller N., Taib N.A.M., Muir K., Mulligan A.M., Nevanlinna H., Newman W.G., Nordestgaard B.G., Ng P.-S., Oosterwijk J.C., Park S.K., Park-Simon T.-W., Perez J.I.A., Peterlongo P., Porteous D.J., Prajzendanc K., Prokofyeva D., Radice P., Rashid M.U., Rhenius V., Rookus M.A., Rudiger T., Saloustros E., Sawyer E.J., Schmutzler R.K., Schneeweiss A., Schurmann P., Shah M., Sohn C., Southey M.C., Surowy H., Suvanto M., Thanasitthichai S., Tomlinson I., Torres D., Truong T., Tzardi M., Valova Y., van Asperen C.J., van Dam R.M., van den Ouweland A.M.W., van der Kolk L.E., van Veen E.M., Wendt C., Williams J.A., Yang X.R., Yoon S.-Y., Zamora M.P., Evans D.G., de la Hoya M., Simard J., Antoniou A.C., Borg A., Andrulis I.L., Chang-Claude J., Garcia-Closas M., Chenevix-Trench G., Milne R.L., Pharoah P.D.P., Schmidt M.K., Spurdle A.B., Vreeswijk M.P.G., Benitez J., Dunning A.M., Kvist A., Teo S.H., Devilee P., Easton D.F., Dorling L., Carvalho S., Allen J., Gonzalez-Neira A., Luccarini C., Wahlstrom C., Pooley K.A., Parsons M.T., Fortuno C., Wang Q., Bolla M.K., Dennis J., Keeman R., Alonso M.R., Alvarez N., Herraez B., Fernandez V., Nunez-Torres R., Osorio A., Valcich J., Li M., Torngren T., Harrington P.A., Baynes C., Conroy D.M., Decker B., Fachal L., Mavaddat N., Ahearn T., Aittomaki K., Antonenkova N.N., Arnold N., Arveux P., Ausems M.G.E.M., Auvinen P., Becher H., Beckmann M.W., Behrens S., Bermisheva M., Bialkowska K., Blomqvist C., Bogdanova N.V., Bogdanova-Markov N., Bojesen S.E., Bonanni B., Borresen-Dale A.-L., Brauch H., Bremer M., Briceno I., Bruning T., Burwinkel B., Cameron D.A., Camp N.J., Campbell A., Carracedo A., Castelao J.E., Cessna M.H., Chanock S.J., Christiansen H., Collee J.M., Cordina-Duverger E., Czene K., Dork T., Ekici A.B., Engel C., Eriksson M., Fasching P.A., Figueroa J., Flyger H., Forsti A., Gabrielson M., Gago-Dominguez M., Georgoulias V., Gil F., Giles G.G., Glendon G., Gomez Garcia E.B., Grenaker Alnaes G.I., Guenel P., Hadjisavvas A., Haeberle L., Hahnen E., Hall P., Hamann U., Harkness E.F., Hartikainen J.M., Hartman M., He W., Heemskerk-Gerritsen B.A.M., Hillemanns P., Hogervorst F.B.L., Hollestelle A., Ho W.K., Hooning M.J., Howell A., Humphreys K., Idris F., Jakubowska A., Jung A., Kapoor P.M., Kerin M.J., Khusnutdinova E., Kim S.-W., Ko Y.-D., Kosma V.-M., Kristensen V.N., Kyriacou K., Lakeman I.M.M., Lee J.W., Lee M.H., Li J., Lindblom A., Lo W.-Y., Loizidou M.A., Lophatananon A., Lubinski J., MacInnis R.J., Madsen M.J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Maurer T., Mavroudis D., McLean C., Meindl A., and Mensenkamp A.R.
Abstract: BACKGROUND Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS The results of this study define
Published: 2021

4. Erratum: Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers (Nature communications (2021) 12 1 (1078)).

Author: Coignard J., Lush M., Beesley J., O'Mara T.A., Dennis J., Tyrer J.P., Barnes D.R., McGuffog L., Leslie G., Bolla M.K., Adank M.A., Agata S., Ahearn T., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Arnold N., Aronson K.J., Arun B.K., Augustinsson A., Azzollini J., Barrowdale D., Baynes C., Becher H., Bermisheva M., Bernstein L., Bialkowska K., Blomqvist C., Bojesen S.E., Bonanni B., Borg A., Brauch H., Brenner H., Burwinkel B., Buys S.S., Caldes T., Caligo M.A., Campa D., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Chung W.K., Claes K.B.M., Clarke C.L., Collee J.M., Conroy D.M., Czene K., Daly M.B., Devilee P., Diez O., Ding Y.C., Domchek S.M., Dork T., Dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Eliassen A.H., Engel C., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Barberan V., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Gehrig A., Georgoulias V., Giles G.G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hart S.N., He W., Hogervorst F.B.L., Hollestelle A., Hopper J.L., Horcasitas D.J., Hulick P.J., Hunter D.J., Imyanitov E.N., Jager A., Jakubowska A., James P.A., Jensen U.B., John E.M., Jones M.E., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khusnutdinova E., Kiiski J.I., Ko Y.-D., Kosma V.-M., Kraft P., Kurian A.W., Laitman Y., Lambrechts D., Le Marchand L., Lester J., Lesueur F., Lindstrom T., Lopez-Fernandez A., Loud J.T., Luccarini C., Mannermaa A., Manoukian S., Margolin S., Martens J.W.M., Mebirouk N., Meindl A., Miller A., Milne R.L., Montagna M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nielsen F.C., O'Brien K.M., Olopade O.I., Olson J.E., Olsson H., Osorio A., Ottini L., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peshkin B., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Polley E.C., Poppe B., Presneau N., Pujana M.A., Punie K., Radice P., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Robson M., Romero A., Rossing M., Saloustros E., Sandler D.P., Santella R., Scheuner M.T., Schmidt M.K., Schmidt G., Scott C., Sharma P., Soucy P., Southey M.C., Spinelli J.J., Steinsnyder Z., Stone J., Stoppa-Lyonnet D., Swerdlow A., Tamimi R.M., Tapper W.J., Taylor J.A., Terry M.B., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Torres D., Trainer A.H., Truong T., Tung N., Vachon C.M., Vega A., Vijai J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wolk A., Yadav S., Yang X.R., Yannoukakos D., Zheng W., Ziogas A., Zorn K.K., Park S.K., Thomassen M., Offit K., Schmutzler R.K., Couch F.J., Simard J., Chenevix-Trench G., Easton D.F., Andrieu N., Antoniou A.C., Coignard J., Lush M., Beesley J., O'Mara T.A., Dennis J., Tyrer J.P., Barnes D.R., McGuffog L., Leslie G., Bolla M.K., Adank M.A., Agata S., Ahearn T., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Arnold N., Aronson K.J., Arun B.K., Augustinsson A., Azzollini J., Barrowdale D., Baynes C., Becher H., Bermisheva M., Bernstein L., Bialkowska K., Blomqvist C., Bojesen S.E., Bonanni B., Borg A., Brauch H., Brenner H., Burwinkel B., Buys S.S., Caldes T., Caligo M.A., Campa D., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Chung W.K., Claes K.B.M., Clarke C.L., Collee J.M., Conroy D.M., Czene K., Daly M.B., Devilee P., Diez O., Ding Y.C., Domchek S.M., Dork T., Dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Eliassen A.H., Engel C., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Barberan V., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Gehrig A., Georgoulias V., Giles G.G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hart S.N., He W., Hogervorst F.B.L., Hollestelle A., Hopper J.L., Horcasitas D.J., Hulick P.J., Hunter D.J., Imyanitov E.N., Jager A., Jakubowska A., James P.A., Jensen U.B., John E.M., Jones M.E., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khusnutdinova E., Kiiski J.I., Ko Y.-D., Kosma V.-M., Kraft P., Kurian A.W., Laitman Y., Lambrechts D., Le Marchand L., Lester J., Lesueur F., Lindstrom T., Lopez-Fernandez A., Loud J.T., Luccarini C., Mannermaa A., Manoukian S., Margolin S., Martens J.W.M., Mebirouk N., Meindl A., Miller A., Milne R.L., Montagna M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nielsen F.C., O'Brien K.M., Olopade O.I., Olson J.E., Olsson H., Osorio A., Ottini L., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peshkin B., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Polley E.C., Poppe B., Presneau N., Pujana M.A., Punie K., Radice P., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Robson M., Romero A., Rossing M., Saloustros E., Sandler D.P., Santella R., Scheuner M.T., Schmidt M.K., Schmidt G., Scott C., Sharma P., Soucy P., Southey M.C., Spinelli J.J., Steinsnyder Z., Stone J., Stoppa-Lyonnet D., Swerdlow A., Tamimi R.M., Tapper W.J., Taylor J.A., Terry M.B., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Torres D., Trainer A.H., Truong T., Tung N., Vachon C.M., Vega A., Vijai J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wolk A., Yadav S., Yang X.R., Yannoukakos D., Zheng W., Ziogas A., Zorn K.K., Park S.K., Thomassen M., Offit K., Schmutzler R.K., Couch F.J., Simard J., Chenevix-Trench G., Easton D.F., Andrieu N., and Antoniou A.C.
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.
Published: 2021

5. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Author: Gesta P., Mulligan A.M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Niederacher D., Nielsen F.C., Nikitina-Zake L., Nogues C., Olah E., Olopade O.I., Ong K.-R., O'Shaughnessy-Kirwan A., Osorio A., Ott C.-E., Papi L., Park S.K., Parsons M.T., Pedersen I.S., Peissel B., Peixoto A., Peterlongo P., Pfeiler G., Phillips K.-A., Prajzendanc K., Pujana M.A., Radice P., Ramser J., Ramus S.J., Rantala J., Rennert G., Risch H.A., Robson M., Ronlund K., Salani R., Schuster H., Senter L., Shah P.D., Sharma P., Side L.E., Singer C.F., Slavin T.P., Soucy P., Southey M.C., Spurdle A.B., Steinemann D., Steinsnyder Z., Stoppa-Lyonnet D., Sutter C., Tan Y.Y., Teixeira M.R., Teo S.H., Thull D.L., Tischkowitz M., Tognazzo S., Toland A.E., Trainer A.H., Tung N., van Engelen K., van Rensburg E.J., Vega A., Vierstraete J., Wagner G., Walker L., Wang-Gohrke S., Wappenschmidt B., Weitzel J.N., Yadav S., Yang X., Yannoukakos D., Zimbalatti D., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Antoniou A.C., GEMO Study Collaborators, EMBRACE Collaborators, kConFab Investigators, HEBON Investigators, GENEPSO Investigators, Barnes D.R., Rookus M.A., McGuffog L., Leslie G., Mooij T.M., Dennis J., Mavaddat N., Aittomaki K., Andrulis I.L., Arnold N., Arun B.K., Azzollini J., Balmana J., Barkardottir R.B., Benitez J., Bialkowska K., Blanco A.M., Blok M.J., Bonanni B., Boonen S.E., Borg A., Bozsik A., Bradbury A.R., Brunet J., Buys S.S., Caldes T., Caligo M.A., Campbell I., Christensen L.L., Chung W.K., Claes K.B.M., Berthet P., Colas C., Adlard J., Ahmed M., Antoniou A., Barrowdale D., Brennan P., Brewer C., Easton D., Evans D.G., Side L., Collonge-Rame M.-A., Cook J., Daly M.B., Davidson R., de la Hoya M., de Putter R., Delnatte C., Diez O., Ding Y.C., Domchek S.M., Dorfling C.M., Dumont M., Eeles R., Ejlertsen B., Engel C., Faivre L., Foretova L., Fostira F., Friedlander M., Friedman E., Frost D., Ganz P.A., Garber J., Gehrig A., Gerdes A.-M., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gschwantler-Kaulich D., Hahnen E., Hamann U., Hanson H., Hentschel J., Hogervorst F.B.L., Hooning M.J., Horvath J., Hu C., Hulick P.J., Imyanitov E.N., Chenevix-Trench G., Spurdle A., Blok M., Devilee P., Hogervorst F., Hooning M., Mensenkamp A., Meijers-Heijboer H., Rookus M., Engelen K., Andrieu N., Isaacs C., Izatt L., Izquierdo A., Jakubowska A., James P.A., Janavicius R., John E.M., Joseph V., Karlan B.Y., Kast K., Koudijs M., Kruse T.A., Kwong A., Laitman Y., Lasset C., Lazaro C., Lester J., Lesueur F., Liljegren A., Loud J.T., Lubinski J., Mai P.L., Manoukian S., Mari V., Mebirouk N., Meijers-Heijboer H.E.J., Meindl A., Mensenkamp A.R., Miller A., Montagna M., Mouret-Fourme E., Mukherjee S., Gesta P., Mulligan A.M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Niederacher D., Nielsen F.C., Nikitina-Zake L., Nogues C., Olah E., Olopade O.I., Ong K.-R., O'Shaughnessy-Kirwan A., Osorio A., Ott C.-E., Papi L., Park S.K., Parsons M.T., Pedersen I.S., Peissel B., Peixoto A., Peterlongo P., Pfeiler G., Phillips K.-A., Prajzendanc K., Pujana M.A., Radice P., Ramser J., Ramus S.J., Rantala J., Rennert G., Risch H.A., Robson M., Ronlund K., Salani R., Schuster H., Senter L., Shah P.D., Sharma P., Side L.E., Singer C.F., Slavin T.P., Soucy P., Southey M.C., Spurdle A.B., Steinemann D., Steinsnyder Z., Stoppa-Lyonnet D., Sutter C., Tan Y.Y., Teixeira M.R., Teo S.H., Thull D.L., Tischkowitz M., Tognazzo S., Toland A.E., Trainer A.H., Tung N., van Engelen K., van Rensburg E.J., Vega A., Vierstraete J., Wagner G., Walker L., Wang-Gohrke S., Wappenschmidt B., Weitzel J.N., Yadav S., Yang X., Yannoukakos D., Zimbalatti D., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Antoniou A.C., GEMO Study Collaborators, EMBRACE Collaborators, kConFab Investigators, HEBON Investigators, GENEPSO Investigators, Barnes D.R., Rookus M.A., McGuffog L., Leslie G., Mooij T.M., Dennis J., Mavaddat N., Aittomaki K., Andrulis I.L., Arnold N., Arun B.K., Azzollini J., Balmana J., Barkardottir R.B., Benitez J., Bialkowska K., Blanco A.M., Blok M.J., Bonanni B., Boonen S.E., Borg A., Bozsik A., Bradbury A.R., Brunet J., Buys S.S., Caldes T., Caligo M.A., Campbell I., Christensen L.L., Chung W.K., Claes K.B.M., Berthet P., Colas C., Adlard J., Ahmed M., Antoniou A., Barrowdale D., Brennan P., Brewer C., Easton D., Evans D.G., Side L., Collonge-Rame M.-A., Cook J., Daly M.B., Davidson R., de la Hoya M., de Putter R., Delnatte C., Diez O., Ding Y.C., Domchek S.M., Dorfling C.M., Dumont M., Eeles R., Ejlertsen B., Engel C., Faivre L., Foretova L., Fostira F., Friedlander M., Friedman E., Frost D., Ganz P.A., Garber J., Gehrig A., Gerdes A.-M., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gschwantler-Kaulich D., Hahnen E., Hamann U., Hanson H., Hentschel J., Hogervorst F.B.L., Hooning M.J., Horvath J., Hu C., Hulick P.J., Imyanitov E.N., Chenevix-Trench G., Spurdle A., Blok M., Devilee P., Hogervorst F., Hooning M., Mensenkamp A., Meijers-Heijboer H., Rookus M., Engelen K., Andrieu N., Isaacs C., Izatt L., Izquierdo A., Jakubowska A., James P.A., Janavicius R., John E.M., Joseph V., Karlan B.Y., Kast K., Koudijs M., Kruse T.A., Kwong A., Laitman Y., Lasset C., Lazaro C., Lester J., Lesueur F., Liljegren A., Loud J.T., Lubinski J., Mai P.L., Manoukian S., Mari V., Mebirouk N., Meijers-Heijboer H.E.J., Meindl A., Mensenkamp A.R., Miller A., Montagna M., Mouret-Fourme E., and Mukherjee S.
Abstract: Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Method(s): Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Result(s): The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3x10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7x10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3x10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4x10-12) carriers. The associations in the prospective cohort were similar. Conclusion(s): Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.Copyright © 2020, The Author(s).
Published: 2021

6. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Author: Radice P., Romero A., Rossing M., Saloustros E., Sandler D.P., Santella R., Scheuner M.T., Schmidt M.K., Schmidt G., Scott C., Sharma P., Soucy P., Southey M.C., Spinelli J.J., Steinsnyder Z., Stone J., Stoppa-Lyonnet D., Swerdlow A., Tamimi R.M., Tapper W.J., Taylor J.A., Terry M.B., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Torres D., Trainer A.H., Truong T., Tung N., Vachon C.M., Vega A., Vijai J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wolk A., Yadav S., Yang X.R., Yannoukakos D., Zheng W., Ziogas A., Zorn K.K., Park S.K., Thomassen M., Offit K., Schmutzler R.K., Couch F.J., Simard J., Chenevix-Trench G., Easton D.F., Andrieu N., Antoniou A.C., Coignard J., Lush M., Beesley J., O'Mara T.A., Dennis J., Tyrer J.P., Barnes D.R., McGuffog L., Leslie G., Bolla M.K., Agata S., Ahearn T., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Arnold N., Aronson K.J., Arun B.K., Augustinsson A., Azzollini J., Barrowdale D., Baynes C., Becher H., Bermisheva M., Bernstein L., Bialkowska K., Blomqvist C., Bojesen S.E., Bonanni B., Borg A., Brauch H., Brenner H., Burwinkel B., Buys S.S., Caldes T., Caligo M.A., Campa D., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Chung W.K., Claes K.B.M., Clarke C.L., Bertrand O., Caputo S., Dupre A., Le Mentec M., Belotti M., Birot A.-M., Buecher B., Fourme E., Gauthier-Villars M., Golmard L., Houdayer C., Moncoutier V., de Pauw A., Saule C., Sinilnikova O., Mazoyer S., Damiola F., Barjhoux L., Verny-Pierre C., Leone M., Boutry-Kryza N., Calender A., Giraud S., Caron O., Guillaud-Bataille M., Bressac-de-Paillerets B., Bignon Y.-J., Uhrhammer N., Lasset C., Bonadona V., Berthet P., Vaur D., Castera L., Popovici C., Sobol H., Bourdon V., Noguchi T., Remenieras A., Nogues C., Coupier I., Pujol P., Dumont A., Revillion F., Adenis C., Muller D., Barouk-Simonet E., Bonnet F., Bubien V., Sevenet N., Longy M., Toulas C., Guimbaud R., Gladieff L., Feillel V., Leroux D., Dreyfus H., Rebischung C., Peysselon M., Coron F., Faivre L., Baurand A., Jacquot C., Bertolone G., Lizard S., Prieur F., Lebrun M., Kientz C., Ferrer S.F., Mari V., Venat-Bouvet L., Delnatte C., Bezieau S., Mortemousque I., Coulet F., Colas C., Soubrier F., Warcoin M., Sokolowska J., Bronner M., Collonge-Rame M.-A., Damette A., Gesta P., Lallaoui H., Chiesa J., Molina-Gomes D., Ingster O., Gregory H., Miedzybrodzka Z., Morrison P.J., Ong K.-R., Donaldson A., Rogers M.T., Kennedy M.J., Porteous M.E., Brewer C., Davidson R., Izatt L., Brady A., Barwell J., Adlard J., Foo C., Lalloo F., Side L.E., Eason J., Henderson A., Walker L., Eeles R.A., Cook J., Snape K., Eccles D., Murray A., McCann E., Conroy D.M., Czene K., Daly M.B., Devilee P., Diez O., Ding Y.C., Domchek S.M., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Eliassen A.H., Engel C., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Barberan V., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Gehrig A., Georgoulias V., Giles G.G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hart S.N., He W., Hogervorst F.B.L., Hollestelle A., Hopper J.L., Horcasitas D.J., Hulick P.J., Hunter D.J., Imyanitov E.N., Fox S., Campbell I., Spurdle A., Webb P., de Fazio A., Tassell M., Kirk J., Lindeman G., Price M., Southey M., Milne R.L., Deb S., Bowtell D., van der Hout A.H., van den Ouweland A.M.W., Mensenkamp A.R., van Deurzen C.H.M., Kets C.M., Seynaeve C., van Asperen C.J., Aalfs C.M., Gomez Garcia E.B., van Leeuwen F.E., de Bock G.H., Meijers-Heijboer H.E.J., Obdeijn I.M., Collee J.M., Gille J.J.P., Oosterwijk J.C., Wijnen J.T., van der Kolk L.E., Hooning M.J., Ausems M.G.E.M., Mourits M.J.E., Blok M.J., Rookus M.A., Adank M.A., van der Luijt R.B., van Cronenburg T.C.T.E.F., van der Pol C.C., Russell N.S., Siesling S., Overbeek L., Wijnands R., de Lange J.L., Clarke C., Graham D., Sachchithananthan M., Marsh D., Scott R., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Simpson P., Jager A., Jakubowska A., James P.A., Jensen U.B., John E.M., Jones M.E., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khusnutdinova E., Kiiski J.I., Ko Y.-D., Kosma V.-M., Kraft P., Kurian A.W., Laitman Y., Lambrechts D., Le Marchand L., Lester J., Lesueur F., Lindstrom T., Lopez-Fernandez A., Loud J.T., Luccarini C., Mannermaa A., Manoukian S., Margolin S., Martens J.W.M., Mebirouk N., Meindl A., Miller A., Montagna M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nielsen F.C., O'Brien K.M., Olopade O.I., Olson J.E., Olsson H., Osorio A., Ottini L., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peshkin B., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Polley E.C., Poppe B., Presneau N., Pujana M.A., Punie K., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Robson M., Radice P., Romero A., Rossing M., Saloustros E., Sandler D.P., Santella R., Scheuner M.T., Schmidt M.K., Schmidt G., Scott C., Sharma P., Soucy P., Southey M.C., Spinelli J.J., Steinsnyder Z., Stone J., Stoppa-Lyonnet D., Swerdlow A., Tamimi R.M., Tapper W.J., Taylor J.A., Terry M.B., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Torres D., Trainer A.H., Truong T., Tung N., Vachon C.M., Vega A., Vijai J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wolk A., Yadav S., Yang X.R., Yannoukakos D., Zheng W., Ziogas A., Zorn K.K., Park S.K., Thomassen M., Offit K., Schmutzler R.K., Couch F.J., Simard J., Chenevix-Trench G., Easton D.F., Andrieu N., Antoniou A.C., Coignard J., Lush M., Beesley J., O'Mara T.A., Dennis J., Tyrer J.P., Barnes D.R., McGuffog L., Leslie G., Bolla M.K., Agata S., Ahearn T., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Arnold N., Aronson K.J., Arun B.K., Augustinsson A., Azzollini J., Barrowdale D., Baynes C., Becher H., Bermisheva M., Bernstein L., Bialkowska K., Blomqvist C., Bojesen S.E., Bonanni B., Borg A., Brauch H., Brenner H., Burwinkel B., Buys S.S., Caldes T., Caligo M.A., Campa D., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Chung W.K., Claes K.B.M., Clarke C.L., Bertrand O., Caputo S., Dupre A., Le Mentec M., Belotti M., Birot A.-M., Buecher B., Fourme E., Gauthier-Villars M., Golmard L., Houdayer C., Moncoutier V., de Pauw A., Saule C., Sinilnikova O., Mazoyer S., Damiola F., Barjhoux L., Verny-Pierre C., Leone M., Boutry-Kryza N., Calender A., Giraud S., Caron O., Guillaud-Bataille M., Bressac-de-Paillerets B., Bignon Y.-J., Uhrhammer N., Lasset C., Bonadona V., Berthet P., Vaur D., Castera L., Popovici C., Sobol H., Bourdon V., Noguchi T., Remenieras A., Nogues C., Coupier I., Pujol P., Dumont A., Revillion F., Adenis C., Muller D., Barouk-Simonet E., Bonnet F., Bubien V., Sevenet N., Longy M., Toulas C., Guimbaud R., Gladieff L., Feillel V., Leroux D., Dreyfus H., Rebischung C., Peysselon M., Coron F., Faivre L., Baurand A., Jacquot C., Bertolone G., Lizard S., Prieur F., Lebrun M., Kientz C., Ferrer S.F., Mari V., Venat-Bouvet L., Delnatte C., Bezieau S., Mortemousque I., Coulet F., Colas C., Soubrier F., Warcoin M., Sokolowska J., Bronner M., Collonge-Rame M.-A., Damette A., Gesta P., Lallaoui H., Chiesa J., Molina-Gomes D., Ingster O., Gregory H., Miedzybrodzka Z., Morrison P.J., Ong K.-R., Donaldson A., Rogers M.T., Kennedy M.J., Porteous M.E., Brewer C., Davidson R., Izatt L., Brady A., Barwell J., Adlard J., Foo C., Lalloo F., Side L.E., Eason J., Henderson A., Walker L., Eeles R.A., Cook J., Snape K., Eccles D., Murray A., McCann E., Conroy D.M., Czene K., Daly M.B., Devilee P., Diez O., Ding Y.C., Domchek S.M., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Eliassen A.H., Engel C., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Barberan V., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Gehrig A., Georgoulias V., Giles G.G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hart S.N., He W., Hogervorst F.B.L., Hollestelle A., Hopper J.L., Horcasitas D.J., Hulick P.J., Hunter D.J., Imyanitov E.N., Fox S., Campbell I., Spurdle A., Webb P., de Fazio A., Tassell M., Kirk J., Lindeman G., Price M., Southey M., Milne R.L., Deb S., Bowtell D., van der Hout A.H., van den Ouweland A.M.W., Mensenkamp A.R., van Deurzen C.H.M., Kets C.M., Seynaeve C., van Asperen C.J., Aalfs C.M., Gomez Garcia E.B., van Leeuwen F.E., de Bock G.H., Meijers-Heijboer H.E.J., Obdeijn I.M., Collee J.M., Gille J.J.P., Oosterwijk J.C., Wijnen J.T., van der Kolk L.E., Hooning M.J., Ausems M.G.E.M., Mourits M.J.E., Blok M.J., Rookus M.A., Adank M.A., van der Luijt R.B., van Cronenburg T.C.T.E.F., van der Pol C.C., Russell N.S., Siesling S., Overbeek L., Wijnands R., de Lange J.L., Clarke C., Graham D., Sachchithananthan M., Marsh D., Scott R., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Simpson P., Jager A., Jakubowska A., James P.A., Jensen U.B., John E.M., Jones M.E., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khusnutdinova E., Kiiski J.I., Ko Y.-D., Kosma V.-M., Kraft P., Kurian A.W., Laitman Y., Lambrechts D., Le Marchand L., Lester J., Lesueur F., Lindstrom T., Lopez-Fernandez A., Loud J.T., Luccarini C., Mannermaa A., Manoukian S., Margolin S., Martens J.W.M., Mebirouk N., Meindl A., Miller A., Montagna M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nielsen F.C., O'Brien K.M., Olopade O.I., Olson J.E., Olsson H., Osorio A., Ottini L., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peshkin B., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Polley E.C., Poppe B., Presneau N., Pujana M.A., Punie K., Rantala J., Rashid M.U., Rennert G., Rennert H.S., and Robson M.
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.Copyright © 2021, The Author(s).
Published: 2021

7. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers (vol 12, 1078, 2021)

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Fox, S, van der Hout, AH, Clarke, C, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Fox, S, van der Hout, AH, Clarke, C, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
Published: 2021

8. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Zhang, H, Ahearn, TU, Lecarpentier, J, Barnes, D, Beesley, J, Qi, G, Jiang, X, O’Mara, TA, Zhao, N, Bolla, MK, Dunning, AM, Dennis, J, Wang, Q, Ful, ZA, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Arun, BK, Auer, PL, Azzollini, J, Barrowdale, D, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Bondavalli, D, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Brucker, SY, Brüning, T, Burwinkel, B, Buys, SS, Byers, H, Caldés, T, Caligo, MA, Calvello, M, Campa, D, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiaens, M, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Diez, O, Domchek, SM, Dörk, T, Dwek, M, Eccles, DM, Ekici, AB, Evans, DG, Fasching, PA, Figueroa, J, Foretova, L, Fostira, F, Friedman, E, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Gronwald, J, Guénel, P, Häberle, L, Hahnen, E, Haiman, CA, Hake, CR, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Hillemanns, P, Hogervorst, FBL, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huebner, H, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jager, A, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khan, S, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Konstantopoulou, I, Koppert, LB, Koutros, S, Kristensen, VN, Laenkholm, A-V, Lambrechts, D, Larsson, SC, Laurent-Puig, P, Lazaro, C, Lazarova, E, Lejbkowicz, F, Leslie, G, Lesueur, F, Lindblom, A, Lissowska, J, Lo, W-Y, Loud, JT, Lubinski, J, Lukomska, A, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Matricardi, L, McGuffog, L, McLean, C, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Mingazheva, E, Montagna, M, Mulligan, AM, Mulot, C, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsen, FC, Nikitina-Zake, L, Nodora, J, Offit, K, Olah, E, Olopade, OI, Olsson, H, Orr, N, Papi, L, Papp, J, Park-Simon, T-W, Parsons, MT, Peissel, B, Peixoto, A, Peshkin, B, Peterlongo, P, Peto, J, Phillips, K-A, Piedmonte, M, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Prokofyeva, D, Rack, B, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Risch, HA, Romero, A, Rookus, MA, Rübner, M, Rüdiger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Scheuner, MT, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schöttker, B, Schürmann, P, Senter, L, Sharma, P, Sherman, ME, Shu, X-O, Singer, CF, Smichkoska, S, Soucy, P, Southey, MC, Spinelli, JJ, Stone, J, Stoppa-Lyonnet, D, Swerdlow, AJ, Szabo, CI, Tamimi, RM, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, M, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van den Ouweland, AMW, van der Kolk, LE, van Veen, EM, vanRensburg, EJ, Vega, A, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wildiers, H, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zheng, W, Zorn, KK, Milne, RL, Kraft, P, Simard, J, Pharoah, PDP, Michailidou, K, Antoniou, AC, Schmidt, MK, Chenevix-Trench, G, Easton, DF, Chatterjee, N, and García-Closas, M
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1,2,3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P
Published: 2020

9. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Zhan, H.Y., Ahearn, T.U., Lecarpentier, J., Barnes, D., Beesley, J., Qi, G.H., Jiang, X., O'Mara, T.A., Zhao, N., Bolla, M.K., Dunning, A.M., Dennis, J., Wang, Q., Abu Ful, Z., Aittomaki, K., Andrulis, I.L., Anton-Culver, H., Arndt, V., Aronson, K.J., Arun, B.K., Auer, P.L., Azzollini, J., Barrowdale, D., Becher, H., Beckmann, M.W., Behrens, S., Benitez, J., Bermisheva, M., Bialkowska, K., Blanco, A., Blomqvist, C., Bogdanova, N.V., Bojesen, S.E., Bonanni, B., Bondavalli, D., Borg, A., Brauch, H., Brenner, H., Briceno, I., Broeks, A., Brucker, S.Y., Bruning, T., Burwinkel, B., Buys, S.S., Byers, H., Caldes, T., Caligo, M.A., Calvello, M., Campa, D., Castelao, J.E., Chang-Claude, J., Chanock, S.J., Christiaens, M., Christiansen, H., Chung, W.K., Claes, K.B.M., Clarke, C.L., Cornelissen, S., Couch, F.J., Cox, A., Cross, S.S., Czene, K., Daly, M.B., Devilee, P., Diez, O., Domchek, S.M., Dork, T., Dwek, M., Eccles, D.M., Ekici, A.B., Evans, D.G., Fasching, P.A., Figueroa, J., Foretova, L., Fostira, F., Friedman, E., Frost, D., Gago-Dominguez, M., Gapstur, S.M., Garber, J., Garcia-Saenz, J.A., Gaudet, M.M., Gayther, S.A., Giles, G.G., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., Gonzalez-Neira, A., Greene, M.H., Gronwald, J., Guenel, P., Haberle, L., Hahnen, E., Haiman, C.A., Hake, C.R., Hall, P., Hamann, U., Harkness, E.F., Heemskerk-Gerritsen, B.A.M., Hillemanns, P., Hogervorst, F.B.L., Holleczek, B., Hollestelle, A., Hooning, M.J., Hoover, R.N., Hopper, J.L., Howell, A., Huebner, H., Hulick, P.J., Imyanitov, E.N., Isaacs, C., Izatt, L., Jager, A., Jakimovska, M., Jakubowska, A., James, P., Janavicius, R., Janni, W., John, E.M., Jones, M.E., Jung, A., Kaaks, R., Kapoor, P.M., Karlan, B.Y., Keeman, R., Khan, S., Khusnutdinova, E., Kitahara, C.M., Ko, Y.D., Konstantopoulou, I., Koppert, L.B., Koutros, S., Kristensen, V.N., Laenkholm, A.V., Lambrechts, D., Larsson, S.C., Laurent-Puig, P., Lazaro, C., Lazarova, E., Lejbkowicz, F., Leslie, G., Lesueur, F., Lindblom, A., Lissowska, J., W.Y. lo, Loud, J.T., Lubinski, J., Lukomska, A., MacInnis, R.J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Matricardi, L., McGuffog, L., McLean, C., Mebirouk, N., Meindl, A., Menon, U., Miller, A., Mingazheva, E., Montagna, M., Mulligan, A.M., Mulot, C., Muranen, T.A., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Neven, P., Newman, W.G., Nielsens, F.C., Nikitina-Zake, L., Nodora, J., Offit, K., Olah, E., Olopade, O.I., Olsson, H., Orr, N., Papi, L., Papp, J., Park-Simon, T.W., Parsons, M.T., Peissel, B., Peixoto, A., Peshkin, B., Peterlongo, P., Peto, J., Phillips, K.A., Piedmonte, M., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Prokofyeva, D., Rack, B., Radice, P., Ramus, S.J., Rantala, J., Rashid, M.U., Rennert, G., Rennert, H.S., Risch, H.A., Romero, A., Rookus, M.A., Rubner, M., Rudiger, T., Saloustros, E., Sampson, S., Sandler, D.P., Sawyer, E.J., Scheuner, M.T., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Schottker, B., Schurmann, P., Senter, L., Sharma, P., Sherman, M.E., Shu, X.O., Singer, C.F., Smichkoska, S., Soucy, P., Southey, M.C., Spinelli, J.J., Stone, J., Stoppa-Lyonnet, D., Swerdlow, A.J., Szabo, C.I., Tamimi, R.M., Tapper, W.J., Taylor, J.A., Teixeira, M.R., Terry, M., Thomassen, M., Thull, D.L., Tischkowitz, M., Toland, A.E., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Troester, M.A., Truong, T., Tung, N., Untch, M., Vachon, C.M., Ouweland, A.M.W. van den, Kolk, L.E. van der, Veen, E.M. van, vanRensburg, E.J., Vega, A., Wappenschmidt, B., Weinberg, C.R., Weitzel, J.N., Wildiers, H., Winqvist, R., Wolk, A., Yang, X.H.R., Yannoukakos, D., Zheng, W., Zorn, K.K., Milne, R.L., Kraft, P., Simard, J., Pharoah, P.D.P., Michailidou, K., Antoniou, A.C., Schmidt, M.K., Chenevix-Trench, G., Easton, D.F., Chatterjee, N., Garcia-Closas, M., kConFab Investigators, ABCTB Investigators, EMBRACE Study, and GEMO Study Collaborators
Abstract: Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade.Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Published: 2020

10. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Zhang, H. (Haoyu), Ahearn, T. U. (Thomas U.), Lecarpentier, J. (Julie), Barnes, D. (Daniel), Beesley, J. (Jonathan), Qi, G. (Guanghao), Hang, X. (Xia), O'Mara, T. A. (Tracy A.), Zhao, N. (Ni), Bolla, M. K. (Manjeet K.), Dunning, A. M. (Alison M.), Dennis, J. (Joe), Wang, Q. (Qin), Abu Ful, Z. (Zumuruda), Aittomaki, K. (Kristiina), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Arun, B. K. (Banu K.), Auer, P. L. (Paul L.), Azzollini, J. (Jacopo), Barrowdale, D. (Daniel), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bialkowska, K. (Katarzyna), Blanco, A. (Ana), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Bonanni, B. (Bernardo), Bondavalli, D. (Davide), Borg, A. (Ake), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Briceno, I. (Ignacio), Broeks, A. (Annegien), Brucker, S. Y. (Sara Y.), Bruening, T. (Thomas), Burwinkel, B. (Barbara), Buys, S. S. (Saundra S.), Byers, H. (Helen), Caldes, T. (Trinidad), Caligo, M. A. (Maria A.), Calvello, M. (Mariarosaria), Campa, D. (Daniele), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Christiaens, M. (Melissa), Christiansen, H. (Hans), Chung, W. K. (Wendy K.), Claes, K. B. (Kathleen B. M.), Clarke, C. L. (Christine L.), Cornelissen, S. (Sten), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Diez, O. (Orland), Domchek, S. M. (Susan M.), Doerk, T. (Thilo), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Foretova, L. (Lenka), Fostira, F. (Florentia), Friedman, E. (Eitan), Frost, D. (Debra), Gago-Dominguez, M. (Manuela), Gapstur, S. M. (Susan M.), Garber, J. (Judy), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Gayther, S. A. (Simon A.), Giles, G. G. (Graham G.), Godwin, A. K. (Andrew K.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Greene, M. H. (Mark H.), Gronwald, J. (Jacek), Guenel, P. (Pascal), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hake, C. R. (Christopher R.), Hall, P. (Per), Hamann, U. (Ute), Harkness, E. F. (Elaine F.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Hillemanns, P. (Peter), Hogervorst, F. B. (Frans B. L.), Holleczek, B. (Bernd), Hollestelle, A. (Antoinette), Hooning, M. J. (Maartje J.), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Howell, A. (Anthony), Huebner, H. (Hanna), Hulick, P. J. (Peter J.), Imyanitov, E. N. (Evgeny N.), Isaacs, C. (Claudine), Izatt, L. (Louise), Jager, A. (Agnes), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, P. (Paul), Janavicius, R. (Ramunas), Janni, W. (Wolfgang), John, E. M. (Esther M.), Jones, M. E. (Michael E.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kapoor, P. M. (Pooja Middha), Karlan, B. Y. (Beth Y.), Keeman, R. (Renske), Khan, S. (Sofia), Khusnutdinova, E. (Elza), Kitahara, C. M. (Cari M.), Ko, Y.-D. (Yon-Dschun), Konstantopoulou, I. (Irene), Koppert, L. B. (Linetta B.), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Laenkholm, A.-V. (Anne-Vibeke), Lambrechts, D. (Diether), Larsson, S. C. (Susanna C.), Laurent-Puig, P. (Pierre), Lazaro, C. (Conxi), Lazarova, E. (Emilija), Lejbkowicz, F. (Flavio), Leslie, G. (Goska), Lesueur, F. (Fabienne), Lindblom, A. (Annika), Lissowska, J. (Jolanta), Lo, W.-Y. (Wing-Yee), Loud, J. T. (Jennifer T.), Lubinski, J. (Jan), Lukomska, A. (Alicja), Maclnnis, R. J. (Robert J.), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martinez, M. E. (Maria Elena), Matricardi, L. (Laura), McGuffog, L. (Lesley), McLean, C. (Catriona), Mebirouk, N. (Noura), Meindl, A. (Alfons), Menon, U. (Usha), Miller, A. (Austin), Mingazheva, E. (Elvira), Montagna, M. (Marco), Mulligan, A. M. (Anna Marie), Mulot, C. (Claire), Muranen, T. A. (Taru A.), Nathanson, K. L. (Katherine L.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Neven, P. (Patrick), Newman, W. G. (William G.), Nielsens, F. C. (Finn C.), Nikitina-Zake, L. (Liene), Nodora, J. (Jesse), Offit, K. (Kenneth), Olah, E. (Edith), Olopade, O. I. (Olufunmilayo, I), Olsson, H. (Hakan), Orr, N. (Nick), Papi, L. (Laura), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. T. (Michael T.), Peissel, B. (Bernard), Peixoto, A. (Ana), Peshkin, B. (Beth), Peterlongo, P. (Paolo), Peto, J. (Julian), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Plaseska-Karanfilska, D. (Dijana), Prajzendanc, K. (Karolina), Prentice, R. (Ross), Prokofyeva, D. (Darya), Rack, B. (Brigitte), Radice, P. (Paolo), Ramus, S. J. (Susan J.), Rantala, J. (Johanna), Rashid, M. U. (Muhammad U.), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Risch, H. A. (Harvey A.), Romero, A. (Atocha), Rookus, M. A. (Matti A.), Ruebner, M. (Matthias), Ruediger, T. (Thomas), Saloustros, E. (Emmanouil), Sampson, S. (Sarah), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Scheuner, M. T. (Maren T.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Schoemaker, M. J. (Minouk J.), Schoettker, B. (Ben), Schuermann, P. (Peter), Senter, L. (Leigha), Sharma, P. (Priyanka), Sherman, M. E. (Mark E.), Shu, X.-O. (Xiao-Ou), Singer, C. F. (Christian F.), Smichkoska, S. (Snezhana), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Stone, J. (Jennifer), Stoppa-Lyonnet, D. (Dominique), Swerdlow, A. J. (Anthony J.), Szabo, C. I. (Csilla, I), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teixeira, M. R. (Manuel R.), Terry, M. (MaryBeth), Thomassen, M. (Mads), Thull, D. L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A. E. (Amanda E.), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Torres, D. (Diana), Troester, M. A. (Melissa A.), Truong, T. (Therese), Tung, N. (Nadine), Untch, M. (Michael), Vachon, C. M. (Celine M.), van den Ouweland, A. M. (Ans M. W.), van der Kolk, L. E. (Lizet E.), van Veen, E. M. (Elke M.), vanRensburg, E. J. (Elizabeth J.), Vega, A. (Ana), Wappenschmidt, B. (Barbara), Weinberg, C. R. (Clarice R.), Weitzel, J. N. (Jeffrey N.), Wildiers, H. (Hans), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Zheng, W. (Wei), Zorn, K. K. (Kristin K.), Milne, R. L. (Roger L.), Kraft, P. (Peter), Simard, J. (Jacques), Pharoah, P. D. (Paul D. P.), Michailidou, K. (Kyriaki), Antoniou, A. C. (Antonis C.), Schmidt, M. K. (Marjanka K.), Chenevix-Trench, G. (Georgia), Easton, D. F. (Douglas F.), Chatterjee, N. (Nilanjan), and Garcia-Closas, M. (Montserrat)
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P
Published: 2020

11. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Author: Ramus S.J., Carroll J.S., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Scott C., Scott R.J., Senter L., Shah M., Sharma P., Shen C.-Y., Shu X.-O., Singer C.F., Slavin T.P., Smichkoska S., Spinelli J.J., Spurdle A.B., Sutter C., Swerdlow A.J., Tamimi R.M., Tan Y.Y., Tapper W.J., Taylor J., Teixeira M.R., Tengstrom M., Teo S.H., Terry M.B., Teule A., Thomassen M., Thull D.L., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Torres-Mejia G., Troester M.A., Truong T., Tung N., Tzardi M., Ulmer H.-U., Vachon C.M., van der Kolk L.E., van Rensburg E.J., Vega A., Viel A., Vijai J., Vogel M.J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wildiers H., Winqvist R., Wolk A., Wu A.H., Yannoukakos D., Zhang Y., Zheng W., Hunter D., Pharoah P.D.P., Chang-Claude J., Garcia-Closas M., Schmidt M.K., Kristensen V.N., French J.D., Antoniou A.C., Chenevix-Trench G., Simard J., Easton D.F., Kraft P., Allen J., Harris M., Fachal L., Aschard H., Beesley J., Barnes D.R., Kar S., Pooley K.A., Dennis J., Michailidou K., Turman C., Soucy P., Lemacon A., Lush M., Tyrer J.P., Ghoussaini M., Marjaneh M.M., Jiang X., Agata S., Aittomaki K., Alonso M.R., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arason A., Arndt V., Aronson K.J., Arun B.K., Auber B., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Beeghly-Fadiel A., Benitez J., Bermisheva M., Bialkowska K., Blanco A.M., Blomqvist C., Blot W., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Bosse K., Brauch H., Brenner H., Briceno I., Brock I.W., Brooks-Wilson A., Bruning T., Burwinkel B., Buys S.S., Cai Q., Caldes T., Caligo M.A., Camp N.J., Campbell I., Carter B.D., Castelao J.E., Chiquette J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Mari V., Berthet P., Castera L., Vaur D., Lallaoui H., Bignon Y.-J., Uhrhammer N., Bonadona V., Lasset C., Revillion F., Vennin P., Muller D., Gomes D.M., Ingster O., Coupier I., Pujol P., Collonge-Rame M.-A., Mortemousque I., Bera O., Rose M., Baurand A., Bertolone G., Faivre L., Dreyfus H., Leroux D., Venat-Bouvet L., Bezieau S., Delnatte C., Chiesa J., Gilbert-Dussardier B., Gesta P., Prieur F.P., Bronner M., Sokolowska J., Coulet F., Boutry-Kryza N., Calender A., Giraud S., Leone M., Fert-Ferrer S., Stoppa-Lyonnet D., Jiao Y., Lesueur F.L., Mebirouk N., Barouk-Simonet E., Bubien V., Longy M., Sevenet N., Gladieff L., Toulas C., Reimineras A., Sobol H., Paillerets B.B.-D., Cabaret O., Caron O., Guillaud-Bataille M., Rouleau E., Belotti M., Buecher B., Caputo S., Colas C., Pauw A.D., Fourme E., Gauthier-Villars M., Golmard L., Moncoutier V., Saule C., Donaldson A., Murray A., Brady A., Brewer C., Pottinger C., Miller C., Gallagher D., Gregory H., Cook J., Eason J., Adlard J., Barwell J., Ong K.-R., Snape K., Walker L., Izatt L., Side L., Tischkowitz M., Rogers M.T., Porteous M.E., Ahmed M., Morrison P.J., Brennan P., Eeles R., Davidson R., Collee J.M., Cornelissen S., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., Devilee P., Diez O., Ding Y.C., Dite G.S., Domchek S.M., Dork T., dos-Santos-Silva I., Droit A., Dubois S., Dumont M., Duran M., Durcan L., Dwek M., Eccles D.M., Engel C., Eriksson M., Evans D.G., Fasching P.A., Fletcher O., Floris G., Flyger H., Foretova L., Foulkes W.D., Friedman E., Fritschi L., Frost D., Gabrielson M., Gago-Dominguez M., Gambino G., Ganz P.A., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Georgoulias V., Giles G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Tibiletti M.G., Greene M.H., Grip M., Gronwald J., Grundy A., Guenel P., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hartikainen J.M., Hartman M., He W., Healey C.S., Heemskerk-Gerritsen B.A.M., Heyworth J., Hillemanns P., Hogervorst F.B.L., Hollestelle A., Hooning M., Hopper J., Howell A., Huang G., Hulick P.J., Imyanitov E.N., Sexton A., Christian A., Trainer A., Spigelman A., Fellows A., Shelling A., Fazio A.D., Blackburn A., Crook A., Meiser B., Patterson B., Clarke C., Saunders C., Hunt C., Amor D., Marsh D., Edkins E., Salisbury E., Haan E., Neidermayr E., Macrea F., Farshid G., Lindeman G., Trench G., Mann G., Gill G., Thorne H., Hickie I., Winship I., Flanagan J., Kollias J., Visvader J., Stone J., Burke J., Saunus J., Forbes J., French J., Tucker K., Wu K., Phillips K., Lipton L., Andrews L., Lobb L., Kentwell M., Spurdle M., Cummings M., Gleeson M., Jenkins M., Young M.A., Delatycki M., Wallis M., Burgess M., Price M., Brown M., Southey M., Bogwitz M., Field M., Friedlander M., Gattas M., Saleh M., Hayward N., Pachter N., Cohen P., Duijf P., James P., Simpson P., Fong P., Butow P., Williams R., Kefford R., Scott R., Milne R.L., Balleine R., Dawson S.-J., Lok S., O'Connell S., Greening S., Nightingale S., Edwards S., Fox S., McLachlan S.-A., Lakhani S., Antill Y., Aalfs C., Meijers-Heijboer H., van Engelen K., Gille H., Boere I., Collee M., van Deurzen C., Obdeijn I.-M., van den Ouweland A., Seynaeve C., Siesling S., Verloop J., van Asperen C., van Cronenburg T., Blok R., de Boer M., Garcia E.G., Adank M., Hogervorst F., Jenner D., van Leeuwen F., Rookus M., Russell N., Schmidt M., van den Belt-Dusebout S., Kets C., Mensenkamp A., de Bock T., van der Hout A., Mourits M., Oosterwijk J., Ausems M., Koudijs M., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Graham D., Sachchithananthan M., Isaacs C., Iwasaki M., Jager A., Jakimovska M., Jakubowska A., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kang D., Kapoor P.M., Karlan B.Y., Keeman R., Kerin M.J., Khusnutdinova E., Kiiski J.I., Kirk J., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Kosma V.-M., Koutros S., Kubelka-Sabit K., Kwong A., Kyriacou K., Laitman Y., Lambrechts D., Lee E., Leslie G., Lester J., Lesueur F., Lindblom A., Lo W.-Y., Long J., Lophatananon A., Loud J.T., Lubinski J., MacInnis R.J., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matsuo K., Maurer T., Mavroudis D., Mayes R., McGuffog L., McLean C., Meindl A., Miller A., Miller N., Montagna M., Moreno F., Muir K., Mulligan A.M., Munoz-Garzon V.M., Muranen T.A., Narod S.A., Nassir R., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Neven P., Nielsen F.C., Nikitina-Zake L., Norman A., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Osorio A., Pankratz V.S., Papp J., Park S.K., Park-Simon T.-W., Parsons M.T., Paul J., Pedersen I.S., Peissel B., Peshkin B., Peterlongo P., Peto J., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Prokofyeva D., Pujana M.A., Pylkas K., Radice P., Canzian F., Rantala J., Rau-Murthy R., Rennert G., Risch H.A., Robson M., Romero A., Rossing M., Saloustros E., Sanchez-Herrero E., Sandler D.P., Santamarina M., Sawyer E.J., Scheuner M.T., Schmidt D.F., Schmutzler R.K., Ramus S.J., Carroll J.S., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Scott C., Scott R.J., Senter L., Shah M., Sharma P., Shen C.-Y., Shu X.-O., Singer C.F., Slavin T.P., Smichkoska S., Spinelli J.J., Spurdle A.B., Sutter C., Swerdlow A.J., Tamimi R.M., Tan Y.Y., Tapper W.J., Taylor J., Teixeira M.R., Tengstrom M., Teo S.H., Terry M.B., Teule A., Thomassen M., Thull D.L., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Torres-Mejia G., Troester M.A., Truong T., Tung N., Tzardi M., Ulmer H.-U., Vachon C.M., van der Kolk L.E., van Rensburg E.J., Vega A., Viel A., Vijai J., Vogel M.J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wildiers H., Winqvist R., Wolk A., Wu A.H., Yannoukakos D., Zhang Y., Zheng W., Hunter D., Pharoah P.D.P., Chang-Claude J., Garcia-Closas M., Schmidt M.K., Kristensen V.N., French J.D., Antoniou A.C., Chenevix-Trench G., Simard J., Easton D.F., Kraft P., Allen J., Harris M., Fachal L., Aschard H., Beesley J., Barnes D.R., Kar S., Pooley K.A., Dennis J., Michailidou K., Turman C., Soucy P., Lemacon A., Lush M., Tyrer J.P., Ghoussaini M., Marjaneh M.M., Jiang X., Agata S., Aittomaki K., Alonso M.R., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arason A., Arndt V., Aronson K.J., Arun B.K., Auber B., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Beeghly-Fadiel A., Benitez J., Bermisheva M., Bialkowska K., Blanco A.M., Blomqvist C., Blot W., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Bosse K., Brauch H., Brenner H., Briceno I., Brock I.W., Brooks-Wilson A., Bruning T., Burwinkel B., Buys S.S., Cai Q., Caldes T., Caligo M.A., Camp N.J., Campbell I., Carter B.D., Castelao J.E., Chiquette J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Mari V., Berthet P., Castera L., Vaur D., Lallaoui H., Bignon Y.-J., Uhrhammer N., Bonadona V., Lasset C., Revillion F., Vennin P., Muller D., Gomes D.M., Ingster O., Coupier I., Pujol P., Collonge-Rame M.-A., Mortemousque I., Bera O., Rose M., Baurand A., Bertolone G., Faivre L., Dreyfus H., Leroux D., Venat-Bouvet L., Bezieau S., Delnatte C., Chiesa J., Gilbert-Dussardier B., Gesta P., Prieur F.P., Bronner M., Sokolowska J., Coulet F., Boutry-Kryza N., Calender A., Giraud S., Leone M., Fert-Ferrer S., Stoppa-Lyonnet D., Jiao Y., Lesueur F.L., Mebirouk N., Barouk-Simonet E., Bubien V., Longy M., Sevenet N., Gladieff L., Toulas C., Reimineras A., Sobol H., Paillerets B.B.-D., Cabaret O., Caron O., Guillaud-Bataille M., Rouleau E., Belotti M., Buecher B., Caputo S., Colas C., Pauw A.D., Fourme E., Gauthier-Villars M., Golmard L., Moncoutier V., Saule C., Donaldson A., Murray A., Brady A., Brewer C., Pottinger C., Miller C., Gallagher D., Gregory H., Cook J., Eason J., Adlard J., Barwell J., Ong K.-R., Snape K., Walker L., Izatt L., Side L., Tischkowitz M., Rogers M.T., Porteous M.E., Ahmed M., Morrison P.J., Brennan P., Eeles R., Davidson R., Collee J.M., Cornelissen S., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., Devilee P., Diez O., Ding Y.C., Dite G.S., Domchek S.M., Dork T., dos-Santos-Silva I., Droit A., Dubois S., Dumont M., Duran M., Durcan L., Dwek M., Eccles D.M., Engel C., Eriksson M., Evans D.G., Fasching P.A., Fletcher O., Floris G., Flyger H., Foretova L., Foulkes W.D., Friedman E., Fritschi L., Frost D., Gabrielson M., Gago-Dominguez M., Gambino G., Ganz P.A., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Georgoulias V., Giles G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Tibiletti M.G., Greene M.H., Grip M., Gronwald J., Grundy A., Guenel P., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hartikainen J.M., Hartman M., He W., Healey C.S., Heemskerk-Gerritsen B.A.M., Heyworth J., Hillemanns P., Hogervorst F.B.L., Hollestelle A., Hooning M., Hopper J., Howell A., Huang G., Hulick P.J., Imyanitov E.N., Sexton A., Christian A., Trainer A., Spigelman A., Fellows A., Shelling A., Fazio A.D., Blackburn A., Crook A., Meiser B., Patterson B., Clarke C., Saunders C., Hunt C., Amor D., Marsh D., Edkins E., Salisbury E., Haan E., Neidermayr E., Macrea F., Farshid G., Lindeman G., Trench G., Mann G., Gill G., Thorne H., Hickie I., Winship I., Flanagan J., Kollias J., Visvader J., Stone J., Burke J., Saunus J., Forbes J., French J., Tucker K., Wu K., Phillips K., Lipton L., Andrews L., Lobb L., Kentwell M., Spurdle M., Cummings M., Gleeson M., Jenkins M., Young M.A., Delatycki M., Wallis M., Burgess M., Price M., Brown M., Southey M., Bogwitz M., Field M., Friedlander M., Gattas M., Saleh M., Hayward N., Pachter N., Cohen P., Duijf P., James P., Simpson P., Fong P., Butow P., Williams R., Kefford R., Scott R., Milne R.L., Balleine R., Dawson S.-J., Lok S., O'Connell S., Greening S., Nightingale S., Edwards S., Fox S., McLachlan S.-A., Lakhani S., Antill Y., Aalfs C., Meijers-Heijboer H., van Engelen K., Gille H., Boere I., Collee M., van Deurzen C., Obdeijn I.-M., van den Ouweland A., Seynaeve C., Siesling S., Verloop J., van Asperen C., van Cronenburg T., Blok R., de Boer M., Garcia E.G., Adank M., Hogervorst F., Jenner D., van Leeuwen F., Rookus M., Russell N., Schmidt M., van den Belt-Dusebout S., Kets C., Mensenkamp A., de Bock T., van der Hout A., Mourits M., Oosterwijk J., Ausems M., Koudijs M., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Graham D., Sachchithananthan M., Isaacs C., Iwasaki M., Jager A., Jakimovska M., Jakubowska A., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kang D., Kapoor P.M., Karlan B.Y., Keeman R., Kerin M.J., Khusnutdinova E., Kiiski J.I., Kirk J., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Kosma V.-M., Koutros S., Kubelka-Sabit K., Kwong A., Kyriacou K., Laitman Y., Lambrechts D., Lee E., Leslie G., Lester J., Lesueur F., Lindblom A., Lo W.-Y., Long J., Lophatananon A., Loud J.T., Lubinski J., MacInnis R.J., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matsuo K., Maurer T., Mavroudis D., Mayes R., McGuffog L., McLean C., Meindl A., Miller A., Miller N., Montagna M., Moreno F., Muir K., Mulligan A.M., Munoz-Garzon V.M., Muranen T.A., Narod S.A., Nassir R., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Neven P., Nielsen F.C., Nikitina-Zake L., Norman A., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Osorio A., Pankratz V.S., Papp J., Park S.K., Park-Simon T.-W., Parsons M.T., Paul J., Pedersen I.S., Peissel B., Peshkin B., Peterlongo P., Peto J., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Prokofyeva D., Pujana M.A., Pylkas K., Radice P., Canzian F., Rantala J., Rau-Murthy R., Rennert G., Risch H.A., Robson M., Romero A., Rossing M., Saloustros E., Sanchez-Herrero E., Sandler D.P., Santamarina M., Sawyer E.J., Scheuner M.T., Schmidt D.F., and Schmutzler R.K.
Abstract: Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.Copyright © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Published: 2020

12. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Author: Eriksson M., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Plaseska-Karanfilska D., Poppe B., Pradhan N., Prajzendanc K., Presneau N., Punie K., Pylkas K., Radice P., Rantala J., Rashid M.U., Rennert G., Risch H.A., Robson M., Romero A., Saloustros E., Sandler D.P., Santos C., Sawyer E.J., Schmidt M.K., Schmidt D.F., Schmutzler R.K., Schoemaker M.J., Scott R.J., Sharma P., Shu X.-O., Simard J., Singer C.F., Skytte A.-B., Soucy P., Southey M.C., Spinelli J.J., Spurdle A.B., Stone J., Swerdlow A.J., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Teule A., Thomassen M., Thone K., Thull D.L., Tischkowitz M., Toland A.E., Tollenaar R.A.E.M., Torres D., Truong T., Tung N., Vachon C.M., van Asperen C.J., van den Ouweland A.M.W., van Rensburg E.J., Vega A., Viel A., Vieiro-Balo P., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Winqvist R., Yang X.R., Yannoukakos D., Ziogas A., Milne R.L., Easton D.F., Chenevix-Trench G., Zheng W., Kraft P., Jiang X., Feng H., Gusev A., Pasaniuc B., Wu L., Long J., Abu-full Z., Aittomaki K., Andrulis I.L., Anton-Culver H., Antoniou A.C., Arason A., Arndt V., Aronson K.J., Arun B.K., Asseryanis E., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barnes D.R., Barrowdale D., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Boeckx B., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Bruning T., Burwinkel B., Cai Q., Caldes T., Caligo M.A., Campbell I., Canisius S., Campa D., Carter B.D., Carter J., Castelao J.E., Chang-Claude J., Chanock S.J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., De Leeneer K., Dennis J., Devilee P., Diez O., Domchek S.M., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Ejlertsen B., Ellberg C., Engel C., Fasching P.A., Fletcher O., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gabrielson M., Ganz P.A., Gapstur S.M., Garber J., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haiman C.A., Hall P., Hamann U., Hake C., He W., Heyworth J., Hogervorst F.B.L., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Huang G., Hulick P.J., Humphreys K., Imyanitov E.N., Isaacs C., Jakimovska M., Jakubowska A., James P., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Joseph V., Jung A., Karlan B.Y., Khusnutdinova E., Kiiski J.I., Konstantopoulou I., Kristensen V.N., Laitman Y., Lambrechts D., Lazaro C., Leroux D., Leslie G., Lester J., Lesueur F., Lindor N., Lindstrom S., Lo W.-Y., Loud J.T., Lubinski J., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martens J.W.M., Martinez M.E., Matricardi L., Maurer T., Mavroudis D., McGuffog L., Meindl A., Menon U., Michailidou K., Kapoor P.M., Miller A., Montagna M., Moreno F., Moserle L., Mulligan A.M., Muranen T.A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nevelsteen I., Nielsen F.C., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Olsson H., Osorio A., Papp J., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peixoto A., Eriksson M., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Plaseska-Karanfilska D., Poppe B., Pradhan N., Prajzendanc K., Presneau N., Punie K., Pylkas K., Radice P., Rantala J., Rashid M.U., Rennert G., Risch H.A., Robson M., Romero A., Saloustros E., Sandler D.P., Santos C., Sawyer E.J., Schmidt M.K., Schmidt D.F., Schmutzler R.K., Schoemaker M.J., Scott R.J., Sharma P., Shu X.-O., Simard J., Singer C.F., Skytte A.-B., Soucy P., Southey M.C., Spinelli J.J., Spurdle A.B., Stone J., Swerdlow A.J., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Teule A., Thomassen M., Thone K., Thull D.L., Tischkowitz M., Toland A.E., Tollenaar R.A.E.M., Torres D., Truong T., Tung N., Vachon C.M., van Asperen C.J., van den Ouweland A.M.W., van Rensburg E.J., Vega A., Viel A., Vieiro-Balo P., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Winqvist R., Yang X.R., Yannoukakos D., Ziogas A., Milne R.L., Easton D.F., Chenevix-Trench G., Zheng W., Kraft P., Jiang X., Feng H., Gusev A., Pasaniuc B., Wu L., Long J., Abu-full Z., Aittomaki K., Andrulis I.L., Anton-Culver H., Antoniou A.C., Arason A., Arndt V., Aronson K.J., Arun B.K., Asseryanis E., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barnes D.R., Barrowdale D., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Boeckx B., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Bruning T., Burwinkel B., Cai Q., Caldes T., Caligo M.A., Campbell I., Canisius S., Campa D., Carter B.D., Carter J., Castelao J.E., Chang-Claude J., Chanock S.J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., De Leeneer K., Dennis J., Devilee P., Diez O., Domchek S.M., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Ejlertsen B., Ellberg C., Engel C., Fasching P.A., Fletcher O., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gabrielson M., Ganz P.A., Gapstur S.M., Garber J., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haiman C.A., Hall P., Hamann U., Hake C., He W., Heyworth J., Hogervorst F.B.L., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Huang G., Hulick P.J., Humphreys K., Imyanitov E.N., Isaacs C., Jakimovska M., Jakubowska A., James P., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Joseph V., Jung A., Karlan B.Y., Khusnutdinova E., Kiiski J.I., Konstantopoulou I., Kristensen V.N., Laitman Y., Lambrechts D., Lazaro C., Leroux D., Leslie G., Lester J., Lesueur F., Lindor N., Lindstrom S., Lo W.-Y., Loud J.T., Lubinski J., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martens J.W.M., Martinez M.E., Matricardi L., Maurer T., Mavroudis D., McGuffog L., Meindl A., Menon U., Michailidou K., Kapoor P.M., Miller A., Montagna M., Moreno F., Moserle L., Mulligan A.M., Muranen T.A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nevelsteen I., Nielsen F.C., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Olsson H., Osorio A., Papp J., Park-Simon T.-W., Parsons M.T., Pedersen I.S., and Peixoto A.
Abstract: Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.Copyright © 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals, Inc.
Published: 2020

13. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Author: Goldgar D.E., Newman W.G., Nielsen F.C., Nikitina-Zake L., Nodora J., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Papi L., Papp J., Park-Simon T.-W., Parsons M.T., Peissel B., Peixoto A., Peshkin B., Peterlongo P., Peto J., Phillips K.-A., Piedmonte M., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Prokofyeva D., Rack B., Radice P., Ramus S.J., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Risch H.A., Romero A., Rookus M.A., Rubner M., Rudiger T., Saloustros E., Sampson S., Sandler D.P., Sawyer E.J., Scheuner M.T., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Senter L., Sharma P., Sherman M.E., Shu X.-O., Singer C.F., Smichkoska S., Soucy P., Southey M.C., Spinelli J.J., Stone J., Stoppa-Lyonnet D., Swerdlow A.J., Szabo C.I., Tamimi R.M., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Thomassen M., Thull D.L., Tischkowitz M., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Troester M.A., Truong T., Tung N., Untch M., Vachon C.M., van den Ouweland A.M.W., van der Kolk L.E., van Veen E.M., vanRensburg E.J., Vega A., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wildiers H., Winqvist R., Wolk A., Yang X.R., Yannoukakos D., Zheng W., Zorn K.K., Milne R.L., Kraft P., Simard J., Pharoah P.D.P., Michailidou K., Antoniou A.C., Schmidt M.K., Chenevix-Trench G., Easton D.F., Chatterjee N., Garcia-Closas M., Zhang H., Ahearn T.U., Lecarpentier J., Barnes D., Beesley J., Qi G., Jiang X., O'Mara T.A., Zhao N., Bolla M.K., Dunning A.M., Dennis J., Wang Q., Ful Z.A., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Aronson K.J., Arun B.K., Auer P.L., Azzollini J., Barrowdale D., Becher H., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Bogdanova N.V., Bojesen S.E., Bonanni B., Bondavalli D., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Brucker S.Y., Bruning T., Burwinkel B., Buys S.S., Byers H., Caldes T., Caligo M.A., Calvello M., Campa D., Castelao J.E., Chang-Claude J., Chanock S.J., Christiaens M., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Cornelissen S., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Diez O., Domchek S.M., Dork T., Dwek M., Eccles D.M., Ekici A.B., Evans D.G., Fasching P.A., Figueroa J., Foretova L., Fostira F., Friedman E., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Giles G.G., Godwin A.K., Goldberg M.S., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haberle L., Hahnen E., Haiman C.A., Hake C.R., Hall P., Hamann U., Harkness E.F., Heemskerk-Gerritsen B.A.M., Hillemanns P., Hogervorst F.B.L., Holleczek B., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Howell A., Huebner H., Hulick P.J., Imyanitov E.N., Isaacs C., Izatt L., Jager A., Jakimovska M., Jakubowska A., James P., Janavicius R., Janni W., John E.M., Jones M.E., Jung A., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khan S., Khusnutdinova E., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Koppert L.B., Koutros S., Kristensen V.N., Laenkholm A.-V., Lambrechts D., Larsson S.C., Laurent-Puig P., Lazaro C., Lazarova E., Lejbkowicz F., Leslie G., Lesueur F., Lindblom A., Lissowska J., Lo W.-Y., Loud J.T., Lubinski J., Lukomska A., MacInnis R.J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matricardi L., McGuffog L., McLean C., Mebirouk N., Meindl A., Menon U., Miller A., Mingazheva E., Montagna M., Mulligan A.M., Mulot C., Muranen T.A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Neven P., Goldgar D.E., Newman W.G., Nielsen F.C., Nikitina-Zake L., Nodora J., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Papi L., Papp J., Park-Simon T.-W., Parsons M.T., Peissel B., Peixoto A., Peshkin B., Peterlongo P., Peto J., Phillips K.-A., Piedmonte M., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Prokofyeva D., Rack B., Radice P., Ramus S.J., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Risch H.A., Romero A., Rookus M.A., Rubner M., Rudiger T., Saloustros E., Sampson S., Sandler D.P., Sawyer E.J., Scheuner M.T., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Senter L., Sharma P., Sherman M.E., Shu X.-O., Singer C.F., Smichkoska S., Soucy P., Southey M.C., Spinelli J.J., Stone J., Stoppa-Lyonnet D., Swerdlow A.J., Szabo C.I., Tamimi R.M., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Thomassen M., Thull D.L., Tischkowitz M., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Troester M.A., Truong T., Tung N., Untch M., Vachon C.M., van den Ouweland A.M.W., van der Kolk L.E., van Veen E.M., vanRensburg E.J., Vega A., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wildiers H., Winqvist R., Wolk A., Yang X.R., Yannoukakos D., Zheng W., Zorn K.K., Milne R.L., Kraft P., Simard J., Pharoah P.D.P., Michailidou K., Antoniou A.C., Schmidt M.K., Chenevix-Trench G., Easton D.F., Chatterjee N., Garcia-Closas M., Zhang H., Ahearn T.U., Lecarpentier J., Barnes D., Beesley J., Qi G., Jiang X., O'Mara T.A., Zhao N., Bolla M.K., Dunning A.M., Dennis J., Wang Q., Ful Z.A., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Aronson K.J., Arun B.K., Auer P.L., Azzollini J., Barrowdale D., Becher H., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Bogdanova N.V., Bojesen S.E., Bonanni B., Bondavalli D., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Brucker S.Y., Bruning T., Burwinkel B., Buys S.S., Byers H., Caldes T., Caligo M.A., Calvello M., Campa D., Castelao J.E., Chang-Claude J., Chanock S.J., Christiaens M., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Cornelissen S., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Diez O., Domchek S.M., Dork T., Dwek M., Eccles D.M., Ekici A.B., Evans D.G., Fasching P.A., Figueroa J., Foretova L., Fostira F., Friedman E., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Giles G.G., Godwin A.K., Goldberg M.S., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haberle L., Hahnen E., Haiman C.A., Hake C.R., Hall P., Hamann U., Harkness E.F., Heemskerk-Gerritsen B.A.M., Hillemanns P., Hogervorst F.B.L., Holleczek B., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Howell A., Huebner H., Hulick P.J., Imyanitov E.N., Isaacs C., Izatt L., Jager A., Jakimovska M., Jakubowska A., James P., Janavicius R., Janni W., John E.M., Jones M.E., Jung A., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khan S., Khusnutdinova E., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Koppert L.B., Koutros S., Kristensen V.N., Laenkholm A.-V., Lambrechts D., Larsson S.C., Laurent-Puig P., Lazaro C., Lazarova E., Lejbkowicz F., Leslie G., Lesueur F., Lindblom A., Lissowska J., Lo W.-Y., Loud J.T., Lubinski J., Lukomska A., MacInnis R.J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matricardi L., McGuffog L., McLean C., Mebirouk N., Meindl A., Menon U., Miller A., Mingazheva E., Montagna M., Mulligan A.M., Mulot C., Muranen T.A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., and Neven P.
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.Copyright © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Published: 2020

14. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Zhan, H, Ahearn, TU, Lecarpentier, J, Barnes, D, Beesley, J, Qi, G, Jiang, X, O'Mara, TA, Zhao, N, Bolla, MK, Dunning, AM, Dennis, J, Wang, Q, Abu Ful, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Arun, BK, Auer, PL, Azzollini, J, Barrowdale, D, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Bondavalli, D, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Brucker, SY, Bruening, T, Burwinkel, B, Buys, SS, Byers, H, Caldes, T, Caligo, MA, Calvello, M, Campa, D, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiaens, M, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Diez, O, Domchek, SM, Doerk, T, Dwek, M, Eccles, DM, Ekici, AB, Evans, DG, Fasching, PA, Figueroa, J, Foretova, L, Fostira, F, Friedman, E, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hake, CR, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Hillemanns, P, Hogervorst, FBL, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huebner, H, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jager, A, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khan, S, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Konstantopoulou, I, Koppert, LB, Koutros, S, Kristensen, VN, Laenkholm, A-V, Lambrechts, D, Larsson, SC, Laurent-Puig, P, Lazaro, C, Lazarova, E, Lejbkowicz, F, Leslie, G, Lesueur, F, Lindblom, A, Lissowska, J, Lo, W-Y, Loud, JT, Lubinski, J, Lukomska, A, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Matricardi, L, McGuffog, L, McLean, C, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Mingazheva, E, Montagna, M, Mulligan, AM, Mulot, C, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsens, FC, Nikitina-Zake, L, Nodora, J, Offit, K, Olah, E, Olopade, O, Olsson, H, Orr, N, Papi, L, Papp, J, Park-Simon, T-W, Parsons, MT, Peissel, B, Peixoto, A, Peshkin, B, Peterlongo, P, Peto, J, Phillips, K-A, Piedmonte, M, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Prokofyeva, D, Rack, B, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Risch, HA, Romero, A, Rookus, MA, Ruebner, M, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Scheuner, MT, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schoettker, B, Schuermann, P, Senter, L, Sharma, P, Sherman, ME, Shu, X-O, Singer, CF, Smichkoska, S, Soucy, P, Southey, MC, Spinelli, JJ, Stone, J, Stoppa-Lyonnet, D, Swerdlow, AJ, Szabo, C, Tamimi, RM, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, M, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van den Ouweland, AMW, van der Kolk, LE, van Veen, EM, vanRensburg, EJ, Vega, A, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wildiers, H, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zheng, W, Zorn, KK, Milne, RL, Kraft, P, Simard, J, Pharoah, PDP, Michailidou, K, Antoniou, AC, Schmidt, MK, Chenevix-Trench, G, Easton, DF, Chatterjee, N, Garcia-Closas, M, Zhan, H, Ahearn, TU, Lecarpentier, J, Barnes, D, Beesley, J, Qi, G, Jiang, X, O'Mara, TA, Zhao, N, Bolla, MK, Dunning, AM, Dennis, J, Wang, Q, Abu Ful, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Arun, BK, Auer, PL, Azzollini, J, Barrowdale, D, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Bondavalli, D, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Brucker, SY, Bruening, T, Burwinkel, B, Buys, SS, Byers, H, Caldes, T, Caligo, MA, Calvello, M, Campa, D, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiaens, M, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Diez, O, Domchek, SM, Doerk, T, Dwek, M, Eccles, DM, Ekici, AB, Evans, DG, Fasching, PA, Figueroa, J, Foretova, L, Fostira, F, Friedman, E, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hake, CR, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Hillemanns, P, Hogervorst, FBL, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huebner, H, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jager, A, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khan, S, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Konstantopoulou, I, Koppert, LB, Koutros, S, Kristensen, VN, Laenkholm, A-V, Lambrechts, D, Larsson, SC, Laurent-Puig, P, Lazaro, C, Lazarova, E, Lejbkowicz, F, Leslie, G, Lesueur, F, Lindblom, A, Lissowska, J, Lo, W-Y, Loud, JT, Lubinski, J, Lukomska, A, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Matricardi, L, McGuffog, L, McLean, C, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Mingazheva, E, Montagna, M, Mulligan, AM, Mulot, C, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsens, FC, Nikitina-Zake, L, Nodora, J, Offit, K, Olah, E, Olopade, O, Olsson, H, Orr, N, Papi, L, Papp, J, Park-Simon, T-W, Parsons, MT, Peissel, B, Peixoto, A, Peshkin, B, Peterlongo, P, Peto, J, Phillips, K-A, Piedmonte, M, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Prokofyeva, D, Rack, B, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Risch, HA, Romero, A, Rookus, MA, Ruebner, M, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Scheuner, MT, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schoettker, B, Schuermann, P, Senter, L, Sharma, P, Sherman, ME, Shu, X-O, Singer, CF, Smichkoska, S, Soucy, P, Southey, MC, Spinelli, JJ, Stone, J, Stoppa-Lyonnet, D, Swerdlow, AJ, Szabo, C, Tamimi, RM, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, M, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van den Ouweland, AMW, van der Kolk, LE, van Veen, EM, vanRensburg, EJ, Vega, A, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wildiers, H, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zheng, W, Zorn, KK, Milne, RL, Kraft, P, Simard, J, Pharoah, PDP, Michailidou, K, Antoniou, AC, Schmidt, MK, Chenevix-Trench, G, Easton, DF, Chatterjee, N, and Garcia-Closas, M
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Published: 2020

15. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Barnes, DR, Rookus, MA, McGuffog, L, Leslie, G, Mooij, TM, Dennis, J, Mavaddat, N, Adlard, J, Ahmed, M, Aittomaki, K, Andrieu, N, Andrulis, IL, Arnold, N, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Benitez, J, Berthet, P, Bialkowska, K, Blanco, AM, Blok, MJ, Bonanni, B, Boonen, SE, Borg, A, Bozsik, A, Bradbury, AR, Brennan, P, Brewer, C, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Christensen, LL, Chung, WK, Claes, KBM, Colas, C, Collonge-Rame, M-A, Cook, J, Daly, MB, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dorfling, CM, Dumont, M, Eeles, R, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Foretova, L, Fostira, F, Friedlander, M, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gehrig, A, Gerdes, A-M, Gesta, P, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gschwantler-Kaulich, D, Hahnen, E, Hamann, U, Hanson, H, Hentschel, J, Hogervorst, FBL, Hooning, MJ, Horvath, J, Hu, C, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kast, K, Koudijs, M, Kruse, TA, Kwong, A, Laitman, Y, Lasset, C, Lazaro, C, Lester, J, Lesueur, F, Liljegren, A, Loud, JT, Lubinski, J, Mai, PL, Manoukian, S, Mari, V, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, A, Montagna, M, Mouret-Fourme, E, Mukherjee, S, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Nielsen, FC, Nikitina-Zake, L, Nogues, C, Olah, E, Olopade, O, Ong, K-R, O'Shaughnessy-Kirwan, A, Osorio, A, Ott, C-E, Papi, L, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Peterlongo, P, Pfeiler, G, Phillips, K-A, Prajzendanc, K, Pujana, MA, Radice, P, Ramser, J, Ramus, SJ, Rantala, J, Rennert, G, Risch, HA, Robson, M, Ronlund, K, Salani, R, Schuster, H, Senter, L, Shah, PD, Sharma, P, Side, LE, Singer, CF, Slavin, TP, Soucy, P, Southey, MC, Spurdle, AB, Steinemann, D, Steinsnyder, Z, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Trainer, AH, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Vierstraete, J, Wagner, G, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Yadav, S, Yang, X, Yannoukakos, D, Zimbalatti, D, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Barnes, DR, Rookus, MA, McGuffog, L, Leslie, G, Mooij, TM, Dennis, J, Mavaddat, N, Adlard, J, Ahmed, M, Aittomaki, K, Andrieu, N, Andrulis, IL, Arnold, N, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Benitez, J, Berthet, P, Bialkowska, K, Blanco, AM, Blok, MJ, Bonanni, B, Boonen, SE, Borg, A, Bozsik, A, Bradbury, AR, Brennan, P, Brewer, C, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Christensen, LL, Chung, WK, Claes, KBM, Colas, C, Collonge-Rame, M-A, Cook, J, Daly, MB, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dorfling, CM, Dumont, M, Eeles, R, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Foretova, L, Fostira, F, Friedlander, M, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gehrig, A, Gerdes, A-M, Gesta, P, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gschwantler-Kaulich, D, Hahnen, E, Hamann, U, Hanson, H, Hentschel, J, Hogervorst, FBL, Hooning, MJ, Horvath, J, Hu, C, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kast, K, Koudijs, M, Kruse, TA, Kwong, A, Laitman, Y, Lasset, C, Lazaro, C, Lester, J, Lesueur, F, Liljegren, A, Loud, JT, Lubinski, J, Mai, PL, Manoukian, S, Mari, V, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, A, Montagna, M, Mouret-Fourme, E, Mukherjee, S, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Nielsen, FC, Nikitina-Zake, L, Nogues, C, Olah, E, Olopade, O, Ong, K-R, O'Shaughnessy-Kirwan, A, Osorio, A, Ott, C-E, Papi, L, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Peterlongo, P, Pfeiler, G, Phillips, K-A, Prajzendanc, K, Pujana, MA, Radice, P, Ramser, J, Ramus, SJ, Rantala, J, Rennert, G, Risch, HA, Robson, M, Ronlund, K, Salani, R, Schuster, H, Senter, L, Shah, PD, Sharma, P, Side, LE, Singer, CF, Slavin, TP, Soucy, P, Southey, MC, Spurdle, AB, Steinemann, D, Steinsnyder, Z, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Trainer, AH, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Vierstraete, J, Wagner, G, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Yadav, S, Yang, X, Yannoukakos, D, Zimbalatti, D, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, and Antoniou, AC
Abstract: PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Published: 2020

16. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Author: Feng, H, Gusev, A, Pasaniuc, B, Wu, L, Long, J, Abu-full, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Auer, PL, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Bruening, T, Burwinkel, B, Cai, Q, Caldes, T, Caligo, MA, Campbell, I, Canisius, S, Campa, D, Carter, BD, Carter, J, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Dennis, J, Devilee, P, Diez, O, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gabrielson, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Hake, C, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Huang, G, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Jung, A, Karlan, BY, Khusnutdinova, E, Kiiski, J, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leroux, D, Leslie, G, Lester, J, Lesueur, F, Lindor, N, Lindstrom, S, Lo, W-Y, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Matricardi, L, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Kapoor, PM, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Plaseska-Karanfilska, D, Poppe, B, Pradhan, N, Prajzendanc, K, Presneau, N, Punie, K, Pylkas, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Risch, HA, Robson, M, Romero, A, Saloustros, E, Sandler, DP, Santos, C, Sawyer, EJ, Schmidt, MK, Schmidt, DF, Schmutzler, RK, Schoemaker, MJ, Scott, RJ, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Skytte, A-B, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Vieiro-Balo, P, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, J, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Milne, RL, Easton, DF, Chenevix-Trench, G, Zheng, W, Kraft, P, Jiang, X, Feng, H, Gusev, A, Pasaniuc, B, Wu, L, Long, J, Abu-full, Z, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Auer, PL, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Bruening, T, Burwinkel, B, Cai, Q, Caldes, T, Caligo, MA, Campbell, I, Canisius, S, Campa, D, Carter, BD, Carter, J, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Dennis, J, Devilee, P, Diez, O, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gabrielson, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Hake, C, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Huang, G, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Jung, A, Karlan, BY, Khusnutdinova, E, Kiiski, J, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leroux, D, Leslie, G, Lester, J, Lesueur, F, Lindor, N, Lindstrom, S, Lo, W-Y, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Matricardi, L, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Kapoor, PM, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Plaseska-Karanfilska, D, Poppe, B, Pradhan, N, Prajzendanc, K, Presneau, N, Punie, K, Pylkas, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Risch, HA, Robson, M, Romero, A, Saloustros, E, Sandler, DP, Santos, C, Sawyer, EJ, Schmidt, MK, Schmidt, DF, Schmutzler, RK, Schoemaker, MJ, Scott, RJ, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Skytte, A-B, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Vieiro-Balo, P, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, J, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Milne, RL, Easton, DF, Chenevix-Trench, G, Zheng, W, Kraft, P, and Jiang, X
Abstract: Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
Published: 2020

17. Platelet GPIB senses environmental conditions and modulates 14-3-3 availability and outside-in signals across alphallbbeta3 accordingly: OC-MO-109

Author: Fox, J EB, Zhang, Y, and Bialkowska, K
Published: 2009
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18. Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Author: Qian, F., Rookus, Matti A., Leslie, G., Risch, H.A., Greene, M.H., Aalfs, C.M., Adank, M.A., Adlard, J., Agnarsson, B.A., Ahmed, M., Aittomaki, K., Andrulis, I.L., Arnold, N., Arun, B.K., Ausems, M., Azzollini, J., Barrowdale, D., Barwell, J., Benitez, J., Bialkowska, K., Bonadona, V., Borde, J., Borg, A., Bradbury, A.R., Brunet, J., Buys, S.S., Caldes, T., Caligo, M.A., Campbell, I., Carter, J., Chiquette, J., Chung, W.K., Claes, K.B.M., Collee, J.M., Collonge-Rame, M.A., Couch, F.J., Daly, M.B., Delnatte, C., Diez, O., Domchek, S.M., Dorfling, C.M., Eason, J., Easton, D.F., Eeles, R., Engel, C., Evans, D.G., Faivre, L., Feliubadalo, L., Foretova, L., Friedman, E., Frost, D., Ganz, P.A., Garber, J., Garcia-Barberan, V., Gehrig, A., Glendon, G., Godwin, A.K., Garcia, E.B., Hamann, U., Hauke, J., Hopper, J.L., Hulick, P.J., Imyanitov, E.N., Isaacs, C., Izatt, L., Jakubowska, A., Janavicius, R., John, E.M., Karlan, B.Y., Kets, C.M., Laitman, Y., Lazaro, C., Leroux, D., Lester, J., Lesueur, F., Loud, J.T., Lubinski, J., Lukomska, A., McGuffog, L., Mebirouk, N., Meijers-Heijboer, H.E., Meindl, A., Miller, A., Montagna, M., Mooij, T.M., Mouret-Fourme, E., Nathanson, K.L., Nehoray, B., Neuhausen, S.L., Nevanlinna, H., Nielsen, F.C., Offit, K., Olah, E., Ong, K.R., Oosterwijk, J.C, Ottini, L., Parsons, M.T., Peterlongo, P., Pfeiler, G., Pradhan, N., et al., Qian, F., Rookus, Matti A., Leslie, G., Risch, H.A., Greene, M.H., Aalfs, C.M., Adank, M.A., Adlard, J., Agnarsson, B.A., Ahmed, M., Aittomaki, K., Andrulis, I.L., Arnold, N., Arun, B.K., Ausems, M., Azzollini, J., Barrowdale, D., Barwell, J., Benitez, J., Bialkowska, K., Bonadona, V., Borde, J., Borg, A., Bradbury, A.R., Brunet, J., Buys, S.S., Caldes, T., Caligo, M.A., Campbell, I., Carter, J., Chiquette, J., Chung, W.K., Claes, K.B.M., Collee, J.M., Collonge-Rame, M.A., Couch, F.J., Daly, M.B., Delnatte, C., Diez, O., Domchek, S.M., Dorfling, C.M., Eason, J., Easton, D.F., Eeles, R., Engel, C., Evans, D.G., Faivre, L., Feliubadalo, L., Foretova, L., Friedman, E., Frost, D., Ganz, P.A., Garber, J., Garcia-Barberan, V., Gehrig, A., Glendon, G., Godwin, A.K., Garcia, E.B., Hamann, U., Hauke, J., Hopper, J.L., Hulick, P.J., Imyanitov, E.N., Isaacs, C., Izatt, L., Jakubowska, A., Janavicius, R., John, E.M., Karlan, B.Y., Kets, C.M., Laitman, Y., Lazaro, C., Leroux, D., Lester, J., Lesueur, F., Loud, J.T., Lubinski, J., Lukomska, A., McGuffog, L., Mebirouk, N., Meijers-Heijboer, H.E., Meindl, A., Miller, A., Montagna, M., Mooij, T.M., Mouret-Fourme, E., Nathanson, K.L., Nehoray, B., Neuhausen, S.L., Nevanlinna, H., Nielsen, F.C., Offit, K., Olah, E., Ong, K.R., Oosterwijk, J.C, Ottini, L., Parsons, M.T., Peterlongo, P., Pfeiler, G., and Pradhan, N., et al.
Abstract: Contains fulltext : 208524.pdf (publisher's version ) (Open Access), BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m(2) increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.
Published: 2019

19. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

Author: Herold N., Rantala J., Rennert G., Risch H.A., Saloustros E., Sanden K., Sawyer E.J., Schmidt M.K., Schmutzler R.K., Sharma P., Shu X.-O., Simard J., Singer C.F., Soucy P., Southey M.C., Spinelli J.J., Spurdle A.B., Stone J., Swerdlow A.J., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Teule A., Thomassen M., Thone K., Thull D.L., Tischkowitz M., Toland A.E., Torres D., Truong T., Tung N., Vachon C.M., van Asperen C.J., van den Ouweland A.M.W., van Rensburg E.J., Vega A., Viel A., Wang Q., Wappenschmidt B., Weitzel J.N., Wendt C., Winqvist R., Yang X.R., Yannoukakos D., Ziogas A., Kraft P., Antoniou A.C., Zheng W., Easton D.F., Milne R.L., Beesley J., Chenevix-Trench G., Ferreira M.A., Gamazon E.R., Al-Ejeh F., Aittomaki K., Andrulis I.L., Anton-Culver H., Arason A., Arndt V., Aronson K.J., Arun B.K., Asseryanis E., Azzollini J., Balmana J., Barnes D.R., Barrowdale D., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blomqvist C., Bogdanova N.V., Bojesen S.E., Bolla M.K., Borg A., Brauch H., Brenner H., Broeks A., Burwinkel B., Caldes T., Caligo M.A., Campa D., Campbell I., Canzian F., Carter J., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Adlard J., Ahmed M., Barwell J., Brady A., Brewer C., Cook J., Davidson R., Donaldson A., Eason J., Eeles R., Evans D.G., Gregory H., Hanson H., Henderson A., Hodgson S., Izatt L., Kennedy M.J., Lalloo F., Miller C., Morrison P.J., Ong K.-R., Perkins J., Porteous M.E., Rogers M.T., Side L.E., Snape K., Walker L., Harrington P.A., Arnold N., Auber B., Bogdanova-Markov N., Borde J., Caliebe A., Ditsch N., Dworniczak B., Engert S., Faust U., Gehrig A., Hahnen E., Hauke J., Hentschel J., Honisch E., Just W., Kast K., Larsen M., Lemke J., Nguyen H.P., Niederacher D., Ott C.-E., Platzer K., Pohl-Rescigno E., Ramser J., Rhiem K., Steinemann D., Sutter C., Varon-Mateeva R., Wang-Gohrke S., Weber B.H.F., Prieur F., Pujol P., Sagne C., Sevenet N., Sobol H., Sokolowska J., Stoppa-Lyonnet D., Venat-Bouvet L., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., de la Hoya M., Dennis J., Devilee P., Diez O., Dork T., Dunning A.M., Dwek M., Eccles D.M., Ejlertsen B., Ellberg C., Engel C., Eriksson M., Fasching P.A., Fletcher O., Flyger H., Friedman E., Frost D., Gabrielson M., Gago-Dominguez M., Ganz P.A., Gapstur S.M., Garber J., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haiman C.A., Hall P., Hamann U., He W., Heyworth J., Hogervorst F.B.L., Hollestelle A., Hoover R.N., Hopper J.L., Hulick P.J., Humphreys K., Imyanitov E.N., Balleine R., Baxter R., Braye S., Carpenter J., Dahlstrom J., Forbes J., Lee S.C., Marsh D., Morey A., Pathmanathan N., Simpson P., Spigelman A., Wilcken N., Yip D., Heemskerk-Gerritsen B.A.M., Rookus M.A., Seynaeve C.M., van der Baan F.H., van der Hout A.H., van der Kolk L.E., van der Luijt R.B., van Deurzen C.H.M., van Doorn H.C., van Engelen K., van Hest L., van Os T.A.M., Verhoef S., Vogel M.J., Wijnen J.T., Miron A., Kapuscinski M., Bane A., Ross E., Buys S.S., Conner T.A., Isaacs C., Jakimovska M., Jakubowska A., James P.A., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Joseph V., Karlan B.Y., Khusnutdinova E., Kiiski J.I., Ko Y.-D., Jones M.E., Konstantopoulou I., Kristensen V.N., Laitman Y., Lambrechts D., Lazaro C., Leslie G., Lester J., Lesueur F., Lindstrom S., Long J., Loud J.T., Lubinski J., Makalic E., Mannermaa A., Manoochehri M., Margolin S., Maurer T., Mavroudis D., McGuffog L., Meindl A., Menon U., Michailidou K., Miller A., Montagna M., Moreno F., Moserle L., Mulligan A.M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nevelsteen I., Nielsen F.C., Nikitina-Zake L., Nussbaum R.L., Offit K., Olah E., Olopade O.I., Olsson H., Osorio A., Papp J., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peixoto A., Peterlongo P., Pharoah P.D.P., Plaseska-Karanfilska D., Poppe B., Presneau N., Radice P., Herold N., Rantala J., Rennert G., Risch H.A., Saloustros E., Sanden K., Sawyer E.J., Schmidt M.K., Schmutzler R.K., Sharma P., Shu X.-O., Simard J., Singer C.F., Soucy P., Southey M.C., Spinelli J.J., Spurdle A.B., Stone J., Swerdlow A.J., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Teule A., Thomassen M., Thone K., Thull D.L., Tischkowitz M., Toland A.E., Torres D., Truong T., Tung N., Vachon C.M., van Asperen C.J., van den Ouweland A.M.W., van Rensburg E.J., Vega A., Viel A., Wang Q., Wappenschmidt B., Weitzel J.N., Wendt C., Winqvist R., Yang X.R., Yannoukakos D., Ziogas A., Kraft P., Antoniou A.C., Zheng W., Easton D.F., Milne R.L., Beesley J., Chenevix-Trench G., Ferreira M.A., Gamazon E.R., Al-Ejeh F., Aittomaki K., Andrulis I.L., Anton-Culver H., Arason A., Arndt V., Aronson K.J., Arun B.K., Asseryanis E., Azzollini J., Balmana J., Barnes D.R., Barrowdale D., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blomqvist C., Bogdanova N.V., Bojesen S.E., Bolla M.K., Borg A., Brauch H., Brenner H., Broeks A., Burwinkel B., Caldes T., Caligo M.A., Campa D., Campbell I., Canzian F., Carter J., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Adlard J., Ahmed M., Barwell J., Brady A., Brewer C., Cook J., Davidson R., Donaldson A., Eason J., Eeles R., Evans D.G., Gregory H., Hanson H., Henderson A., Hodgson S., Izatt L., Kennedy M.J., Lalloo F., Miller C., Morrison P.J., Ong K.-R., Perkins J., Porteous M.E., Rogers M.T., Side L.E., Snape K., Walker L., Harrington P.A., Arnold N., Auber B., Bogdanova-Markov N., Borde J., Caliebe A., Ditsch N., Dworniczak B., Engert S., Faust U., Gehrig A., Hahnen E., Hauke J., Hentschel J., Honisch E., Just W., Kast K., Larsen M., Lemke J., Nguyen H.P., Niederacher D., Ott C.-E., Platzer K., Pohl-Rescigno E., Ramser J., Rhiem K., Steinemann D., Sutter C., Varon-Mateeva R., Wang-Gohrke S., Weber B.H.F., Prieur F., Pujol P., Sagne C., Sevenet N., Sobol H., Sokolowska J., Stoppa-Lyonnet D., Venat-Bouvet L., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., de la Hoya M., Dennis J., Devilee P., Diez O., Dork T., Dunning A.M., Dwek M., Eccles D.M., Ejlertsen B., Ellberg C., Engel C., Eriksson M., Fasching P.A., Fletcher O., Flyger H., Friedman E., Frost D., Gabrielson M., Gago-Dominguez M., Ganz P.A., Gapstur S.M., Garber J., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haiman C.A., Hall P., Hamann U., He W., Heyworth J., Hogervorst F.B.L., Hollestelle A., Hoover R.N., Hopper J.L., Hulick P.J., Humphreys K., Imyanitov E.N., Balleine R., Baxter R., Braye S., Carpenter J., Dahlstrom J., Forbes J., Lee S.C., Marsh D., Morey A., Pathmanathan N., Simpson P., Spigelman A., Wilcken N., Yip D., Heemskerk-Gerritsen B.A.M., Rookus M.A., Seynaeve C.M., van der Baan F.H., van der Hout A.H., van der Kolk L.E., van der Luijt R.B., van Deurzen C.H.M., van Doorn H.C., van Engelen K., van Hest L., van Os T.A.M., Verhoef S., Vogel M.J., Wijnen J.T., Miron A., Kapuscinski M., Bane A., Ross E., Buys S.S., Conner T.A., Isaacs C., Jakimovska M., Jakubowska A., James P.A., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Joseph V., Karlan B.Y., Khusnutdinova E., Kiiski J.I., Ko Y.-D., Jones M.E., Konstantopoulou I., Kristensen V.N., Laitman Y., Lambrechts D., Lazaro C., Leslie G., Lester J., Lesueur F., Lindstrom S., Long J., Loud J.T., Lubinski J., Makalic E., Mannermaa A., Manoochehri M., Margolin S., Maurer T., Mavroudis D., McGuffog L., Meindl A., Menon U., Michailidou K., Miller A., Montagna M., Moreno F., Moserle L., Mulligan A.M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nevelsteen I., Nielsen F.C., Nikitina-Zake L., Nussbaum R.L., Offit K., Olah E., Olopade O.I., Olsson H., Osorio A., Papp J., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peixoto A., Peterlongo P., Pharoah P.D.P., Plaseska-Karanfilska D., Poppe B., Presneau N., and Radice P.
Abstract: Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.Copyright © 2019, The Author(s).
Published: 2019

20. Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Author: Qian, F, Rookus, MA, Leslie, G, Risch, HA, Greene, MH, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arnold, N, Arun, BK, Ausems, MGEM, Azzollini, J, Barrowdale, D, Barwell, J, Benitez, J, Bialkowska, K, Bonadona, V, Borde, J, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Carter, J, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Collonge-Rame, M-A, Couch, FJ, Daly, MB, Delnatte, C, Diez, O, Domchek, SM, Dorfling, CM, Eason, J, Easton, DF, Eeles, R, Engel, C, Evans, DG, Faivre, L, Feliubado, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Garcia-Barberan, V, Gehrig, A, Glendon, G, Godwin, AK, Garcia, EBG, Hamann, U, Hauke, J, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, Janavicius, R, John, EM, Karlan, BY, Kets, CM, Laitman, Y, Lazaro, C, Leroux, D, Lester, J, Lesueur, F, Loud, JT, Lubinski, J, Lukomska, A, McGuffog, L, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mooij, TM, Mouret-Fourme, E, Nathanson, KL, Nehoray, B, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, Offit, K, Olah, E, Ong, K-R, Oosterwijk, JC, Ottini, L, Parsons, MT, Peterlongo, P, Pfeiler, G, Pradhan, N, Radice, P, Ramus, SJ, Rantala, J, Rennert, G, Robson, M, Rodriguez, GC, Salani, R, Scheuner, MT, Schmutzler, RK, Shah, PD, Side, LE, Simard, J, Singer, CF, Steinemann, D, Stoppa-Lyonnet, D, Tan, YY, Teixeira, MR, Terry, MB, Thomassen, M, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van Asperen, CJ, van Engelen, K, van Rensburg, EJ, Venat-Bouvet, L, Vierstraete, J, Wagner, G, Walker, L, Weitze, JN, Yannoukakos, D, Antoniou, AC, Goldgar, DE, Olopade, O, Chenevix-Trench, G, Rebbeck, TR, Huo, D, Qian, F, Rookus, MA, Leslie, G, Risch, HA, Greene, MH, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arnold, N, Arun, BK, Ausems, MGEM, Azzollini, J, Barrowdale, D, Barwell, J, Benitez, J, Bialkowska, K, Bonadona, V, Borde, J, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Carter, J, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Collonge-Rame, M-A, Couch, FJ, Daly, MB, Delnatte, C, Diez, O, Domchek, SM, Dorfling, CM, Eason, J, Easton, DF, Eeles, R, Engel, C, Evans, DG, Faivre, L, Feliubado, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Garcia-Barberan, V, Gehrig, A, Glendon, G, Godwin, AK, Garcia, EBG, Hamann, U, Hauke, J, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, Janavicius, R, John, EM, Karlan, BY, Kets, CM, Laitman, Y, Lazaro, C, Leroux, D, Lester, J, Lesueur, F, Loud, JT, Lubinski, J, Lukomska, A, McGuffog, L, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mooij, TM, Mouret-Fourme, E, Nathanson, KL, Nehoray, B, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, Offit, K, Olah, E, Ong, K-R, Oosterwijk, JC, Ottini, L, Parsons, MT, Peterlongo, P, Pfeiler, G, Pradhan, N, Radice, P, Ramus, SJ, Rantala, J, Rennert, G, Robson, M, Rodriguez, GC, Salani, R, Scheuner, MT, Schmutzler, RK, Shah, PD, Side, LE, Simard, J, Singer, CF, Steinemann, D, Stoppa-Lyonnet, D, Tan, YY, Teixeira, MR, Terry, MB, Thomassen, M, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van Asperen, CJ, van Engelen, K, van Rensburg, EJ, Venat-Bouvet, L, Vierstraete, J, Wagner, G, Walker, L, Weitze, JN, Yannoukakos, D, Antoniou, AC, Goldgar, DE, Olopade, O, Chenevix-Trench, G, Rebbeck, TR, and Huo, D
Abstract: BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.
Published: 2019

21. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author: Ferreira, MA, Gamazon, ER, Al-Ejeh, F, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Azzollini, J, Balmana, J, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bolla, MK, Borg, A, Brauch, H, Brenner, H, Broeks, A, Burwinkel, B, Caldes, T, Caligo, MA, Campa, D, Campbell, I, Canzian, F, Carter, J, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, Dennis, J, Devilee, P, Diez, O, Doerk, T, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Friedman, E, Frost, D, Gabrielson, M, Gago-Dominguez, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hoover, RN, Hopper, JL, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, PA, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Karlan, BY, Khusnutdinova, E, Kiiski, J, Ko, Y-D, Jones, ME, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Lindstrom, S, Long, J, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Margolin, S, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Nussbaum, RL, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Pharoah, PDP, Plaseska-Karanfilska, D, Poppe, B, Presneau, N, Radice, P, Rantala, J, Rennert, G, Risch, HA, Saloustros, E, Sanden, K, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Wang, Q, Wappenschmidt, B, Weitzel, JN, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Kraft, P, Antoniou, AC, Zheng, W, Easton, DF, Milne, RL, Beesley, J, Chenevix-Trench, G, Arnold, N, Auber, B, Bogdanova-Markov, N, Borde, J, Caliebe, A, Ditsch, N, Dworniczak, B, Engert, S, Faust, U, Gehrig, A, Hahnen, E, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Just, W, Kast, K, Larsen, M, Lemke, J, Huu, PN, Niederacher, D, Ott, C-E, Platzer, K, Pohl-Rescigno, E, Ramser, J, Rhiem, K, Steinemann, D, Sutter, C, Varon-Mateeva, R, Wang-Gohrke, S, Weber, BHF, Prieur, F, Pujol, P, Sagne, C, Sevenet, N, Sobol, H, Sokolowska, J, Stoppa-Lyonnet, D, Venat-Bouvet, L, Adlard, J, Ahmed, M, Barwell, J, Brady, A, Brewer, C, Cook, J, Davidson, R, Donaldson, A, Eason, J, Eeles, R, Evans, DG, Gregory, H, Hanson, H, Henderson, A, Hodgson, S, Izatt, L, Kennedy, MJ, Lalloo, F, Miller, C, Morrison, PJ, Ong, K-R, Perkins, J, Porteous, ME, Rogers, MT, Side, LE, Snape, K, Walker, L, Harrington, PA, Heemskerk-Gerritsen, BAM, Rookus, MA, Seynaeve, CM, van der Baan, FH, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, van Deurzen, CHM, van Doorn, HC, van Engelen, K, van Hest, L, van Os, TAM, Verhoef, S, Vogel, MJ, Wijnen, JT, Miron, A, Kapuscinski, M, Bane, A, Ross, E, Buys, SS, Conner, TA, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, SC, Marsh, D, Morey, A, Pathmanathan, N, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Ferreira, MA, Gamazon, ER, Al-Ejeh, F, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arason, A, Arndt, V, Aronson, KJ, Arun, BK, Asseryanis, E, Azzollini, J, Balmana, J, Barnes, DR, Barrowdale, D, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bolla, MK, Borg, A, Brauch, H, Brenner, H, Broeks, A, Burwinkel, B, Caldes, T, Caligo, MA, Campa, D, Campbell, I, Canzian, F, Carter, J, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, Dennis, J, Devilee, P, Diez, O, Doerk, T, Dunning, AM, Dwek, M, Eccles, DM, Ejlertsen, B, Ellberg, C, Engel, C, Eriksson, M, Fasching, PA, Fletcher, O, Flyger, H, Friedman, E, Frost, D, Gabrielson, M, Gago-Dominguez, M, Ganz, PA, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hamann, U, He, W, Heyworth, J, Hogervorst, FBL, Hollestelle, A, Hoover, RN, Hopper, JL, Hulick, PJ, Humphreys, K, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, PA, Janavicius, R, Jankowitz, RC, John, EM, Johnson, N, Joseph, V, Karlan, BY, Khusnutdinova, E, Kiiski, J, Ko, Y-D, Jones, ME, Konstantopoulou, I, Kristensen, VN, Laitman, Y, Lambrechts, D, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Lindstrom, S, Long, J, Loud, JT, Lubinski, J, Makalic, E, Mannermaa, A, Manoochehri, M, Margolin, S, Maurer, T, Mavroudis, D, McGuffog, L, Meindl, A, Menon, U, Michailidou, K, Miller, A, Montagna, M, Moreno, F, Moserle, L, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nevelsteen, I, Nielsen, FC, Nikitina-Zake, L, Nussbaum, RL, Offit, K, Olah, E, Olopade, O, Olsson, H, Osorio, A, Papp, J, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peixoto, A, Peterlongo, P, Pharoah, PDP, Plaseska-Karanfilska, D, Poppe, B, Presneau, N, Radice, P, Rantala, J, Rennert, G, Risch, HA, Saloustros, E, Sanden, K, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Soucy, P, Southey, MC, Spinelli, JJ, Spurdle, AB, Stone, J, Swerdlow, AJ, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, MB, Teule, A, Thomassen, M, Thoene, K, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Truong, T, Tung, N, Vachon, CM, van Asperen, CJ, van den Ouweland, AMW, van Rensburg, EJ, Vega, A, Viel, A, Wang, Q, Wappenschmidt, B, Weitzel, JN, Wendt, C, Winqvist, R, Yang, XR, Yannoukakos, D, Ziogas, A, Kraft, P, Antoniou, AC, Zheng, W, Easton, DF, Milne, RL, Beesley, J, Chenevix-Trench, G, Arnold, N, Auber, B, Bogdanova-Markov, N, Borde, J, Caliebe, A, Ditsch, N, Dworniczak, B, Engert, S, Faust, U, Gehrig, A, Hahnen, E, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Just, W, Kast, K, Larsen, M, Lemke, J, Huu, PN, Niederacher, D, Ott, C-E, Platzer, K, Pohl-Rescigno, E, Ramser, J, Rhiem, K, Steinemann, D, Sutter, C, Varon-Mateeva, R, Wang-Gohrke, S, Weber, BHF, Prieur, F, Pujol, P, Sagne, C, Sevenet, N, Sobol, H, Sokolowska, J, Stoppa-Lyonnet, D, Venat-Bouvet, L, Adlard, J, Ahmed, M, Barwell, J, Brady, A, Brewer, C, Cook, J, Davidson, R, Donaldson, A, Eason, J, Eeles, R, Evans, DG, Gregory, H, Hanson, H, Henderson, A, Hodgson, S, Izatt, L, Kennedy, MJ, Lalloo, F, Miller, C, Morrison, PJ, Ong, K-R, Perkins, J, Porteous, ME, Rogers, MT, Side, LE, Snape, K, Walker, L, Harrington, PA, Heemskerk-Gerritsen, BAM, Rookus, MA, Seynaeve, CM, van der Baan, FH, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, van Deurzen, CHM, van Doorn, HC, van Engelen, K, van Hest, L, van Os, TAM, Verhoef, S, Vogel, MJ, Wijnen, JT, Miron, A, Kapuscinski, M, Bane, A, Ross, E, Buys, SS, Conner, TA, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, SC, Marsh, D, Morey, A, Pathmanathan, N, Simpson, P, Spigelman, A, Wilcken, N, and Yip, D
Abstract: Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
Published: 2019

22. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author: Ferreira, M. A. (Manuel A.), Gamazon, E. R. (Eric R.), Al-Ejeh, F. (Fares), Aittomaki, K. (Kristiina), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arason, A. (Adalgeir), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Arun, B. K. (Banu K.), Asseryanis, E. (Ella), Azzollini, J. (Jacopo), Balmana, J. (Judith), Barnes, D. R. (Daniel R.), Barrowdale, D. (Daniel), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bialkowska, K. (Katarzyna), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Borg, A. (Ake), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Broeks, A. (Annegien), Burwinkel, B. (Barbara), Caldes, T. (Trinidad), Caligo, M. A. (Maria A.), Campa, D. (Daniele), Campbell, I. (Ian), Canzian, F. (Federico), Carter, J. (Jonathan), Carter, B. D. (Brian D.), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Christiansen, H. (Hans), Chung, W. K. (Wendy K.), Claes, K. B. (Kathleen B. M.), Clarke, C. L. (Christine L.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), de la Hoya, M. (Miguel), Dennis, J. (Joe), Devilee, P. (Peter), Diez, O. (Orland), Doerk, T. (Thilo), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ejlertsen, B. (Bent), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P. A. (Peter A.), Fletcher, O. (Olivia), Flyger, H. (Henrik), Friedman, E. (Eitan), Frost, D. (Debra), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Ganz, P. A. (Patricia A.), Gapstur, S. M. (Susan M.), Garber, J. (Judy), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Glendon, G. (Gord), Godwin, A. K. (Andrew K.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Greene, M. H. (Mark H.), Gronwald, J. (Jacek), Guenel, P. (Pascal), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), He, W. (Wei), Heyworth, J. (Jane), Hogervorst, F. B. (Frans B. L.), Hollestelle, A. (Antoinette), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Hulick, P. J. (Peter J.), Humphreys, K. (Keith), Imyanitov, E. N. (Evgeny N.), Isaacs, C. (Claudine), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, P. A. (Paul A.), Janavicius, R. (Ramunas), Jankowitz, R. C. (Rachel C.), John, E. M. (Esther M.), Johnson, N. (Nichola), Joseph, V. (Vijai), Karlan, B. Y. (Beth Y.), Khusnutdinova, E. (Elza), Kiiski, J. I. (Johanna, I), Ko, Y.-D. (Yon-Dschun), Jones, M. E. (Michael E.), Konstantopoulou, I. (Irene), Kristensen, V. N. (Vessela N.), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lazaro, C. (Conxi), Leslie, G. (Goska), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindstrom, S. (Sara), Long, J. (Jirong), Loud, J. T. (Jennifer T.), Lubinski, J. (Jan), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Maurer, T. (Tabea), Mavroudis, D. (Dimitrios), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menon, U. (Usha), Michailidou, K. (Kyriaki), Miller, A. (Austin), Montagna, M. (Marco), Moreno, F. (Fernando), Moserle, L. (Lidia), Mulligan, A. M. (Anna Marie), Nathanson, K. L. (Katherine L.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Nevelsteen, I. (Ines), Nielsen, F. C. (Finn C.), Nikitina-Zake, L. (Liene), Nussbaum, R. L. (Robert L.), Offit, K. (Kenneth), Olah, E. (Edith), Olopade, O. I. (Olufunmilayo, I), Olsson, H. (Hakan), Osorio, A. (Ana), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. T. (Michael T.), Pedersen, I. S. (Inge Sokilde), Peixoto, A. (Ana), Peterlongo, P. (Paolo), Pharoah, P. D. (Paul D. P.), Plaseska-Karanfilska, D. (Dijana), Poppe, B. (Bruce), Presneau, N. (Nadege), Radice, P. (Paolo), Rantala, J. (Johanna), Rennert, G. (Gad), Risch, H. A. (Harvey A.), Saloustros, E. (Emmanouil), Sanden, K. (Kristin), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Sharma, P. (Priyanka), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Singer, C. F. (Christian F.), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Spurdle, A. B. (Amanda B.), Stone, J. (Jennifer), Swerdlow, A. J. (Anthony J.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teixeira, M. R. (Manuel R.), Terry, M. B. (Mary Beth), Teule, A. (Alex), Thomassen, M. (Mads), Thoene, K. (Kathrin), Thull, D. L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A. E. (Amanda E.), Torres, D. (Diana), Truong, T. (Therese), Tung, N. (Nadine), Vachon, C. M. (Celine M.), van Asperen, C. J. (Christi J.), van den Ouweland, A. M. (Ans M. W.), van Rensburg, E. J. (Elizabeth J.), Vega, A. (Ana), Viel, A. (Alessandra), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weitzel, J. N. (Jeffrey N.), Wendt, C. (Camilla), Winqvist, R. (Robert), Yang, X. R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Kraft, P. (Peter), Antoniou, A. C. (Antonis C.), Zheng, W. (Wei), Easton, D. F. (Douglas F.), Milne, R. L. (Roger L.), Beesley, J. (Jonathan), Chenevix-Trench, G. (Georgia), Arnold, N. (Norbert), Auber, B. (Bernd), Bogdanova-Markov, N. (Nadja), Borde, J. (Julika), Caliebe, A. (Almuth), Ditsch, N. (Nina), Dworniczak, B. (Bernd), Engert, S. (Stefanie), Faust, U. (Ulrike), Gehrig, A. (Andrea), Hahnen, E. (Eric), Hauke, J. (Jan), Hentschel, J. (Julia), Herold, N. (Natalie), Honisch, E. (Ellen), Just, W. (Walter), Kast, K. (Karin), Larsen, M. (Mirjam), Lemke, J. (Johannes), . (), Niederacher, D. (Dieter), Ott, C.-E. (Claus-Eric), Platzer, K. (Konrad), Pohl-Rescigno, E. (Esther), Ramser, J. (Juliane), Rhiem, K. (Kerstin), Steinemann, D. (Doris), Sutter, C. (Christian), Varon-Mateeva, R. (Raymonda), Wang-Gohrke, S. (Shan), Weber, B. H. (Bernhard H. F.), Prieur, F. (Fabienne), Pujol, P. (Pascal), Sagne, C. (Charlotte), Sevenet, N. (Nicolas), Sobol, H. (Hagay), Sokolowska, J. (Johanna), Stoppa-Lyonnet, D. (Dominique), Venat-Bouvet, L. (Laurence), Adlard, J. (Julian), Ahmed, M. (Munaza), Barwell, J. (Julian), Brady, A. (Angela), Brewer, C. (Carole), Cook, J. (Jackie), Davidson, R. (Rosemarie), Donaldson, A. (Alan), Eason, J. (Jacqueline), Eeles, R. (Ros), Evans, D. G. (D. Gareth), Gregory, H. (Helen), Hanson, H. (Helen), Henderson, A. (Alex), Hodgson, S. (Shirley), Izatt, L. (Louise), Kennedy, M. J. (M. John), Lalloo, F. (Fiona), Miller, C. (Clare), Morrison, P. J. (Patrick J.), Ong, K.-r. (Kai-ren), Perkins, J. (Jo), Porteous, M. E. (Mary E.), Rogers, M. T. (Mark T.), Side, L. E. (Lucy E.), Snape, K. (Katie), Walker, L. (Lisa), Harrington, P. A. (Patricia A.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Rookus, M. A. (Matti A.), Seynaeve, C. M. (Caroline M.), van der Baan, F. H. (Frederieke H.), van der Hout, A. H. (Annemieke H.), van der Kolk, L. E. (Lizet E.), van der Luijt, R. B. (Rob B.), van Deurzen, C. H. (Carolien H. M.), van Doorn, H. C. (Helena C.), van Engelen, K. (Klaartje), van Hest, L. (Liselotte), van Os, T. A. (Theo A. M.), Verhoef, S. (Senno), Vogel, M. J. (Maartje J.), Wijnen, J. T. (Juul T.), Miron, A. (Alexander), Kapuscinski, M. (Miroslav), Bane, A. (Anita), Ross, E. (Eric), Buys, S. S. (Saundra S.), Conner, T. A. (Thomas A.), Balleine, R. (Rosemary), Baxter, R. (Robert), Braye, S. (Stephen), Carpenter, J. (Jane), Dahlstrom, J. (Jane), Forbes, J. (John), Lee, S. C. (Soon C.), Marsh, D. (Deborah), Morey, A. (Adrienne), Pathmanathan, N. (Nirmala), Simpson, P. (Peter), Spigelman, A. (Allan), Wilcken, N. (Nicholas), Yip, D. (Desmond), Ferreira, M. A. (Manuel A.), Gamazon, E. R. (Eric R.), Al-Ejeh, F. (Fares), Aittomaki, K. (Kristiina), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arason, A. (Adalgeir), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Arun, B. K. (Banu K.), Asseryanis, E. (Ella), Azzollini, J. (Jacopo), Balmana, J. (Judith), Barnes, D. R. (Daniel R.), Barrowdale, D. (Daniel), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bialkowska, K. (Katarzyna), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Borg, A. (Ake), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Broeks, A. (Annegien), Burwinkel, B. (Barbara), Caldes, T. (Trinidad), Caligo, M. A. (Maria A.), Campa, D. (Daniele), Campbell, I. (Ian), Canzian, F. (Federico), Carter, J. (Jonathan), Carter, B. D. (Brian D.), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Christiansen, H. (Hans), Chung, W. K. (Wendy K.), Claes, K. B. (Kathleen B. M.), Clarke, C. L. (Christine L.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), de la Hoya, M. (Miguel), Dennis, J. (Joe), Devilee, P. (Peter), Diez, O. (Orland), Doerk, T. (Thilo), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ejlertsen, B. (Bent), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P. A. (Peter A.), Fletcher, O. (Olivia), Flyger, H. (Henrik), Friedman, E. (Eitan), Frost, D. (Debra), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Ganz, P. A. (Patricia A.), Gapstur, S. M. (Susan M.), Garber, J. (Judy), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Glendon, G. (Gord), Godwin, A. K. (Andrew K.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Greene, M. H. (Mark H.), Gronwald, J. (Jacek), Guenel, P. (Pascal), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), He, W. (Wei), Heyworth, J. (Jane), Hogervorst, F. B. (Frans B. L.), Hollestelle, A. (Antoinette), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Hulick, P. J. (Peter J.), Humphreys, K. (Keith), Imyanitov, E. N. (Evgeny N.), Isaacs, C. (Claudine), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, P. A. (Paul A.), Janavicius, R. (Ramunas), Jankowitz, R. C. (Rachel C.), John, E. M. (Esther M.), Johnson, N. (Nichola), Joseph, V. (Vijai), Karlan, B. Y. (Beth Y.), Khusnutdinova, E. (Elza), Kiiski, J. I. (Johanna, I), Ko, Y.-D. (Yon-Dschun), Jones, M. E. (Michael E.), Konstantopoulou, I. (Irene), Kristensen, V. N. (Vessela N.), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lazaro, C. (Conxi), Leslie, G. (Goska), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindstrom, S. (Sara), Long, J. (Jirong), Loud, J. T. (Jennifer T.), Lubinski, J. (Jan), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Maurer, T. (Tabea), Mavroudis, D. (Dimitrios), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menon, U. (Usha), Michailidou, K. (Kyriaki), Miller, A. (Austin), Montagna, M. (Marco), Moreno, F. (Fernando), Moserle, L. (Lidia), Mulligan, A. M. (Anna Marie), Nathanson, K. L. (Katherine L.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Nevelsteen, I. (Ines), Nielsen, F. C. (Finn C.), Nikitina-Zake, L. (Liene), Nussbaum, R. L. (Robert L.), Offit, K. (Kenneth), Olah, E. (Edith), Olopade, O. I. (Olufunmilayo, I), Olsson, H. (Hakan), Osorio, A. (Ana), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. T. (Michael T.), Pedersen, I. S. (Inge Sokilde), Peixoto, A. (Ana), Peterlongo, P. (Paolo), Pharoah, P. D. (Paul D. P.), Plaseska-Karanfilska, D. (Dijana), Poppe, B. (Bruce), Presneau, N. (Nadege), Radice, P. (Paolo), Rantala, J. (Johanna), Rennert, G. (Gad), Risch, H. A. (Harvey A.), Saloustros, E. (Emmanouil), Sanden, K. (Kristin), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Sharma, P. (Priyanka), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Singer, C. F. (Christian F.), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Spurdle, A. B. (Amanda B.), Stone, J. (Jennifer), Swerdlow, A. J. (Anthony J.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teixeira, M. R. (Manuel R.), Terry, M. B. (Mary Beth), Teule, A. (Alex), Thomassen, M. (Mads), Thoene, K. (Kathrin), Thull, D. L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A. E. (Amanda E.), Torres, D. (Diana), Truong, T. (Therese), Tung, N. (Nadine), Vachon, C. M. (Celine M.), van Asperen, C. J. (Christi J.), van den Ouweland, A. M. (Ans M. W.), van Rensburg, E. J. (Elizabeth J.), Vega, A. (Ana), Viel, A. (Alessandra), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weitzel, J. N. (Jeffrey N.), Wendt, C. (Camilla), Winqvist, R. (Robert), Yang, X. R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Kraft, P. (Peter), Antoniou, A. C. (Antonis C.), Zheng, W. (Wei), Easton, D. F. (Douglas F.), Milne, R. L. (Roger L.), Beesley, J. (Jonathan), Chenevix-Trench, G. (Georgia), Arnold, N. (Norbert), Auber, B. (Bernd), Bogdanova-Markov, N. (Nadja), Borde, J. (Julika), Caliebe, A. (Almuth), Ditsch, N. (Nina), Dworniczak, B. (Bernd), Engert, S. (Stefanie), Faust, U. (Ulrike), Gehrig, A. (Andrea), Hahnen, E. (Eric), Hauke, J. (Jan), Hentschel, J. (Julia), Herold, N. (Natalie), Honisch, E. (Ellen), Just, W. (Walter), Kast, K. (Karin), Larsen, M. (Mirjam), Lemke, J. (Johannes), . (), Niederacher, D. (Dieter), Ott, C.-E. (Claus-Eric), Platzer, K. (Konrad), Pohl-Rescigno, E. (Esther), Ramser, J. (Juliane), Rhiem, K. (Kerstin), Steinemann, D. (Doris), Sutter, C. (Christian), Varon-Mateeva, R. (Raymonda), Wang-Gohrke, S. (Shan), Weber, B. H. (Bernhard H. F.), Prieur, F. (Fabienne), Pujol, P. (Pascal), Sagne, C. (Charlotte), Sevenet, N. (Nicolas), Sobol, H. (Hagay), Sokolowska, J. (Johanna), Stoppa-Lyonnet, D. (Dominique), Venat-Bouvet, L. (Laurence), Adlard, J. (Julian), Ahmed, M. (Munaza), Barwell, J. (Julian), Brady, A. (Angela), Brewer, C. (Carole), Cook, J. (Jackie), Davidson, R. (Rosemarie), Donaldson, A. (Alan), Eason, J. (Jacqueline), Eeles, R. (Ros), Evans, D. G. (D. Gareth), Gregory, H. (Helen), Hanson, H. (Helen), Henderson, A. (Alex), Hodgson, S. (Shirley), Izatt, L. (Louise), Kennedy, M. J. (M. John), Lalloo, F. (Fiona), Miller, C. (Clare), Morrison, P. J. (Patrick J.), Ong, K.-r. (Kai-ren), Perkins, J. (Jo), Porteous, M. E. (Mary E.), Rogers, M. T. (Mark T.), Side, L. E. (Lucy E.), Snape, K. (Katie), Walker, L. (Lisa), Harrington, P. A. (Patricia A.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Rookus, M. A. (Matti A.), Seynaeve, C. M. (Caroline M.), van der Baan, F. H. (Frederieke H.), van der Hout, A. H. (Annemieke H.), van der Kolk, L. E. (Lizet E.), van der Luijt, R. B. (Rob B.), van Deurzen, C. H. (Carolien H. M.), van Doorn, H. C. (Helena C.), van Engelen, K. (Klaartje), van Hest, L. (Liselotte), van Os, T. A. (Theo A. M.), Verhoef, S. (Senno), Vogel, M. J. (Maartje J.), Wijnen, J. T. (Juul T.), Miron, A. (Alexander), Kapuscinski, M. (Miroslav), Bane, A. (Anita), Ross, E. (Eric), Buys, S. S. (Saundra S.), Conner, T. A. (Thomas A.), Balleine, R. (Rosemary), Baxter, R. (Robert), Braye, S. (Stephen), Carpenter, J. (Jane), Dahlstrom, J. (Jane), Forbes, J. (John), Lee, S. C. (Soon C.), Marsh, D. (Deborah), Morey, A. (Adrienne), Pathmanathan, N. (Nirmala), Simpson, P. (Peter), Spigelman, A. (Allan), Wilcken, N. (Nicholas), and Yip, D. (Desmond)
Abstract: Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
Published: 2019

23. Dynamic modulation of cytoskeletal proteins linking integrins to signaling complexes in spreading cells. Role of skelemin in initial integrin-induced spreading.

Author: Reddy, K B, Bialkowska, K, and Fox, J E
Abstract: Recently we showed that signaling across beta3-integrin leads to activation of calpain and formation of integrin clusters that are involved in Rac activation. The subsequent activation of Rac and Rho leads to the formation of focal complexes and focal adhesions, respectively. The goal of the present study was to determine whether different proteins link the integrin to the cytoskeleton in the different complexes. We show that talin is present in focal adhesions but not in the calpain-induced clusters. alpha-Actinin colocalized with integrin at various sites, including the calpain-induced clusters. Skelemin, a protein shown recently to interact with beta1- and beta3-integrin in vitro, colocalized with integrin in calpain-induced clusters but was absent from focal adhesions. Cells transiently expressing skelemin C2 motifs, which contain the integrin binding site, failed to form integrin clusters or to spread on a substrate for beta1- and beta3-integrins. These results 1) suggest a dynamic reorganization of integrin complexes during cell spreading, 2) show that different cytoskeletal proteins link integrins in different complexes, and 3) demonstrate that skelemin is responsible for linking integrin to the calpain-induced clusters, and 4) show that the integrin-skelemin interaction is essential for transmission of signals leading to the initial steps of cell spreading.
Published: 2001
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24. Interaction of erythrocyte spectrin with some nonbilayer phospholipids

Author: Michalak, K., Bobrowska, M., Bialkowska, K., Szopa, J., and Aleksander F. Sikorski

25. Role of Kindlin 2 in prostate cancer.

Author: Bialkowska K, El Khalki L, Rana PS, Wang W, Lindner DJ, Parker Y, Languino LR, Altieri DC, Pluskota E, Sossey-Alaoui K, and Plow EF
Subjects: Male, Humans, Animals, Cell Line, Tumor, Mice, Cell Movement, Cell Proliferation, Integrins metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Prostatic Neoplasms genetics, Neoplasm Proteins metabolism, Neoplasm Proteins genetics, Membrane Proteins metabolism, Membrane Proteins genetics, Cell Adhesion
Abstract: Kindlin-2 is a cytoskeletal adapter protein that is present in many different cell types. By virtue of its interaction with multiple binding partners, Kindlin-2 intercalates into numerous signaling pathways and cytoskeletal nodes. A specific interaction of Kindlin-2 that is of paramount importance in many cellular responses is its direct binding to the cytoplasmic tails of integrins, an interaction that controls many of the adhesive, migratory and signaling responses mediated by members of the integrin family of cell-surface heterodimers. Kindlin-2 is highly expressed in many cancers and is particularly prominent in prostate cancer cells. CRISPR/cas9 was used as a primary approach to knockout expression of Kindlin-2 in both androgen-independent and dependent prostate cancer cell lines, and the effects of Kindlin-2 suppression on oncogenic properties of these prostate cancer cell lines was examined. Adhesion to extracellular matrix proteins was markedly blunted, consistent with the control of integrin function by Kindlin-2. Migration across matrices was also affected. Anchorage independent growth was markedly suppressed. These observations indicate that Kindlin-2 regulates hallmark features of prostate cancer cells. In androgen expressing cells, testosterone-stimulated adhesion was Kindlin-2-dependent. Furthermore, tumor growth of a prostate cancer cell line lacking Kindlin-2 and implanted into the prostate gland of immunocompromised mice was markedly blunted and was associated with suppression of angiogenesis in the developing tumor. These results establish a key role of Kindlin-2 in prostate cancer progression and suggest that Kindlin-2 represents an interesting therapeutic target for treatment of prostate cancer., (© 2024. The Author(s).)
Published: 2024
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26. Parkin ubiquitination of Kindlin-2 enables mitochondria-associated metastasis suppression.

Author: Yeon M, Bertolini I, Agarwal E, Ghosh JC, Tang HY, Speicher DW, Keeney F, Sossey-Alaoui K, Pluskota E, Bialkowska K, Plow EF, Languino LR, Skordalakes E, Caino MC, and Altieri DC
Subjects: Cell Movement, Mitochondria metabolism, Ubiquitination, Humans, Membrane Proteins metabolism, Ubiquitin-Protein Ligases metabolism
Abstract: Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson's disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.5 h. Loss of K2 inhibits focal adhesion turnover and β1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-extracellular matrix interactions, migration, and invasion. Conversely, Parkin does not affect tumor cell proliferation, cell cycle transitions, or apoptosis. Expression of a Parkin Ub-resistant K2 Lys581Ala/Lys582Ala double mutant is sufficient to restore membrane lamellipodia dynamics, correct mitochondrial fusion/fission, and preserve single-cell migration and invasion. In a 3D model of mammary gland developmental morphogenesis, impaired K2 Ub drives multiple oncogenic traits of EMT, increased cell proliferation, reduced apoptosis, and disrupted basal-apical polarity. Therefore, deregulated K2 is a potent oncogene, and its Ub by Parkin enables mitochondria-associated metastasis suppression., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2023
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27. PREDICT validity for prognosis of breast cancer patients with pathogenic BRCA1/2 variants.

Author: Muranen TA, Morra A, Khan S, Barnes DR, Bolla MK, Dennis J, Keeman R, Leslie G, Parsons MT, Wang Q, Ahearn TU, Aittomäki K, Andrulis IL, Arun BK, Behrens S, Bialkowska K, Bojesen SE, Camp NJ, Chang-Claude J, Czene K, Devilee P, Domchek SM, Dunning AM, Engel C, Evans DG, Gago-Dominguez M, García-Closas M, Gerdes AM, Glendon G, Guénel P, Hahnen E, Hamann U, Hanson H, Hooning MJ, Hoppe R, Izatt L, Jakubowska A, James PA, Kristensen VN, Lalloo F, Lindeman GJ, Mannermaa A, Margolin S, Neuhausen SL, Newman WG, Peterlongo P, Phillips KA, Pujana MA, Rantala J, Rønlund K, Saloustros E, Schmutzler RK, Schneeweiss A, Singer CF, Suvanto M, Tan YY, Teixeira MR, Thomassen M, Tischkowitz M, Tripathi V, Wappenschmidt B, Zhao E, Easton DF, Antoniou AC, Chenevix-Trench G, Pharoah PDP, Schmidt MK, Blomqvist C, and Nevanlinna H
Abstract: We assessed the PREDICT v 2.2 for prognosis of breast cancer patients with pathogenic germline BRCA1 and BRCA2 variants, using follow-up data from 5453 BRCA1/2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC). PREDICT for estrogen receptor (ER)-negative breast cancer had modest discrimination for BRCA1 carrier patients overall (Gönen & Heller unbiased concordance 0.65 in CIMBA, 0.64 in BCAC), but it distinguished clearly the high-mortality group from lower risk categories. In an analysis of low to high risk categories by PREDICT score percentiles, the observed mortality was consistently lower than the expected mortality, but the confidence intervals always included the calibration slope. Altogether, our results encourage the use of the PREDICT ER-negative model in management of breast cancer patients with germline BRCA1 variants. For the PREDICT ER-positive model, the discrimination was slightly lower in BRCA2 variant carriers (concordance 0.60 in CIMBA, 0.65 in BCAC). Especially, inclusion of the tumor grade distorted the prognostic estimates. The breast cancer mortality of BRCA2 carriers was underestimated at the low end of the PREDICT score distribution, whereas at the high end, the mortality was overestimated. These data suggest that BRCA2 status should also be taken into consideration with tumor characteristics, when estimating the prognosis of ER-positive breast cancer patients., (© 2023. The Author(s).)
Published: 2023
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28. Kindlin-3 deficiency leads to impaired erythropoiesis and erythrocyte cytoskeleton.

Author: Szpak D, Turpin C, Goreke U, Bialkowska K, Bledzka KM, Verbovetskiy D, Mohandas N, Gurkan UA, Qin J, Plow EF, and Pluskota E
Subjects: Animals, Humans, Mice, Actins metabolism, Anemia, Hemolytic, Erythrocyte Membrane metabolism, Integrins metabolism, Cytoskeletal Proteins metabolism, Erythropoiesis
Abstract: Kindlin-3 (K3) is critical for the activation of integrin adhesion receptors in hematopoietic cells. In humans and mice, K3 deficiency is associated with impaired immunity and bone development, bleeding, and aberrant erythrocyte shape. To delineate how K3 deficiency (K3KO) contributes to anemia and misshaped erythrocytes, mice deficient in erythroid (K3KO∖EpoR-cre) or myeloid cell K3 (K3KO∖Lyz2cre), knockin mice expressing mutant K3 (Q597W598 to AA) with reduced integrin-activation function (K3KI), and control wild-type (WT) K3 mice were studied. Both K3-deficient strains and K3KI mice showed anemia at baseline, reduced response to erythropoietin stimulation, and compromised recovery after phenylhydrazine (PHZ)-induced hemolytic anemia as compared with K3WT. Erythroid K3KO and K3 (Q597W598 to AA) showed arrested erythroid differentiation at proerythroblast stage, whereas macrophage K3KO showed decreased erythroblast numbers at all developmental stages of terminal erythroid differentiation because of reduced erythroblastic island (EBI) formation attributable to decreased expression and activation of erythroblast integrin α4β1 and macrophage αVβ3. Peripheral blood smears of K3KO∖EpoR-cre mice, but not of the other mouse strains, showed numerous aberrant tear drop-shaped erythrocytes. K3 deficiency in these erythrocytes led to disorganized actin cytoskeleton, reduced deformability, and increased osmotic fragility. Mechanistically, K3 directly interacted with F-actin through an actin-binding site K3-LK48. Taken together, these findings document that erythroid and macrophage K3 are critical contributors to erythropoiesis in an integrin-dependent manner, whereas F-actin binding to K3 maintains the membrane cytoskeletal integrity and erythrocyte biconcave shape. The dual function of K3 in erythrocytes and in EBIs establish an important functional role for K3 in normal erythroid function., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Published: 2023
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29. Targeted Deletion of Kindlin-2 in Mouse Mammary Glands Inhibits Tumor Growth, Invasion, and Metastasis Downstream of a TGF-β/EGF Oncogenic Signaling Pathway.

Author: Wang W, Rana PS, Alkrekshi A, Bialkowska K, Markovic V, Schiemann WP, Plow EF, Pluskota E, and Sossey-Alaoui K
Abstract: Breast cancer (BC) is one of the leading causes of cancer-related deaths due in part to its invasive and metastatic properties. Kindlin-2 (FERMT2) is associated with the pathogenesis of several cancers. Although the role of Kindlin-2 in regulating the invasion-metastasis cascade in BC is widely documented, its function in BC initiation and progression remains to be fully elucidated. Accordingly, we generated a floxed mouse strain by targeting the Fermt2 (K2 lox/lox ) locus, followed by tissue-specific deletion of Kindlin-2 in the myoepithelial compartment of the mammary glands by crossing the K2 lox/lox mice with K14-Cre mice. Loss of Kindlin-2 in mammary epithelial cells (MECs) showed no deleterious effects on mammary gland development, fertility, and lactation in mice bearing Kindlin-2-deletion. However, in a syngeneic mouse model of BC, mammary gland, specific knockout of Kindlin-2 inhibited the growth and metastasis of murine E0771 BC cells inoculated into the mammary fat pads. However, injecting the E0771 cells into the lateral tail vein of Kindlin-2-deleted mice had no effect on tumor colonization in the lungs, thereby establishing a critical role of MEC Kindlin-2 in supporting BC tumor growth and metastasis. Mechanistically, we found the MEC Kindlin-2-mediated inhibition of tumor growth and metastasis is accomplished through its regulation of the TGF-β/ERK MAP kinase signaling axis. Thus, Kindlin-2 within the mammary gland microenvironment facilitates the progression and metastasis of BC.
Published: 2022
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30. Phosphorylation of Kindlins and the Control of Integrin Function.

Author: Bialkowska K, Qin J, and Plow EF
Subjects: Animals, Humans, Membrane Proteins chemistry, Phosphorylation, Protein Domains, Protein Processing, Post-Translational, Integrins metabolism, Membrane Proteins metabolism
Abstract: Integrins serve as conduits for the transmission of information between cells and their extracellular environment. Signaling across integrins is bidirectional, transducing both inside-out and outside-signaling. Integrin activation, a transition from a low affinity/avidity state to a high affinity/avidity state for cognate ligands, is an outcome of inside-signaling. Such activation is particularly important for the recognition of soluble ligands by blood cells but also influences cell-cell and cell-matrix interactions. Integrin activation depends on a complex series of interactions, which both accelerate and inhibit their interconversion from the low to the high affinity/avidity state. There are three components regarded as being most proximately involved in integrin activation: the integrin cytoplasmic tails, talins and kindlins. The participation of each of these molecules in integrin activation is highly regulated by post-translation modifications. The importance of targeted phosphorylation of integrin cytoplasmic tails and talins in integrin activation is well-established, but much less is known about the role of post-translational modification of kindlins. The kindlins, a three-member family of 4.1-ezrin-radixin-moesin (FERM)-domain proteins in mammals, bind directly to the cytoplasmic tails of integrin beta subunits. This commentary provides a synopsis of the emerging evidence for the role of kindlin phosphorylation in integrin regulation.
Published: 2021
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31. Plasminogen-induced foam cell formation by macrophages occurs through a histone 2B (H2B)-PAR1 pathway and requires integrity of clathrin-coated pits.

Author: Izem L, Bialkowska K, Pluskota E, Das M, Das R, Nieman MT, and Plow EF
Subjects: Animals, Clathrin metabolism, Fibrinolysin metabolism, Histones, Macrophages metabolism, Mice, Receptor, PAR-1, Foam Cells metabolism, Plasminogen metabolism
Abstract: Objective: Plasminogen/plasmin is a serine protease system primarily responsible for degrading fibrin within blood clots. Plasminogen mediates its functions by interacting with plasminogen receptors on the cell surface. H2B, one such plasminogen receptor, is found on the surface of several cell types including macrophages. Both basic and clinical studies support the role of plasminogen in the process of foam cell formation (FCF), a hallmark of atherosclerosis. Growing evidence also implicates serine protease-activated receptors (PARs) in atherosclerosis. These receptors are also found on macrophages, and plasmin is capable of activating PAR1 and PAR4. The goal of this study was to determine the extent of H2B's contribution to plasminogen-mediated FCF by macrophages and if PARs are involved in this process., Approach and Results: Treating macrophages with plasminogen increases their oxidized low-density lipoprotein uptake and plasminogen-mediated foam cell formation (Plg-FCF) significantly. The magnitude of Plg-FCF correlates with cell-surface expression of the H2B level. H2B blockade or downregulation reduces Plg-FCF, whereas its overexpression or high endogenous levels increases Plg-FCF. Modulating PAR1 level in mouse macrophages affects Plg-FCF. Activation/overexpression of PAR1 increases and its blockade/knockdown reduces this response. Confocal imaging indicates that both H2B and PAR1 colocalize with clathrin coated pits on the surface of macrophages, and reducing expression of clathrin or interfering with the clathrin-coated pits integrity reduces Plg-FCF., Conclusion: Our data indicate that the magnitude of Plg-FCF by macrophages is proportional to the H2B levels and demonstrate for the first time that PAR1 is involved in this process and that the integrity of clathrin-coated pits is required for the full effect of Plg-induced FCF., (© 2021 International Society on Thrombosis and Haemostasis.)
Published: 2021
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32. Kindlins as modulators of breast cancer progression.

Author: Plow EF, Pluskota E, and Bialkowska K
Abstract: Kindlin-1 (K1, FERMT1), Kindlin-2 (K2, FERMT2), and Kindlin-3 (K3, FERMT3) are the three members of the kindlin family of adapter proteins found in mammals. One or more kindlins are found in most cell types, K1 primarily in epithelial cells, K3 in primarily hematopoietic cells and also endothelial cells, and K2 is very broadly distributed. The kindlins consist primarily of a 4.1-erzin-radixin-moiesin (FERM) domain, which is transected by a lipid-binding plextrin-homology (PH) domain. Deficiencies of each kindlin in mice and/ or humans have profound pathogenic consequences. The most well-established function of kindlins depends on their ability to participate in the activat integrin adhesion receptors. This function depends on the binding of each kindlin to the beta subunit of integrins where it cooperates with talin to enhance avidity of interactions with cognate extracellular matrix ligands. Deficiencies of many different integrins are lethal, are critical for normal development of mammary tissue, and excessive expression and/or activation of certain integrins are associated with progression and metastasis of breast cancer. However, via its interaction with many other intracellular proteins, kindlins can influence numerous cellular responses. Changes in expression of each of the three kindlins have been reported in association with breast cancer, with several studies indicating that kindlins are among the most upregulated genes in breast cancer. The association of abnormal functions of K2 with breast cancer is particularly extensive with many reports indicating that it is a major driver of breast cancer via its promotion of cancer cell proliferation, survival, adhesion, migration, invasion, the epithelial-to-mesenchymal transition and its influence on macrophage recruitment and phenotype. These associations suggest that the kindlins and their functions represent an intriguing therapeutic target for exploration of breast cancer therapy.
Published: 2021

33. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Author: Zhang H, Ahearn TU, Lecarpentier J, Barnes D, Beesley J, Qi G, Jiang X, O'Mara TA, Zhao N, Bolla MK, Dunning AM, Dennis J, Wang Q, Ful ZA, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Aronson KJ, Arun BK, Auer PL, Azzollini J, Barrowdale D, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bialkowska K, Blanco A, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Bondavalli D, Borg A, Brauch H, Brenner H, Briceno I, Broeks A, Brucker SY, Brüning T, Burwinkel B, Buys SS, Byers H, Caldés T, Caligo MA, Calvello M, Campa D, Castelao JE, Chang-Claude J, Chanock SJ, Christiaens M, Christiansen H, Chung WK, Claes KBM, Clarke CL, Cornelissen S, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Diez O, Domchek SM, Dörk T, Dwek M, Eccles DM, Ekici AB, Evans DG, Fasching PA, Figueroa J, Foretova L, Fostira F, Friedman E, Frost D, Gago-Dominguez M, Gapstur SM, Garber J, García-Sáenz JA, Gaudet MM, Gayther SA, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Gronwald J, Guénel P, Häberle L, Hahnen E, Haiman CA, Hake CR, Hall P, Hamann U, Harkness EF, Heemskerk-Gerritsen BAM, Hillemanns P, Hogervorst FBL, Holleczek B, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Howell A, Huebner H, Hulick PJ, Imyanitov EN, Isaacs C, Izatt L, Jager A, Jakimovska M, Jakubowska A, James P, Janavicius R, Janni W, John EM, Jones ME, Jung A, Kaaks R, Kapoor PM, Karlan BY, Keeman R, Khan S, Khusnutdinova E, Kitahara CM, Ko YD, Konstantopoulou I, Koppert LB, Koutros S, Kristensen VN, Laenkholm AV, Lambrechts D, Larsson SC, Laurent-Puig P, Lazaro C, Lazarova E, Lejbkowicz F, Leslie G, Lesueur F, Lindblom A, Lissowska J, Lo WY, Loud JT, Lubinski J, Lukomska A, MacInnis RJ, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martinez ME, Matricardi L, McGuffog L, McLean C, Mebirouk N, Meindl A, Menon U, Miller A, Mingazheva E, Montagna M, Mulligan AM, Mulot C, Muranen TA, Nathanson KL, Neuhausen SL, Nevanlinna H, Neven P, Newman WG, Nielsen FC, Nikitina-Zake L, Nodora J, Offit K, Olah E, Olopade OI, Olsson H, Orr N, Papi L, Papp J, Park-Simon TW, Parsons MT, Peissel B, Peixoto A, Peshkin B, Peterlongo P, Peto J, Phillips KA, Piedmonte M, Plaseska-Karanfilska D, Prajzendanc K, Prentice R, Prokofyeva D, Rack B, Radice P, Ramus SJ, Rantala J, Rashid MU, Rennert G, Rennert HS, Risch HA, Romero A, Rookus MA, Rübner M, Rüdiger T, Saloustros E, Sampson S, Sandler DP, Sawyer EJ, Scheuner MT, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schöttker B, Schürmann P, Senter L, Sharma P, Sherman ME, Shu XO, Singer CF, Smichkoska S, Soucy P, Southey MC, Spinelli JJ, Stone J, Stoppa-Lyonnet D, Swerdlow AJ, Szabo CI, Tamimi RM, Tapper WJ, Taylor JA, Teixeira MR, Terry M, Thomassen M, Thull DL, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Torres D, Troester MA, Truong T, Tung N, Untch M, Vachon CM, van den Ouweland AMW, van der Kolk LE, van Veen EM, vanRensburg EJ, Vega A, Wappenschmidt B, Weinberg CR, Weitzel JN, Wildiers H, Winqvist R, Wolk A, Yang XR, Yannoukakos D, Zheng W, Zorn KK, Milne RL, Kraft P, Simard J, Pharoah PDP, Michailidou K, Antoniou AC, Schmidt MK, Chenevix-Trench G, Easton DF, Chatterjee N, and García-Closas M
Subjects: BRCA1 Protein genetics, Breast Neoplasms pathology, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Linkage Disequilibrium, Mutation, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, Breast Neoplasms genetics, Genome-Wide Association Study
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype 1-3 . To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10 -8 ), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Published: 2020
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34. Site-specific phosphorylation regulates the functions of kindlin-3 in a variety of cells.

Author: Bialkowska K, Sossey-Alaoui K, Pluskota E, Izem L, Qin J, and Plow EF
Subjects: Animals, Antibodies, Monoclonal immunology, Blood Platelets cytology, Breast Neoplasms immunology, Breast Neoplasms metabolism, CHO Cells, Cell Line, Tumor, Cricetulus, Cytoskeletal Proteins immunology, Cytoskeletal Proteins metabolism, Female, Humans, Integrin beta Chains metabolism, Leukemia, Erythroblastic, Acute immunology, Mice, Mice, Nude, Phosphorylation, Platelet Glycoprotein GPIIb-IIIa Complex metabolism, Membrane Proteins immunology, Membrane Proteins metabolism, Neoplasm Proteins immunology, Neoplasm Proteins metabolism
Abstract: Studies of isolated cells, mice, and humans have demonstrated the vital role of the FERM domain protein kindlin-3 in integrin activation in certain hematopoietic and non-hematopoietic cells, consequent to binding to integrin β-subunits. To explore regulatory mechanisms, we developed a monoclonal antibody that selectively recognizes the phosphorylated form of Ser 484 (pS 484 ) in kindlin-3. Activation of platelets, HEL megakaryocytic-like cells and BT549 breast cancer cells led to enhanced expression of pS 484 as assessed by immunofluorescence or Western blotting. In platelets, pS 484 rose rapidly and transiently upon stimulation. When a mutant form of kindlin-3, T 482 S 484 /AA kindlin-3, was transduced into mouse megakaryocytes, it failed to support activation of integrin α IIb β 3 , whereas wild-type kindlin-3 did. In MDA-MB231 breast cancer cells, expression of T 482 S 484 /AA kindlin-3 suppressed cell spreading, migration, invasion, and VEGF production. Wild-type kindlin-3 expressing cells markedly increased tumor growth in vivo, whereas T 482 S 484 /AA kindlin-3 significantly blunted tumor progression. Thus, our data establish that a unique phosphorylation event in kindlin-3 regulates its cellular functions., (© 2020 Bialkowska et al.)
Published: 2020
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35. Non-catalytic signaling by pseudokinase ILK for regulating cell adhesion.

Author: Vaynberg J, Fukuda K, Lu F, Bialkowska K, Chen Y, Plow EF, and Qin J
Subjects: Adaptor Proteins, Signal Transducing chemistry, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Catalytic Domain genetics, Cell Line, Tumor, Cell Movement, Cytoskeleton metabolism, Humans, LIM Domain Proteins chemistry, LIM Domain Proteins genetics, LIM Domain Proteins metabolism, Membrane Proteins chemistry, Membrane Proteins genetics, Membrane Proteins metabolism, Microfilament Proteins chemistry, Microfilament Proteins genetics, Microfilament Proteins metabolism, Mutation, Protein Binding, Protein Interaction Domains and Motifs genetics, Protein Serine-Threonine Kinases chemistry, Protein Serine-Threonine Kinases genetics, Stress Fibers metabolism, Actin Cytoskeleton metabolism, Cell Adhesion physiology, Focal Adhesions metabolism, Protein Serine-Threonine Kinases metabolism, Signal Transduction genetics
Abstract: Dynamic communication between integrin-containing complexes (focal adhesions, FAs) and actin filaments is critical for regulating cell adhesion. Pseudokinase ILK plays a key role in this process but the underlying mechanism remains highly elusive. Here we show that by recruiting FA adaptors PINCH and Parvin into a heterotrimeric complex (IPP), ILK triggers F-actin filament bundling - a process known to generate force/mechanical signal to promote cytoskeleton reassembly and dynamic cell adhesion. Structural, biochemical, and functional analyses revealed that the F-actin bundling is orchestrated by two previously unrecognized WASP-Homology-2 actin binding motifs within IPP, one from PINCH and the other from Parvin. Strikingly, this process is also sensitized to Mg-ATP bound to the pseudoactive site of ILK and its dysregulation severely impairs stress fibers formation, cell spreading, and migration. These data identify a crucial mechanism for ILK, highlighting its uniqueness as a pseudokinase to transduce non-catalytic signal and regulate cell adhesion.
Published: 2018
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36. Kindlin-2 interacts with endothelial adherens junctions to support vascular barrier integrity.

Author: Pluskota E, Bledzka KM, Bialkowska K, Szpak D, Soloviev DA, Jones SV, Verbovetskiy D, and Plow EF
Subjects: Animals, Aorta cytology, Binding Sites, Cells, Cultured, Cytoskeletal Proteins genetics, Cytoskeletal Proteins metabolism, Endothelial Cells metabolism, Female, HEK293 Cells, Humans, Lung blood supply, Lung physiology, Male, Mice, Transgenic, Muscle Proteins genetics, Muscle Proteins metabolism, Protein Domains, Skin blood supply, Skin Physiological Phenomena, Trachea blood supply, Trachea physiology, Umbilical Veins cytology, beta Catenin metabolism, Adherens Junctions physiology, Cytoskeletal Proteins physiology, Endothelial Cells physiology, Muscle Proteins physiology
Abstract: Key Points: A reduction in Kindlin-2 levels in endothelial cells compromises vascular barrier function. Kindlin-2 is a previously unrecognized component of endothelial adherens junctions. By interacting directly and simultaneously with β- or γ-catenin and cortical actin filaments, Kindlin-2 stabilizes adherens junctions. The Kindlin-2 binding sites for β- and γ-catenin reside within its F1 and F3 subdomains. Although Kindlin-2 does not associate directly with tight junctions, its downregulation also destabilizes these junctions. Thus, impairment of both adherens and tight junctions may contribute to enhanced leakiness of vasculature in Kindlin-2 +/- mice., Abstract: Endothelial cells (EC) establish a physical barrier between the blood and surrounding tissue. Impairment of this barrier can occur during inflammation, ischaemia or sepsis and cause severe organ dysfunction. Kindlin-2, which is primarily recognized as a focal adhesion protein in EC, was not anticipated to have a role in vascular barrier. We tested the role of Kindlin-2 in regulating vascular integrity using several different approaches to decrease Kindlin-2 levels in EC. Reduced levels of Kindlin-2 in Kindlin-2 +/- mice aortic endothelial cells (MAECs) from these mice, and human umbilical ECs (HUVEC) treated with Kindlin-2 siRNA showed enhanced basal and platelet-activating factor (PAF) or lipopolysaccharide-stimulated vascular leakage compared to wild-type (WT) counterparts. PAF preferentially disrupted the Kindlin-2 +/- MAECs barrier to BSA and dextran and reduced transendothelial resistance compared to WT cells. Kindlin-2 co-localized and co-immunoprecipitated with vascular endothelial cadherin-based complexes, including β- and γ-catenin and actin, components of adherens junctions (AJ). Direct interaction of Kindlin-2 with β- and γ-catenin and actin was demonstrated in co-immunoprecipitation and surface plasmon resonance experiments. In thrombin-stimulated HUVECs, Kindlin-2 and cortical actin dissociated from stable AJs and redistributed to radial actin stress fibres of remodelling focal AJs. The β- and γ-catenin binding site resides within the F1 and F3 subdomains of Kindlin-2 but not the integrin binding site in F3. These results establish a previously unrecognized and vital role of Kindlin-2 with respect to maintaining the vascular barrier by linking Vascuar endothelial cadherin-based complexes to cortical actin and thereby stabilizing AJ., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)
Published: 2017
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37. Kindlin-2 Regulates the Growth of Breast Cancer Tumors by Activating CSF-1-Mediated Macrophage Infiltration.

Author: Sossey-Alaoui K, Pluskota E, Bialkowska K, Szpak D, Parker Y, Morrison CD, Lindner DJ, Schiemann WP, and Plow EF
Subjects: Animals, Apoptosis, Breast Neoplasms immunology, Breast Neoplasms metabolism, Cell Movement, Cell Proliferation, Female, Humans, Macrophages, Peritoneal immunology, Macrophages, Peritoneal metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, Nude, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Biomarkers, Tumor metabolism, Breast Neoplasms pathology, Macrophage Colony-Stimulating Factor metabolism, Macrophages, Peritoneal pathology, Membrane Proteins metabolism, Neoplasm Proteins metabolism, Transforming Growth Factor beta1 metabolism
Abstract: Interplay between tumor cells and host cells in the tumor microenvironment dictates the development of all cancers. In breast cancer, malignant cells educate host macrophages to adopt a protumorigenic phenotype. In this study, we show how the integrin-regulatory protein kindlin-2 (FERMT2) promotes metastatic progression of breast cancer through the recruitment and subversion of host macrophages. Kindlin-2 expression was elevated in breast cancer biopsy tissues where its levels correlated with reduced patient survival. On the basis of these observations, we used CRISPR/Cas9 technology to ablate Kindlin-2 expression in human MDA-MB-231 and murine 4T1 breast cancer cells. Kindlin-2 deficiency inhibited invasive and migratory properties in vitro without affecting proliferation rates. However, in vivo tumor outgrowth was inhibited by >80% in a manner associated with reduced macrophage infiltration and secretion of the macrophage attractant and growth factor colony-stimulating factor-1 (CSF-1). The observed loss of CSF-1 appeared to be caused by a more proximal deficiency in TGFβ-dependent signaling in Kindlin-2-deficient cells. Collectively, our results illuminate a Kindlin-2/TGFβ/CSF-1 signaling axis employed by breast cancer cells to capture host macrophage functions that drive tumor progression. Cancer Res; 77(18); 5129-41. ©2017 AACR ., (©2017 American Association for Cancer Research.)
Published: 2017
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38. The extreme C-terminal region of kindlin-2 is critical to its regulation of integrin activation.

Author: Hirbawi J, Bialkowska K, Bledzka KM, Liu J, Fukuda K, Qin J, and Plow EF
Subjects: Amino Acid Substitution, Animals, CHO Cells, Cell Line, Tumor, Cricetulus, Gene Deletion, Humans, Integrin alpha2 chemistry, Integrin alpha2 genetics, Integrin beta3 chemistry, Integrin beta3 genetics, Leukemia, Erythroblastic, Acute pathology, Luminescent Proteins genetics, Luminescent Proteins metabolism, Macrophages cytology, Membrane Proteins chemistry, Membrane Proteins genetics, Mice, Mutation, Neoplasm Proteins agonists, Neoplasm Proteins chemistry, Neoplasm Proteins genetics, Peptide Fragments chemistry, Peptide Fragments genetics, Peptide Fragments metabolism, Protein Interaction Domains and Motifs, Protein Multimerization, RAW 264.7 Cells, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins metabolism, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Talin chemistry, Talin genetics, Talin metabolism, Integrin alpha2 metabolism, Integrin beta3 metabolism, Leukemia, Erythroblastic, Acute metabolism, Macrophages metabolism, Membrane Proteins metabolism, Neoplasm Proteins metabolism
Abstract: Kindlin-2 (K2), a 4.1R-ezrin-radixin-moesin (FERM) domain adaptor protein, mediates numerous cellular responses, including integrin activation. The C-terminal 15-amino acid sequence of K2 is remarkably conserved across species but is absent in canonical FERM proteins, including talin. In CHO cells expressing integrin αIIbβ3, co-expression of K2 with talin head domain resulted in robust integrin activation, but this co-activation was lost after deletion of as few as seven amino acids from the K2 C terminus. This dependence on the C terminus was also observed in activation of endogenous αIIbβ3 in human erythroleukemia (HEL) cells and β1 integrin activation in macrophage-like RAW264.1 cells. Kindlin-1 (K1) exhibited a similar dependence on its C terminus for integrin activation. Expression of the K2 C terminus as an extension of membrane-anchored P-selectin glycoprotein ligand-1 (PSGL-1) inhibited integrin-dependent cell spreading. Deletion of the K2 C terminus did not affect its binding to the integrin β3 cytoplasmic tail, but combined biochemical and NMR analyses indicated that it can insert into the F2 subdomain. We suggest that this insertion determines the topology of the K2 FERM domain, and its deletion may affect the positioning of the membrane-binding functions of the F2 subdomain and the integrin-binding properties of its F3 subdomain. Free C-terminal peptide can still bind to K2 and displace the endogenous K2 C terminus but may not restore the conformation needed for integrin co-activation. Our findings indicate that the extreme C terminus of K2 is essential for integrin co-activation and highlight the importance of an atypical architecture of the K2 FERM domain in regulating integrin activation., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
Published: 2017
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39. Kindlin-2 directly binds actin and regulates integrin outside-in signaling.

Author: Bledzka K, Bialkowska K, Sossey-Alaoui K, Vaynberg J, Pluskota E, Qin J, and Plow EF
Subjects: Amino Acid Sequence, Animals, Binding Sites physiology, CHO Cells, Cell Adhesion physiology, Cell Line, Cell Line, Tumor, Cricetulus, Cytoskeletal Proteins metabolism, HeLa Cells, Human Umbilical Vein Endothelial Cells, Humans, Mice, Molecular Sequence Data, Protein Binding physiology, Protein Structure, Tertiary, Talin metabolism, Actins metabolism, Membrane Proteins metabolism, Neoplasm Proteins metabolism, Platelet Glycoprotein GPIIb-IIIa Complex metabolism, Signal Transduction physiology
Abstract: Reduced levels of kindlin-2 (K2) in endothelial cells derived from K2(+/-)mice or C2C12 myoblastoid cells treated with K2 siRNA showed disorganization of their actin cytoskeleton and decreased spreading. These marked changes led us to examine direct binding between K2 and actin. Purified K2 interacts with F-actin in cosedimentation and surface plasmon resonance analyses and induces actin aggregation. We further find that the F0 domain of K2 binds actin. A mutation, LK(47)/AA, within a predicted actin binding site (ABS) of F0 diminishes its interaction with actin by approximately fivefold. Wild-type K2 and K2 bearing the LK(47)/AA mutation were equivalent in their ability to coactivate integrin αIIbβ3 in a CHO cell system when coexpressed with talin. However, K2-LK(47)/AA exhibited a diminished ability to support cell spreading and actin organization compared with wild-type K2. The presence of an ABS in F0 of K2 that influences outside-in signaling across integrins establishes a new foundation for considering how kindlins might regulate cellular responses., (© 2016 Bledzka et al.)
Published: 2016
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40. Of Kindlins and Cancer.

Author: Plow EF, Das M, Bialkowska K, and Sossey-Alaoui K
Abstract: Kindlins are 4.1-ezrin-ridixin-moesin (FERM) domain containing proteins. There are three kindlins in mammals, which share high sequence identity. Kindlin-1 is expressed primarily in epithelial cells, kindlin-2 is widely distributed and is particularly abundant in adherent cells, and kindlin-3 is expressed primarily in hematopoietic cells. These distributions are not exclusive; some cells express multiple kindlins, and transformed cells often exhibit aberrant expression, both in the isoforms and the levels of kindlins. Great interest in the kindlins has emerged from the recognition that they play major roles in controlling integrin function. In vitro studies, in vivo studies of mice deficient in kindlins, and studies of patients with genetic deficiencies of kindlins have clearly established that they regulate the capacity of integrins to mediate their functions. Kindlins are adaptor proteins; their function emanate from their interaction with binding partners, including the cytoplasmic tails of integrins and components of the actin cytoskeleton. The purpose of this review is to provide a brief overview of kindlin structure and function, a consideration of their binding partners, and then to focus on the relationship of each kindlin family member with cancer. In view of many correlations of kindlin expression levels and neoplasia and the known association of integrins with tumor progression and metastasis, we consider whether regulation of kindlins or their function would be attractive targets for treatment of cancer.
Published: 2016
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41. Site-specific phosphorylation of kindlin-3 protein regulates its capacity to control cellular responses mediated by integrin αIIbβ3.

Author: Bialkowska K, Byzova TV, and Plow EF
Subjects: Animals, CHO Cells, Cell Adhesion genetics, Cricetinae, Cricetulus, Gene Expression Regulation, Human Umbilical Vein Endothelial Cells, Humans, Membrane Proteins genetics, Neoplasm Proteins genetics, Phosphorylation genetics, Platelet Glycoprotein GPIIb-IIIa Complex metabolism, Blood Platelets metabolism, Hematopoiesis genetics, Membrane Proteins metabolism, Neoplasm Proteins metabolism, Platelet Glycoprotein GPIIb-IIIa Complex genetics
Abstract: The contributions of integrins to cellular responses depend upon their activation, which is regulated by binding of proteins to their cytoplasmic tails. Kindlins are integrin cytoplasmic tail binding partners and are essential for optimal integrin activation, and kindlin-3 fulfills this role in hematopoietic cells. Here, we used human platelets and human erythroleukemia (HEL) cells, which express integrin αIIbβ3, to investigate whether phosphorylation of kindlin-3 regulates integrin activation. When HEL cells were stimulated with thrombopoietin or phorbol 12-myristate 13-acetate (PMA), αIIbβ3 became activated as evidenced by binding of an activation-specific monoclonal antibody and soluble fibrinogen, adherence and spreading on fibrinogen, colocalization of β3 integrin and kindlin-3 in focal adhesions, and enhanced β3 integrin-kindlin-3 association in immunoprecipitates. Kindlin-3 knockdown impaired adhesion and spreading on fibrinogen. Stimulation of HEL cells with agonists significantly increased kindlin-3 phosphorylation as detected by mass spectrometric sequencing. Thr(482) or Ser(484) was identified as a phosphorylation site, which resides in a sequence not conserved in kindlin-1 or kindlin-2. These same residues were phosphorylated in kindlin-3 when platelets were stimulated with thrombin. When expressed in HEL cells, T482A/S484A kindlin-3 decreased soluble ligand binding and cell spreading on fibrinogen compared with wild-type kindlin-3. A membrane-permeable peptide containing residues 476-485 of kindlin-3 was introduced into HEL cells and platelets; adhesion and spreading of both cell types were blunted compared with a scrambled control peptide. These data identify a role of kindlin-3 phosphorylation in integrin β3 activation and provide a basis for functional differences between kindlin-3 and the two other kindlin paralogs., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
Published: 2015
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42. Overexpression of full-length cholesteryl ester transfer protein in SW872 cells reduces lipid accumulation.

Author: Izem L, Greene DJ, Bialkowska K, and Morton RE
Subjects: Apolipoproteins E biosynthesis, Apolipoproteins E genetics, Cell Line, Tumor, Cholesterol Ester Transfer Proteins genetics, Cytoplasm genetics, Fatty Acid Synthase, Type I genetics, Fatty Acid Synthase, Type I metabolism, Gene Expression Regulation physiology, Humans, PPAR gamma biosynthesis, PPAR gamma genetics, RNA, Messenger biosynthesis, RNA, Messenger genetics, Sterol Regulatory Element Binding Protein 1 genetics, Sterol Regulatory Element Binding Protein 1 metabolism, Triglycerides genetics, Cholesterol Ester Transfer Proteins metabolism, Cytoplasm metabolism, Lipid Metabolism physiology, Triglycerides metabolism
Abstract: Cells produce two cholesteryl ester transfer protein (CETP) isoforms, full-length and a shorter variant produced by alternative splicing. Blocking synthesis of both isoforms disrupts lipid metabolism and storage. To further define the role of CETP in cellular lipid metabolism, we stably overexpressed full-length CETP in SW872 cells. These CETP(+) cells had several-fold higher intracellular CETP and accumulated 50% less TG due to a 26% decrease in TG synthesis and 2.5-fold higher TG turnover rate. Reduced TG synthesis was due to decreased fatty acid uptake and impaired conversion of diglyceride to TG even though diacylglycerol acyltransferase activity was normal. Sterol-regulatory element binding protein 1 mRNA levels were normal, and although PPARγ expression was reduced, the expression of several of its target genes including adipocyte triglyceride lipase, FASN, and APOE was normal. CETP(+) cells contained smaller lipid droplets, consistent with their higher levels of perilipin protein family (PLIN) 3 compared with PLIN1 and PLIN2. Intracellular CETP was mostly associated with the endoplasmic reticulum, although CETP near lipid droplets poorly colocalized with this membrane. A small pool of CETP resided in the cytoplasm, and a subfraction coisolated with lipid droplets. These data show that overexpression of full-length CETP disrupts lipid homeostasis resulting in the formation of smaller, more metabolically active lipid droplets., (Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.)
Published: 2015
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43. Direct interaction of kindlin-3 with integrin αIIbβ3 in platelets is required for supporting arterial thrombosis in mice.

Author: Xu Z, Chen X, Zhi H, Gao J, Bialkowska K, Byzova TV, Pluskota E, White GC 2nd, Liu J, Plow EF, and Ma YQ
Subjects: Amino Acid Substitution, Animals, Bleeding Time, Blood Platelets ultrastructure, Carotid Artery Thrombosis blood, Carotid Artery Thrombosis chemically induced, Cell Shape, Chlorides toxicity, Clot Retraction, Cytoskeletal Proteins chemistry, Cytoskeletal Proteins genetics, Disease Models, Animal, Female, Ferric Compounds toxicity, Gene Knock-In Techniques, Genes, Reporter, Male, Mice, Mice, Inbred C57BL, Microspheres, Platelet Activation, Platelet Glycoprotein GPIIb-IIIa Complex chemistry, Protein Interaction Mapping, Recombinant Fusion Proteins metabolism, Blood Platelets physiology, Carotid Artery Thrombosis physiopathology, Cytoskeletal Proteins physiology, Platelet Glycoprotein GPIIb-IIIa Complex physiology
Abstract: Objective: Kindlin-3 is a critical supporter of integrin function in platelets. Lack of expression of kindlin-3 protein in patients impairs integrin αIIbβ3-mediated platelet aggregation. Although kindlin-3 has been categorized as an integrin-binding partner, the functional significance of the direct interaction of kindlin-3 with integrin αIIbβ3 in platelets has not been established. Here, we evaluated the significance of the binding of kindlin-3 to integrin αIIbβ3 in platelets in supporting integrin αIIbβ3-mediated platelet functions., Approach and Results: We generated a strain of kindlin-3 knockin (K3KI) mice that express a kindlin-3 mutant that carries an integrin-interaction defective substitution. K3KI mice could survive normally and express integrin αIIbβ3 on platelets similar to their wild-type counterparts. Functional analysis revealed that K3KI mice exhibited defective platelet function, including impaired integrin αIIbβ3 activation, suppressed platelet spreading and platelet aggregation, prolonged tail bleeding time, and absence of platelet-mediated clot retraction. In addition, whole blood drawn from K3KI mice showed resistance to in vitro thrombus formation and, as a consequence, K3KI mice were protected from in vivo arterial thrombosis., Conclusions: These observations demonstrate that the direct binding of kindlin-3 to integrin αIIbβ3 is involved in supporting integrin αIIbβ3 activation and integrin αIIbβ3-dependent responses of platelets and consequently contributes significantly to arterial thrombus formation., (© 2014 American Heart Association, Inc.)
Published: 2014
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44. Kindlin-3 enhances breast cancer progression and metastasis by activating Twist-mediated angiogenesis.

Author: Sossey-Alaoui K, Pluskota E, Davuluri G, Bialkowska K, Das M, Szpak D, Lindner DJ, Downs-Kelly E, Thompson CL, and Plow EF
Subjects: Animals, Cell Line, Tumor, Disease Progression, Female, Humans, Integrin beta1 metabolism, Mice, Mice, SCID, Neoplasm Metastasis, Protein Structure, Tertiary, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Vascular Endothelial Growth Factor A metabolism, Breast Neoplasms metabolism, Gene Expression Regulation, Neoplastic, Membrane Proteins metabolism, Neoplasm Proteins metabolism, Neovascularization, Pathologic, Nuclear Proteins metabolism, Twist-Related Protein 1 metabolism
Abstract: The FERM domain containing protein Kindlin-3 has been recognized as a major regulator of integrin function in hematopoietic cells, but its role in neoplasia is totally unknown. We have examined the relationship between Kindlin-3 and breast cancer in mouse models and human tissues. Human breast tumors showed a ∼7-fold elevation in Kindlin-3 mRNA compared with nonneoplastic tissue by quantitative polymerase chain reaction. Kindlin-3 overexpression in a breast cancer cell line increased primary tumor growth and lung metastasis by 2.5- and 3-fold, respectively, when implanted into mice compared with cells expressing vector alone. Mechanistically, the Kindlin-3-overexpressing cells displayed a 2.2-fold increase in vascular endothelial growth factor (VEGF) secretion and enhanced β1 integrin activation. Increased VEGF secretion resulted from enhanced production of Twist, a transcription factor that promotes tumor angiogenesis. Knockdown of Twist diminished VEGF production, and knockdown of β1 integrins diminished Twist and VEGF production by Kindlin-3-overexpressing cells, while nontargeting small interfering RNA had no effect on expression of these gene products. Thus, Kindlin-3 influences breast cancer progression by influencing the crosstalk between β1 integrins and Twist to increase VEGF production. This signaling cascade enhances breast cancer cell invasion and tumor angiogenesis and metastasis.
Published: 2014
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45. Kindlin-2 regulates hemostasis by controlling endothelial cell-surface expression of ADP/AMP catabolic enzymes via a clathrin-dependent mechanism.

Author: Pluskota E, Ma Y, Bledzka KM, Bialkowska K, Soloviev DA, Szpak D, Podrez EA, Fox PL, Hazen SL, Dowling JJ, Ma YQ, and Plow EF
Subjects: 5'-Nucleotidase biosynthesis, Adenosine Diphosphate metabolism, Adenosine Monophosphate metabolism, Animals, Antigens, CD biosynthesis, Apyrase biosynthesis, Cell Membrane metabolism, Female, Flow Cytometry, Immunoprecipitation, Male, Mice, Mice, Knockout, Platelet Aggregation physiology, Protein Transport physiology, Surface Plasmon Resonance, Blood Platelets metabolism, Clathrin metabolism, Cytoskeletal Proteins metabolism, Endothelial Cells metabolism, Hemostasis physiology, Muscle Proteins metabolism
Abstract: Kindlin-2, a widely distributed cytoskeletal protein, has been implicated in integrin activation, and its absence is embryonically lethal in mice. In the present study, we tested whether hemostasis might be perturbed in kindlin-2(+/-) mice. Bleeding time and carotid artery occlusion time were significantly prolonged in kindlin-2(+/-) mice. Whereas plasma concentrations/activities of key coagulation/fibrinolytic proteins and platelet counts and aggregation were similar in wild-type and kindlin-2(+/-) mice, kindlin-2(+/-) endothelial cells (ECs) showed enhanced inhibition of platelet aggregation induced by adenosine 5'-diphosphate (ADP) or low concentrations of other agonists. Cell-surface expression of 2 enzymes involved in ADP/adenosine 5'-monophosphate (AMP) degradation, adenosine triphosphate (ATP) diphosphohydrolase (CD39) and ecto-5'-nucleotidase (CD73) were increased twofold to threefold on kindlin-2(+/-) ECs, leading to enhanced ATP/ADP catabolism and production of adenosine, an inhibitor of platelet aggregation. Trafficking of CD39 and CD73 at the EC surface was altered in kindlin-2(+/-) mice. Mechanistically, this was attributed to direct interaction of kindlin-2 with clathrin heavy chain, thereby controlling endocytosis and recycling of CD39 and CD73. The interaction of kindlin-2 with clathrin was independent of its integrin binding site but still dependent on a site within its F3 subdomain. Thus, kindlin-2 regulates trafficking of EC surface enzymes that control platelet responses and hemostasis.
Published: 2013
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46. Spatial coordination of kindlin-2 with talin head domain in interaction with integrin β cytoplasmic tails.

Author: Bledzka K, Liu J, Xu Z, Perera HD, Yadav SP, Bialkowska K, Qin J, Ma YQ, and Plow EF
Subjects: Animals, Blotting, Western, CHO Cells, Calorimetry, Chromatography, High Pressure Liquid, Cricetinae, Magnetic Resonance Spectroscopy, Protein Structure, Tertiary, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Surface Plasmon Resonance, Cytoplasm metabolism, Integrin beta Chains chemistry, Integrin beta Chains metabolism, Membrane Proteins chemistry, Membrane Proteins metabolism, Neoplasm Proteins chemistry, Neoplasm Proteins metabolism, Talin chemistry, Talin metabolism
Abstract: Both talin head domain and kindlin-2 interact with integrin β cytoplasmic tails, and they function in concert to induce integrin activation. Binding of talin head domain to β cytoplasmic tails has been characterized extensively, but information on the interaction of kindin-2 with this integrin segment is limited. In this study, we systematically examine the interactions of kindlin-2 with integrin β tails. Kindlin-2 interacted well with β(1) and β(3) tails but poorly with the β(2) cytoplasmic tail. This binding selectivity was determined by the non-conserved residues, primarily the three amino acids at the extreme C terminus of the β(3) tail, and the sequence in β(2) was non-permissive. The region at the C termini of integrin β(1) and β(3) tails recognized by kindlin-2 was a binding core of 12 amino acids. Kindlin-2 and talin head do not interact with one another but can bind simultaneously to the integrin β(3) tail without enhancing or inhibiting the interaction of the other binding partner. Kindlin-2 itself failed to directly unclasp integrin α/β tail complex, indicating that kindlin-2 must cooperate with talin to support the integrin activation mechanism.
Published: 2012
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47. miR-31 is a broad regulator of β1-integrin expression and function in cancer cells.

Author: Augoff K, Das M, Bialkowska K, McCue B, Plow EF, and Sossey-Alaoui K
Subjects: Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Adhesion physiology, Cell Line, Tumor, Female, Humans, Integrin beta1 genetics, Integrin beta1 metabolism, MicroRNAs genetics, Signal Transduction, Transfection, Breast Neoplasms metabolism, Integrin beta1 biosynthesis, MicroRNAs metabolism
Abstract: Integrins are adhesion receptors involved in bidirectional signaling that are crucial for various cellular responses during normal homeostasis and pathologic conditions such as cancer progression and metastasis. Aberrant expression of noncoding microRNAs (miRNA) has been implicated in the deregulation of integrin expression and activity, leading to the development and progression of cancer tumors, including their acquisition of the metastatic phenotype. miR-31 is a key regulator of several critical genes involved in the invasion-metastasis cascade in cancer. Using diverse cell-based, genetic, biochemical, flow cytometry, and functional analyses, we report that miR-31 is a master regulator of integrins as it targets multiple α subunit partners (α2, α5, and αV) of β1 integrins and also β3 integrins. We found that expression of miR-31 in cancer cells resulted in a significant repression of these integrin subunits both at the mRNA and protein levels. Loss of expression of α2, α5, αV, and β3 was a direct consequence of miR-31 targeting conserved seed sequences in the 3' untranslated region of these integrin subunits leading to their posttranscriptional repression, which was reflected in their diminished surface expression in live cells. The biological consequence of decreased the cell surface of these integrins was a significant inhibition of cell spreading in a ligand-dependent manner. Although different reports have shown that a single integrin can be regulated by several miRNAs, here we show that a single miRNA, miR-31, is able to specifically target several integrin subunits to regulate key aspects of cancer cell invasion and metastasis., (Mol Cancer Res; 9(11); 1500-8. ©2011 AACR.)
Published: 2011
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48. Tiam1 is recruited to β1-integrin complexes by 14-3-3ζ where it mediates integrin-induced Rac1 activation and motility.

Author: O'Toole TE, Bialkowska K, Li X, and Fox JE
Subjects: HeLa Cells, Humans, T-Lymphoma Invasion and Metastasis-inducing Protein 1, 14-3-3 Proteins metabolism, Blood Platelets metabolism, Cell Movement, Guanine Nucleotide Exchange Factors metabolism, Integrin beta1 metabolism, rac1 GTP-Binding Protein metabolism
Abstract: 14-3-3 is an adaptor protein that localizes to the leading edge of spreading cells, returning to the cytoplasm as spreading ceases. Previously, we showed that integrin-induced Rac1 activation and spreading were inhibited by sequestration of 14-3-3ζ and restored by its overexpression. Here, we determined whether 14-3-3 mediates integrin signaling by localizing a guanine nucleotide exchange factor (GEF) to Rac1-activating integrin complexes. We showed that GST-14-3-3ζ recruited the Rac1-GEF, Tiam1, from cell lysates through Tiam1 residues 1-182 (N(1-182) Tiam1). The physiological relevance of this interaction was examined in serum-starved Hela cells plated on fibronectin. Both Tiam1 and N(1-182) Tiam1 were recruited to 14-3-3-containing β1-integrin complexes, as shown by co-localization and co-immunoprecipitation. Integrin-induced Rac1 activation was inhibited when Tiam1 was depleted with siRNA or by overexpression of catalytically inactive N(1-182) Tiam1, which was incorporated into 14-3-3/β1-integrin complexes and inhibited spreading in a manner that was overcome by constitutively active Rac1. Integrin-induced Rac1 activation, spreading, and migration were also inhibited by overexpression of 14-3-3ζ S58D, which was unable to recruit Tiam1 from lysates, co-immunoprecipitate with Tiam1, or mediate its incorporation into β1-integrin complexes. Taken together, these findings suggest a previously unrecognized mechanism of integrin-induced Rac1 activation in which 14-3-3 dimers localize Tiam1 to integrin complexes, where it mediates integrin-dependent Rac1 activation, thus initiating motility-inducing pathways. Moreover, since Tiam1 is recruited to other sites of localized Rac1 activation through its PH-CC-EX domain, the present findings show that a mechanism involving its N-terminal 182 residues is utilized to recruit Tiam1 to motility-inducing integrin complexes., (Copyright © 2011 Wiley-Liss, Inc.)
Published: 2011
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49. The integrin coactivator kindlin-2 plays a critical role in angiogenesis in mice and zebrafish.

Author: Pluskota E, Dowling JJ, Gordon N, Golden JA, Szpak D, West XZ, Nestor C, Ma YQ, Bialkowska K, Byzova T, and Plow EF
Subjects: Animals, Base Sequence, Cell Line, Tumor, Cytoskeletal Proteins antagonists & inhibitors, Cytoskeletal Proteins genetics, Female, Gene Knockdown Techniques, Integrin alphaVbeta3 physiology, Male, Mice, Mice, Knockout, Neovascularization, Pathologic pathology, Oligodeoxyribonucleotides, Antisense genetics, Prostatic Neoplasms blood supply, Prostatic Neoplasms physiopathology, Signal Transduction, Vascular Endothelial Growth Factor A physiology, Zebrafish, Zebrafish Proteins antagonists & inhibitors, Zebrafish Proteins genetics, Cytoskeletal Proteins physiology, Neovascularization, Pathologic physiopathology, Neovascularization, Physiologic physiology, Zebrafish Proteins physiology
Abstract: Kindlin-2, a widely distributed cytoskeletal protein, has been implicated in integrin activation, and its absence is embryonically lethal in mice and causes severe developmental defects in zebrafish. Knockdown of kindlin-2 levels in endothelial cells resulted in defective adhesive and migratory responses, suggesting that angiogenesis might be aberrant even with partial reduction of kindlin-2. This hypothesis has now been tested in the kindlin-2(+/-) mice. RM1 prostate tumors grown in kindlin-2(+/-) mice had fewer blood vessels, which were thinner and shorter and supported less tumor growth compared with wild-type littermates. The vessels that did form in the kindlin-2(+/-) mice lacked smooth muscle cells and pericytes and had thinner basement membranes, indicative of immature vessels. VEGF-induced angiogenesis in matrigel implants was also abnormal in the kindlin-2(+/-) mice. Vessels in the kindlin-2(+/-) mice were leaky, and BM transplantation from kindlin-2(+/-) to WT mice did not correct this defect. Endothelial cells derived from kindlin-2(+/-) mice had integrin expression levels similar to WT mice but reduced αVβ3-dependent signaling, migration, adhesion, spreading, and tube formation. Developmental angiogenesis was markedly impaired by kindlin-2 morpholinos in zebrafish. Taken together, kindlin-2 plays an important role in pathologic and developmental angiogenesis, which arises from defective activation of integrin αVβ3.
Published: 2011
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50. Tyrosine phosphorylation of integrin beta3 regulates kindlin-2 binding and integrin activation.

Author: Bledzka K, Bialkowska K, Nie H, Qin J, Byzova T, Wu C, Plow EF, and Ma YQ
Subjects: Amino Acid Motifs, Humans, Integrin beta3 chemistry, Integrin beta3 genetics, Membrane Proteins chemistry, Membrane Proteins genetics, Neoplasm Proteins chemistry, Neoplasm Proteins genetics, Phosphorylation physiology, Protein Binding, Protein Structure, Tertiary, Tyrosine chemistry, Tyrosine genetics, Integrin beta3 metabolism, Membrane Proteins metabolism, Neoplasm Proteins metabolism, Tyrosine metabolism
Abstract: Kindlins are essential for integrin activation in cell systems and do so by working in a cooperative fashion with talin via their direct interaction with integrin β cytoplasmic tails (CTs). Kindlins interact with the membrane-distal NxxY motif, which is distinct from the talin-binding site within the membrane-proximal NxxY motif. The Tyr residues in both motifs can be phosphorylated, and it has been suggested that this modification of the membrane-proximal NxxY motif negatively regulates interaction with the talin head domain. However, the influence of Tyr phosphorylation of the membrane-distal NxxY motif on kindlin binding is unknown. Using mutational analyses and phosphorylated peptides, we show that phosphorylation of the membrane-distal NITY(759) motif in the β(3) CT disrupts kindlin-2 recognition. Phosphorylation of this membrane-distal Tyr also disables the ability of kindlin-2 to coactivate the integrin. In direct binding studies, peptides corresponding to the non-phosphorylated β(3) CT interacted well with kindlin-2, whereas the Tyr(759)-phosphorylated peptide failed to bind kindlin-2 with measurable affinity. These observations indicate that transitions between the phosphorylated and non-phosphorylated states of the integrin β(3) CT determine reactivity with kindlin-2 and govern the role of kindlin-2 in regulating integrin activation.
Published: 2010
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