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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. 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

3. 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

4. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

Author: Morra A., Escala-Garcia M., Beesley J., Keeman R., Canisius S., Ahearn T.U., Andrulis I.L., Anton-Culver H., Arndt V., Auer P.L., Augustinsson A., Beane Freeman L.E., Becher H., Beckmann M.W., Behrens S., Bojesen S.E., Bolla M.K., Brenner H., Bruning T., Buys S.S., Caan B., Campa D., Canzian F., Castelao J.E., Chang-Claude J., Chanock S.J., Cheng T.-Y.D., Clarke C.L., Colonna S.V., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Dennis J., Dork T., Dossus L., Dunning A.M., Dwek M., Eccles D.M., Ekici A.B., Eliassen A.H., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fritschi L., Gago-Dominguez M., Garcia-Saenz J.A., Giles G.G., Grip M., Guenel P., Gundert M., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hart S.N., Hartikainen J.M., Hartmann A., He W., Hooning M.J., Hoppe R., Hopper J.L., Howell A., Hunter D.J., Jager A., Jakubowska A., Janni W., John E.M., Jung A.Y., Kaaks R., Keupers M., Kitahara C.M., Koutros S., Kraft P., Kristensen V.N., Kurian A.W., Lacey J.V., Lambrechts D., Le Marchand L., Lindblom A., Linet M., Luben R.N., Lubinski J., Lush M., Mannermaa A., Manoochehri M., Margolin S., Martens J.W.M., Martinez M.E., Mavroudis D., Michailidou K., Milne R.L., Mulligan A.M., Muranen T.A., Nevanlinna H., Newman W.G., Nielsen S.F., Nordestgaard B.G., Olshan A.F., Olsson H., Orr N., Park-Simon T.-W., Patel A.V., Peissel B., Peterlongo P., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Rack B., Rennert G., Rennert H.S., Rhenius V., Romero A., Roylance R., Ruebner M., Saloustros E., Sawyer E.J., Schmutzler R.K., Schneeweiss A., Scott C., Shah M., Smichkoska S., Southey M.C., Stone J., Surowy H., Swerdlow A.J., Tamimi R.M., Tapper W.J., Teras L.R., Terry M.B., Tollenaar R.A.E.M., Tomlinson I., Troester M.A., Truong T., Vachon C.M., Wang Q., Hurson A.N., Winqvist R., Wolk A., Ziogas A., Brauch H., Garcia-Closas M., Pharoah P.D.P., Easton D.F., Chenevix-Trench G., Schmidt M.K., Morra A., Escala-Garcia M., Beesley J., Keeman R., Canisius S., Ahearn T.U., Andrulis I.L., Anton-Culver H., Arndt V., Auer P.L., Augustinsson A., Beane Freeman L.E., Becher H., Beckmann M.W., Behrens S., Bojesen S.E., Bolla M.K., Brenner H., Bruning T., Buys S.S., Caan B., Campa D., Canzian F., Castelao J.E., Chang-Claude J., Chanock S.J., Cheng T.-Y.D., Clarke C.L., Colonna S.V., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Dennis J., Dork T., Dossus L., Dunning A.M., Dwek M., Eccles D.M., Ekici A.B., Eliassen A.H., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fritschi L., Gago-Dominguez M., Garcia-Saenz J.A., Giles G.G., Grip M., Guenel P., Gundert M., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hart S.N., Hartikainen J.M., Hartmann A., He W., Hooning M.J., Hoppe R., Hopper J.L., Howell A., Hunter D.J., Jager A., Jakubowska A., Janni W., John E.M., Jung A.Y., Kaaks R., Keupers M., Kitahara C.M., Koutros S., Kraft P., Kristensen V.N., Kurian A.W., Lacey J.V., Lambrechts D., Le Marchand L., Lindblom A., Linet M., Luben R.N., Lubinski J., Lush M., Mannermaa A., Manoochehri M., Margolin S., Martens J.W.M., Martinez M.E., Mavroudis D., Michailidou K., Milne R.L., Mulligan A.M., Muranen T.A., Nevanlinna H., Newman W.G., Nielsen S.F., Nordestgaard B.G., Olshan A.F., Olsson H., Orr N., Park-Simon T.-W., Patel A.V., Peissel B., Peterlongo P., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Rack B., Rennert G., Rennert H.S., Rhenius V., Romero A., Roylance R., Ruebner M., Saloustros E., Sawyer E.J., Schmutzler R.K., Schneeweiss A., Scott C., Shah M., Smichkoska S., Southey M.C., Stone J., Surowy H., Swerdlow A.J., Tamimi R.M., Tapper W.J., Teras L.R., Terry M.B., Tollenaar R.A.E.M., Tomlinson I., Troester M.A., Truong T., Vachon C.M., Wang Q., Hurson A.N., Winqvist R., Wolk A., Ziogas A., Brauch H., Garcia-Closas M., Pharoah P.D.P., Easton D.F., Chenevix-Trench G., and Schmidt M.K.
Abstract: BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHOD(S): We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP <0.15). RESULT(S): Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSION(S): We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on br
Published: 2021

5. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Morra, A, Escala-Garcia, M, Beesley, J, Keeman, R, Canisius, S, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Augustinsson, A, Freeman, LEB, Becher, H, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brenner, H, Bruening, T, Buys, SS, Caan, B, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Cheng, T-YD, Clarke, CL, Colonna, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Dork, T, Dossus, L, Dunning, AM, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, Gago-Dominguez, M, Garcia-Saenz, JA, Giles, GG, Grip, M, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Hartikainen, JM, Hartmann, A, He, W, Hooning, MJ, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, Janni, W, John, EM, Jung, AY, Kaaks, R, Keupers, M, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Linet, M, Luben, RN, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, Michailidou, K, Milne, RL, Mulligan, AM, Muranen, TA, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Olshan, AF, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peissel, B, Peterlongo, P, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Presneau, N, Rack, B, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Lubinski, J, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teras, LR, Terry, MB, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Hurson, AN, Winqvist, R, Wolk, A, Ziogas, A, Brauch, H, Garcia-Closas, M, Pharoah, PDP, Easton, DF, Chenevix-Trench, G, Schmidt, MK, Morra, A, Escala-Garcia, M, Beesley, J, Keeman, R, Canisius, S, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Augustinsson, A, Freeman, LEB, Becher, H, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brenner, H, Bruening, T, Buys, SS, Caan, B, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Cheng, T-YD, Clarke, CL, Colonna, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Dork, T, Dossus, L, Dunning, AM, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, Gago-Dominguez, M, Garcia-Saenz, JA, Giles, GG, Grip, M, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Hartikainen, JM, Hartmann, A, He, W, Hooning, MJ, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, Janni, W, John, EM, Jung, AY, Kaaks, R, Keupers, M, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Linet, M, Luben, RN, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, Michailidou, K, Milne, RL, Mulligan, AM, Muranen, TA, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Olshan, AF, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peissel, B, Peterlongo, P, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Presneau, N, Rack, B, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Lubinski, J, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teras, LR, Terry, MB, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Hurson, AN, Winqvist, R, Wolk, A, Ziogas, A, Brauch, H, Garcia-Closas, M, Pharoah, PDP, Easton, DF, Chenevix-Trench, G, and Schmidt, MK
Abstract: BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast
Published: 2021

6. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Morra, A. (Anna), Escala-Garcia, M. (Maria), Beesley, J. (Jonathan), Keeman, R. (Renske), Canisius, S. (Sander), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Auer, P. L. (Paul L.), Augustinsson, A. (Annelie), Freeman, L. E. (Laura E. Beane), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Brenner, H. (Hermann), Bruening, T. (Thomas), Buys, S. S. (Saundra S.), Caan, B. (Bette), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Cheng, T. D. (Ting-Yuan David), Clarke, C. L. (Christine L.), Colonna, S. V. (Sarah, V), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Dennis, J. (Joe), Dork, T. (Thilo), Dossus, L. (Laure), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Flyger, H. (Henrik), Fritschi, L. (Lin), Gago-Dominguez, M. (Manuela), Garcia-Saenz, J. A. (Jose A.), Giles, G. G. (Graham G.), Grip, M. (Mervi), Guenel, P. (Pascal), Guendert, M. (Melanie), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hart, S. N. (Steven N.), Hartikainen, J. M. (Jaana M.), Hartmann, A. (Arndt), He, W. (Wei), Hooning, M. J. (Maartje J.), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Howell, A. (Anthony), Hunter, D. J. (David J.), Jager, A. (Agnes), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Jung, A. Y. (Audrey Y.), Kaaks, R. (Rudolf), Keupers, M. (Machteld), Kitahara, C. M. (Cari M.), Koutros, S. (Stella), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kurian, A. W. (Allison W.), Lacey, J. V. (James, V), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lindblom, A. (Annika), Linet, M. (Martha), Luben, R. N. (Robert N.), Lush, M. (Michael), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Martens, J. W. (John W. M.), Martinez, M. E. (Maria Elena), Mavroudis, D. (Dimitrios), Michailidou, K. (Kyriaki), Milne, R. L. (Roger L.), Mulligan, A. M. (Anna Marie), Muranen, T. A. (Taru A.), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Olshan, A. F. (Andrew F.), Olsson, H. (Hakan), Orr, N. (Nick), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peissel, B. (Bernard), Peterlongo, P. (Paolo), Plaseska-Karanfilska, D. (Dijana), Prajzendanc, K. (Karolina), Prentice, R. (Ross), Presneau, N. (Nadege), Rack, B. (Brigitte), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Rhenius, V. (Valerie), Romero, A. (Atocha), Roylance, R. (Rebecca), Lubinski, J. (Jan), Ruebner, M. (Matthias), Saloustros, E. (Emmanouil), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Scott, C. (Christopher), Shah, M. (Mitul), Smichkoska, S. (Snezhana), Southey, M. C. (Melissa C.), Stone, J. (Jennifer), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Truong, T. (Therese), Vachon, C. M. (Celine M.), Wang, Q. (Qin), Hurson, A. N. (Amber N.), Winqvist, R. (Robert), Wolk, A. (Alicja), Ziogas, A. (Argyrios), Brauch, H. (Hiltrud), Garcia-Closas, M. (Montserrat), Pharoah, P. D. (Paul D. P.), Easton, D. F. (Douglas F.), Chenevix-Trench, G. (Georgia), Schmidt, M. K. (Marjanka K.), Morra, A. (Anna), Escala-Garcia, M. (Maria), Beesley, J. (Jonathan), Keeman, R. (Renske), Canisius, S. (Sander), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Auer, P. L. (Paul L.), Augustinsson, A. (Annelie), Freeman, L. E. (Laura E. Beane), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Brenner, H. (Hermann), Bruening, T. (Thomas), Buys, S. S. (Saundra S.), Caan, B. (Bette), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Cheng, T. D. (Ting-Yuan David), Clarke, C. L. (Christine L.), Colonna, S. V. (Sarah, V), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Dennis, J. (Joe), Dork, T. (Thilo), Dossus, L. (Laure), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Flyger, H. (Henrik), Fritschi, L. (Lin), Gago-Dominguez, M. (Manuela), Garcia-Saenz, J. A. (Jose A.), Giles, G. G. (Graham G.), Grip, M. (Mervi), Guenel, P. (Pascal), Guendert, M. (Melanie), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hart, S. N. (Steven N.), Hartikainen, J. M. (Jaana M.), Hartmann, A. (Arndt), He, W. (Wei), Hooning, M. J. (Maartje J.), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Howell, A. (Anthony), Hunter, D. J. (David J.), Jager, A. (Agnes), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Jung, A. Y. (Audrey Y.), Kaaks, R. (Rudolf), Keupers, M. (Machteld), Kitahara, C. M. (Cari M.), Koutros, S. (Stella), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kurian, A. W. (Allison W.), Lacey, J. V. (James, V), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lindblom, A. (Annika), Linet, M. (Martha), Luben, R. N. (Robert N.), Lush, M. (Michael), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Martens, J. W. (John W. M.), Martinez, M. E. (Maria Elena), Mavroudis, D. (Dimitrios), Michailidou, K. (Kyriaki), Milne, R. L. (Roger L.), Mulligan, A. M. (Anna Marie), Muranen, T. A. (Taru A.), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Olshan, A. F. (Andrew F.), Olsson, H. (Hakan), Orr, N. (Nick), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peissel, B. (Bernard), Peterlongo, P. (Paolo), Plaseska-Karanfilska, D. (Dijana), Prajzendanc, K. (Karolina), Prentice, R. (Ross), Presneau, N. (Nadege), Rack, B. (Brigitte), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Rhenius, V. (Valerie), Romero, A. (Atocha), Roylance, R. (Rebecca), Lubinski, J. (Jan), Ruebner, M. (Matthias), Saloustros, E. (Emmanouil), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Scott, C. (Christopher), Shah, M. (Mitul), Smichkoska, S. (Snezhana), Southey, M. C. (Melissa C.), Stone, J. (Jennifer), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Truong, T. (Therese), Vachon, C. M. (Celine M.), Wang, Q. (Qin), Hurson, A. N. (Amber N.), Winqvist, R. (Robert), Wolk, A. (Alicja), Ziogas, A. (Argyrios), Brauch, H. (Hiltrud), Garcia-Closas, M. (Montserrat), Pharoah, P. D. (Paul D. P.), Easton, D. F. (Douglas F.), Chenevix-Trench, G. (Georgia), and Schmidt, M. K. (Marjanka K.)
Abstract: Background: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP & 0.15). Results: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E−08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E−07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E−08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E−08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic varia
Published: 2021

7. 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

8. 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

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

Author: Fachal, L., Aschard, H., Beesley, J., Barnes, D.R., Allen, J., Kar, S., Pooley, K.A., Dennis, J., Michailidou, K., Turman, C., Soucy, P., Lemaçon, A., Lush, M., Tyrer, J.P., Ghoussaini, M., Marjaneh, M.M., Jiang, X., Agata, S., Aittomäki, 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., Balmaña, J., Barkardottir, R.B., Barrowdale, D., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Białkowska, 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., Brüning, T., Burwinkel, B., Buys, S.S., Cai, Q., Caldés, T., Caligo, M.A., Camp, N.J., Campbell, I., Canzian, F., Carroll, J.S., 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., Révillion, 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., Bézieau, 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., Collée, 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., Dörk, 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., García-Sáenz, J.A., Gaudet, M.M., Georgoulias, V., Giles, G., Glendon, G., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., González-Neira, A., Tibiletti, M.G., Greene, M.H., Grip, M., Gronwald, J., Grundy, A., Guénel, P., Hahnen, E., Haiman, C.A., Håkansson, 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., Scott, C., Amor, D., Marsh, D., Edkins, E., Salisbury, E., Haan, E., Neidermayr, E., Macrea, F., Farshid, G., Lindeman, G., Chenevix-Trench, G., Mann, G., Gill, G., Thorne, H., Hickie, I., Winship, I., Flanagan, J., Kollias, J., Visvader, J., Stone, J., Taylor, J., Burke, J., Saunus, J., Forbes, J., Kirk, J., French, J., Tucker, K., Wu, K., Phillips, K., Lipton, L., Andrews, L., Lobb, L., Kentwell, M., Spurdle, M., Cummings, M., Gleeson, M., Harris, 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., van Deurzen, C., Obdeijn, I.-M., van den Ouweland, A., Seynaeve, C., Siesling, S., Verloop, J., van Asperen, C.J., 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., James, P.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., 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., Lubiński, 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., Muñoz-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., Pylkäs, K., Radice, P., Ramus, S.J., Rantala, J., Rau-Murthy, R., Rennert, G., Risch, H.A., Robson, M., Romero, A., Rossing, M., Saloustros, E., Sánchez-Herrero, E., Sandler, D.P., Santamariña, M., Sawyer, E.J., Scheuner, M.T., Schmidt, D.F., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Schöttker, B., Schürmann, P., Scott, R.J., Senter, L., Seynaeve, C.M., Shah, M., Sharma, P., Shen, C.-Y., Shu, X.-O., Singer, C.F., Slavin, T.P., Smichkoska, S., Southey, M.C., Spinelli, J.J., Spurdle, A.B., Sutter, C., Swerdlow, A.J., Tamimi, R.M., Tan, Y.Y., Tapper, W.J., Taylor, J.A., Teixeira, M.R., Tengström, M., Teo, S.H., Terry, M.B., Teulé, A., Thomassen, M., Thull, D.L., Toland, A.E., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Torres-Mejía, 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., García-Closas, M., Schmidt, M.K., Kristensen, V.N., French, J.D., Edwards, S.L., Antoniou, A.C., Simard, J., Easton, D.F., Kraft, P., Dunning, A.M., Collaborators, GEMO Study, Collaborators, EMBRACE, Investigators, KConFab, Investigators, HEBON, Investigators, ABCTB, Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R, Duijf, Pascal, Dunning, Alison M, GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, MUMC+: MA Medische Oncologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), European Commission, Government of Canada, Canadian Institutes of Health Research, National Institutes of Health (US), Cancer Research UK, Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, University of Cambridge [UK] (CAM), NSCAD, University of Cyprus [Nicosia], Harvard T.H. Chan School of Public Health, This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie de la Science et de l’Innovation du Québec’ (through Genome Québec) and the Quebec Breast Cancer Foundation), the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492), and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note., We thank all of the individuals who took part in these studies, as well as all of the researchers, clinicians, technicians and administrative staff who enabled this work to be carried out, European Project: 656144,H2020,H2020-MSCA-IF-2014,RADIOGENFF(2016), European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), European Project: 633784,H2020,H2020-PHC-2014-two-stage,B-CAST(2015), European Project: 634935,H2020,H2020-PHC-2014-two-stage,BRIDGES(2015), Clinical Genetics, Medical Oncology, Pathology, Radiology & Nuclear Medicine, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Cyprus [Nicosia] (UCY), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Life Course Epidemiology (LCE), Targeted Gynaecologic Oncology (TARGON), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Aschard, Hugues [0000-0002-7554-6783], Barnes, Daniel R [0000-0002-3781-7570], Dennis, Joe [0000-0003-4591-1214], Michailidou, Kyriaki [0000-0001-7065-1237], Lemaçon, Audrey [0000-0002-1817-7029], Andrulis, Irene L [0000-0002-4226-6435], Arason, Adalgeir [0000-0003-0480-886X], Arndt, Volker [0000-0001-9320-8684], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Bojesen, Stig E [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Campbell, Ian [0000-0002-7773-4155], Carroll, Jason S [0000-0003-3643-0080], Claes, Kathleen BM [0000-0003-0841-7372], Collée, J Margriet [0000-0002-9272-9346], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dwek, Miriam [0000-0001-7184-2932], Fletcher, Olivia [0000-0001-9387-7116], Floris, Giuseppe [0000-0003-2391-5425], Foulkes, William D [0000-0001-7427-4651], García-Sáenz, José A [0000-0001-6880-0301], Greene, Mark H [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Heemskerk-Gerritsen, Bernadette AM [0000-0002-9724-6693], Hollestelle, Antoinette [0000-0003-1166-1966], Hulick, Peter J [0000-0001-8397-4078], Jakimovska, Milena [0000-0002-1506-0669], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Konstantopoulou, Irene [0000-0002-0470-0309], Leslie, Goska [0000-0001-5756-6222], Lesueur, Fabienne [0000-0001-7404-4549], Matsuo, Keitaro [0000-0003-1761-6314], McLean, Catriona [0000-0002-0302-5727], Miller, Austin [0000-0001-9739-8462], Muir, Kenneth [0000-0001-6429-988X], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Orr, Nick [0000-0003-2866-942X], Pankratz, V Shane [0000-0002-3742-040X], Parsons, Michael T [0000-0003-3242-8477], Paul, James [0000-0001-7367-5816], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Robson, Mark [0000-0002-3109-1692], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher [0000-0003-1340-0647], Scott, Rodney J [0000-0001-7724-3404], Spurdle, Amanda B [0000-0003-1337-7897], Stone, Jennifer [0000-0001-5077-0124], Sutter, Christian [0000-0003-4051-5888], Tan, Yen Yen [0000-0003-1063-5352], Teixeira, Manuel R [0000-0002-4896-5982], Toland, Amanda E [0000-0002-0271-1792], Tomlinson, Ian [0000-0003-3037-1470], Viel, Alessandra [0000-0003-2804-0840], Vijai, Joseph [0000-0002-7933-151X], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Pharoah, Paul DP [0000-0001-8494-732X], Schmidt, Marjanka K [0000-0002-2228-429X], Milne, Roger L [0000-0001-5764-7268], Edwards, Stacey L [0000-0001-7428-4139], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F [0000-0003-2444-3247], Kraft, Peter [0000-0002-4472-8103], Dunning, Alison M [0000-0001-6651-7166], Apollo - University of Cambridge Repository, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Human genetics, CCA - Cancer biology and immunology, Molecular cell biology and Immunology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Doctoral Programme in Clinical Research, Staff Services, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology
Subjects: CHROMATIN, Linkage disequilibrium, Genome-wide association study, Regulatory Sequences, Nucleic Acid, Genome-wide association studies, Linkage Disequilibrium, Basic medicine, 0302 clinical medicine, Breast cancer, MESH: Risk Factors, Risk Factors, COMPREHENSIVE MOLECULAR PORTRAITS, 11 Medical and Health Sciences, HEBON Investigators, Genetics & Heredity, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], PROTEIN FUNCTION, Tumor, breast tumor, MESH: Polymorphism, Single Nucleotide, 1184 Genetics, developmental biology, physiology, MESH: Genetic Predisposition to Disease, apoptosis, Chromosome Mapping, Single Nucleotide, 3. Good health, MESH: Linkage Disequilibrium, Female, MESH: Biomarkers, Tumor, Biomarkers, Tumor/genetics, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, MESH: Bayes Theorem, Quantitative Trait Loci, ABCTB Investigators, INTEGRATIVE ANALYSIS, Breast Neoplasms, Computational biology, Biology, Quantitative trait locus, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, ENHANCER, GEMO Study Collaborators, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, REVEALS, Genetics, Biomarkers, Tumor, MESH: Regulatory Sequences, Nucleic Acid, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, FUNCTIONAL VARIANTS, EMBRACE Collaborators, Gene, 030304 developmental biology, Genetic association, Bayes Theorem, Genome-Wide Association Study, MESH: Humans, Science & Technology, Nucleic Acid, gene mapping, 06 Biological Sciences, MESH: Quantitative Trait Loci, DNA binding site, ESTROGEN-RECEPTOR, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Clinical medicine, Expression quantitative trait loci, MESH: Genome-Wide Association Study, Human genome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, KConFab Investigators, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Chromosome Mapping, Chromosome Mapping/methods, Regulatory Sequences, MESH: Female, Biomarkers, 030217 neurology & neurosurgery, MESH: Breast Neoplasms, Developmental Biology
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., This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie de la Science et de l’Innovation du Québec’ (through Genome Québec) and the Quebec Breast Cancer Foundation); the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE; part of the GAME-ON initiative).
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. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Author: Feng, H. (Helian), Gusev, A. (Alexander), Pasaniuc, B. (Bogdan), Wu, L. (Lang), Long, J. (Jirong), Abu-full, Z. (Zomoroda), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene L.), Anton-Culver, H. (Hoda), Antoniou, A.C. (Antonis C.), Arason, A. (Adalgeir), Arndt, V. (Volker), Aronson, K.J. (Kristan J.), Arun, B.K. (Banu), Asseryanis, E. (Ella), Auer, P.L. (Paul L.), Azzollini, J., Balmaña, J. (Judith), Barkardottir, R.B. (Rosa B.), Barnes, D. (Daniel), Barrowdale, D. (Daniel), Beckmann, M.W. (Matthias), Behrens, T.W. (Timothy), Benítez, J. (Javier), Bermisheva, M. (Marina), Białkowska, K. (Katarzyna), Blanco, A. (Ana), Blomqvist, C. (Carl), Boeckx, B. (Bram), Bogdanova, N.V. (Natalia V.), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borg, Å. (Åke), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Briceno, I. (Ignacio), Broeks, A. (Annegien), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Canisius, S. (Sander), Campa, D. (Daniele), Carter, B.D. (Brian D.), Carter, J. (Jonathan), Castelao, J.E. (Jose ), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Christiansen, H. (Hans), Chung, W. (Wendy), Claes, K.B.M. (Kathleen B. M.), Clarke, C. (Christine), Couch, F.J. (Fergus), Cox, A. (Angela), Cross, S.S. (Simon S.), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary), de la Hoya, M. (Miguel), De Leeneer, K. (Kim), Dennis, J. (Joe), Devilee, P. (Peter), Diez, O. (Orland), Domchek, S.M. (Susan), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, 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), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fostira, F. (Florentia), Friedman, E. (Eitan), Fritschi, L. (Lin), Frost, D. (Debra), Gabrielson, M. (Marike), Ganz, P.A. (Patricia A.), Gapstur, S.M. (Susan M.), Garber, J. (Judy), García-Closas, M. (Montserrat), García-Sáenz, J.A. (José A.), Gaudet, M.M. (Mia M.), Giles, G.G. (Graham G.), Glendon, G. (Gord), Godwin, A.K. (Andrew), Goldberg, M.S. (Mark), Radice, P. (Paolo), González-Neira, A. (Anna), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Guénel, P. (Pascal), Haiman, C.A. (Christopher), Hall, P. (Per), Hamann, U. (Ute), Hake, C. (Christopher), He, W. (Wei), Heyworth, J. (Jane), Hogervorst, F.B.L. (Frans B.L.), Hollestelle, A. (Antoinette), Hooning, M.J. (Maartje J.), Hoover, R.N. (Robert), Hopper, J.L. (John), Huang, G. (Guanmengqian), Hulick, P.J. (Peter J.), Humphreys, K. (Keith), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, M. (Margaret), Janavicius, R. (Ramunas), Jankowitz, R.C. (Rachel C.), John, E.M. (Esther), Johnson, N. (Nichola), Joseph, V. (Vijai), Jung, A. (Audrey), Karlan, B.Y. (Beth), Khusnutdinova, E.K. (Elza), Kiiski, J.I. (Johanna I.), Konstantopoulou, I. (Irene), Kristensen, V. (Vessela), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lázaro, C. (Conxi), Leroux, D. (Dominique), Leslie, G. (Goska), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindor, N.M. (Noralane), Lindström, S. (Sara), Lo, W.-Y. (Wing-Yee), Loud, J.T. (Jennifer T.), Lubinski, J. (Jan), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martens, J.W.M. (John), Martinez, M.E. (Maria E.), Matricardi, L. (Laura), Maurer, T. (Tabea), Mavroudis, D. (Dimitris), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menon, U. (Usha), Michailidou, K. (Kyriaki), Kapoor, P.M. (Pooja M.), Miller, A. (Austin), Montagna, M. (Marco), Moreno, F. (Fernando), Moserle, L. (Lidia), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru A.), Nathanson, K.L. (Katherine), Floris, O.A.M., Nevanlinna, H. (Heli), Nevelsteen, I. (Ines), Nielsen, F. (Finn), Nikitina-Zake, L. (Liene), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olofunmilayo), Olsson, H. (Håkan), Osorio, A. (Ana), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. (Marilyn), Pedersen, I.S. (Inge S.), Peixoto, A. (Ana), Peterlongo, P. (Paolo), Peto, J. (Julian), Pharoah, P.D.P. (Paul), Phillips, K.-A. (Kelly-Anne), Plaseska-Karanfilska, D. (Dijana), Poppe, B. (Bruce), Pradhan, N. (Nisha), Prajzendanc, K. (Karolina), Presneau, N. (Nadege), Punie, K. (Kevin), Pylkäs, K. (Katri), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Risch, H.A. (Harvey A.), Robson, M. (Mark), Romero, A. (Atocha), Saloustros, E. (Emmanouil), Sandler, D.P. (Dale P.), Santos, C. (Catarina), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Schmidt, D.F. (Daniel), Schmutzler, R.K. (Rita), Schoemaker, M.J. (Minouk J.), Scott, R.J. (Rodney), Sharma, P. (Priyanka), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Singer, C.F. (Christian), Skytte, A.-B. (Anne-Bine), Soucy, P. (Penny), Southey, M.C. (Melissa), Spinelli, J.J. (John J.), Spurdle, A.B. (Amanda), Stone, J. (Jennifer), Swerdlow, A.J. (Anthony ), Tapper, W.J. (William J.), Taylor, J.A. (Jack A.), Teixeira, P.J., Terry, M.B. (Mary Beth), Teulé, A. (Alex), Thomassen, M. (Mads), Thöne, K. (Kathrin), Thull, D.L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Torres, D. (Diana), Truong, T. (Thérèse), Tung, N. (Nadine), Vachon, C. (Celine), van Asperen, C.J. (Christi J.), Ouweland, A.M.W. (Ans) van den, Rensburg, E.J. (Elizabeth) van, Vega, A. (Ana), Viel, A. (Alessandra), Vieiro-Balo, P. (Paula), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wendt, C. (Camilla), Winqvist, R. (Robert), Yang, X.R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Milne, R.L. (Roger), Adamo, P. (Pio) d', Chenevix-Trench, G. (Georgia), Zheng, W. (Wei), Kraft, P. (Peter), Jiang, X. (Xia), Feng, H. (Helian), Gusev, A. (Alexander), Pasaniuc, B. (Bogdan), Wu, L. (Lang), Long, J. (Jirong), Abu-full, Z. (Zomoroda), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene L.), Anton-Culver, H. (Hoda), Antoniou, A.C. (Antonis C.), Arason, A. (Adalgeir), Arndt, V. (Volker), Aronson, K.J. (Kristan J.), Arun, B.K. (Banu), Asseryanis, E. (Ella), Auer, P.L. (Paul L.), Azzollini, J., Balmaña, J. (Judith), Barkardottir, R.B. (Rosa B.), Barnes, D. (Daniel), Barrowdale, D. (Daniel), Beckmann, M.W. (Matthias), Behrens, T.W. (Timothy), Benítez, J. (Javier), Bermisheva, M. (Marina), Białkowska, K. (Katarzyna), Blanco, A. (Ana), Blomqvist, C. (Carl), Boeckx, B. (Bram), Bogdanova, N.V. (Natalia V.), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borg, Å. (Åke), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Briceno, I. (Ignacio), Broeks, A. (Annegien), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Canisius, S. (Sander), Campa, D. (Daniele), Carter, B.D. (Brian D.), Carter, J. (Jonathan), Castelao, J.E. (Jose ), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Christiansen, H. (Hans), Chung, W. (Wendy), Claes, K.B.M. (Kathleen B. M.), Clarke, C. (Christine), Couch, F.J. (Fergus), Cox, A. (Angela), Cross, S.S. (Simon S.), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary), de la Hoya, M. (Miguel), De Leeneer, K. (Kim), Dennis, J. (Joe), Devilee, P. (Peter), Diez, O. (Orland), Domchek, S.M. (Susan), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, 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), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fostira, F. (Florentia), Friedman, E. (Eitan), Fritschi, L. (Lin), Frost, D. (Debra), Gabrielson, M. (Marike), Ganz, P.A. (Patricia A.), Gapstur, S.M. (Susan M.), Garber, J. (Judy), García-Closas, M. (Montserrat), García-Sáenz, J.A. (José A.), Gaudet, M.M. (Mia M.), Giles, G.G. (Graham G.), Glendon, G. (Gord), Godwin, A.K. (Andrew), Goldberg, M.S. (Mark), Radice, P. (Paolo), González-Neira, A. (Anna), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Guénel, P. (Pascal), Haiman, C.A. (Christopher), Hall, P. (Per), Hamann, U. (Ute), Hake, C. (Christopher), He, W. (Wei), Heyworth, J. (Jane), Hogervorst, F.B.L. (Frans B.L.), Hollestelle, A. (Antoinette), Hooning, M.J. (Maartje J.), Hoover, R.N. (Robert), Hopper, J.L. (John), Huang, G. (Guanmengqian), Hulick, P.J. (Peter J.), Humphreys, K. (Keith), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, M. (Margaret), Janavicius, R. (Ramunas), Jankowitz, R.C. (Rachel C.), John, E.M. (Esther), Johnson, N. (Nichola), Joseph, V. (Vijai), Jung, A. (Audrey), Karlan, B.Y. (Beth), Khusnutdinova, E.K. (Elza), Kiiski, J.I. (Johanna I.), Konstantopoulou, I. (Irene), Kristensen, V. (Vessela), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lázaro, C. (Conxi), Leroux, D. (Dominique), Leslie, G. (Goska), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindor, N.M. (Noralane), Lindström, S. (Sara), Lo, W.-Y. (Wing-Yee), Loud, J.T. (Jennifer T.), Lubinski, J. (Jan), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martens, J.W.M. (John), Martinez, M.E. (Maria E.), Matricardi, L. (Laura), Maurer, T. (Tabea), Mavroudis, D. (Dimitris), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menon, U. (Usha), Michailidou, K. (Kyriaki), Kapoor, P.M. (Pooja M.), Miller, A. (Austin), Montagna, M. (Marco), Moreno, F. (Fernando), Moserle, L. (Lidia), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru A.), Nathanson, K.L. (Katherine), Floris, O.A.M., Nevanlinna, H. (Heli), Nevelsteen, I. (Ines), Nielsen, F. (Finn), Nikitina-Zake, L. (Liene), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olofunmilayo), Olsson, H. (Håkan), Osorio, A. (Ana), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. (Marilyn), Pedersen, I.S. (Inge S.), Peixoto, A. (Ana), Peterlongo, P. (Paolo), Peto, J. (Julian), Pharoah, P.D.P. (Paul), Phillips, K.-A. (Kelly-Anne), Plaseska-Karanfilska, D. (Dijana), Poppe, B. (Bruce), Pradhan, N. (Nisha), Prajzendanc, K. (Karolina), Presneau, N. (Nadege), Punie, K. (Kevin), Pylkäs, K. (Katri), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Risch, H.A. (Harvey A.), Robson, M. (Mark), Romero, A. (Atocha), Saloustros, E. (Emmanouil), Sandler, D.P. (Dale P.), Santos, C. (Catarina), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Schmidt, D.F. (Daniel), Schmutzler, R.K. (Rita), Schoemaker, M.J. (Minouk J.), Scott, R.J. (Rodney), Sharma, P. (Priyanka), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Singer, C.F. (Christian), Skytte, A.-B. (Anne-Bine), Soucy, P. (Penny), Southey, M.C. (Melissa), Spinelli, J.J. (John J.), Spurdle, A.B. (Amanda), Stone, J. (Jennifer), Swerdlow, A.J. (Anthony ), Tapper, W.J. (William J.), Taylor, J.A. (Jack A.), Teixeira, P.J., Terry, M.B. (Mary Beth), Teulé, A. (Alex), Thomassen, M. (Mads), Thöne, K. (Kathrin), Thull, D.L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Torres, D. (Diana), Truong, T. (Thérèse), Tung, N. (Nadine), Vachon, C. (Celine), van Asperen, C.J. (Christi J.), Ouweland, A.M.W. (Ans) van den, Rensburg, E.J. (Elizabeth) van, Vega, A. (Ana), Viel, A. (Alessandra), Vieiro-Balo, P. (Paula), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wendt, C. (Camilla), Winqvist, R. (Robert), Yang, X.R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Milne, R.L. (Roger), Adamo, P. (Pio) d', Chenevix-Trench, G. (Georgia), Zheng, W. (Wei), Kraft, P. (Peter), and Jiang, X. (Xia)
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
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15. 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

16. 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

17. 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, JN, 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, JN, 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

18. Genome-wide association study of germline variants and breast cancer-specific mortality

Author: Escala-Garcia, M., Guo, Q., Dork, T., Canisius, S., Keeman, R., Dennis, J., Beesley, J., Lecarpentier, J., Bolla, M.K., Wang, Q., Abraham, J., Andrulis, I.L., Anton-Culver, H., Arndt, V., Auer, P.L., Beckmann, M.W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Boeckx, B., Bojesen, S.E., Bonanni, B., Borresen-Dale, A.L., Brauch, H., Brenner, H., Brentnall, A., Brinton, L., Broberg, P., Brock, I.W., Brucker, S.Y., Burwinkel, B., Caldas, C., Caldes, T., Campa, D., Canzian, F., Carracedo, A., Carter, B.D., Castelao, J.E., Chang-Claude, J., Chanock, S.J., Chenevix-Trench, G., Cheng, T.Y.D., Chin, S.F., Clarke, C.L., Cordina-Duverger, E., Couch, F.J., Cox, D.G., Cox, A., Cross, S.S., Czene, K., Daly, M.B., Devilee, P., Dunn, J.A., Dunning, A.M., Durcan, L., Dwek, M., Earl, H.M., Ekici, A.B., Eliassen, A.H., Ellberg, C., Engel, C., Eriksson, M., Evans, D.G., Figueroa, J., Flesch-Janys, D., Flyger, H., Gabrielson, M., Gago-Dominguez, M., Galle, E., Gapstur, S.M., Garcia-Closas, M., Garcia-Saenz, J.A., Gaudet, M.M., George, A., Georgoulias, V., Giles, G.G., Glendon, G., Goldgar, D.E., Gonzalez-Neira, A., Alnaes, G.I.G., Grip, M., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C.A., Hakansson, N., Hall, P., Hamann, U., Hankinson, S., Harkness, E.F., Harrington, P.A., Hart, S.N., Hartikainen, J.M., Hein, A., Hillemanns, P., Hiller, L., Holleczek, B., Hollestelle, A., Hooning, M.J., Hoover, R.N., Hopper, J.L., Howell, A., Huang, G.M.Q., Humphreys, K., Hunter, D.J., Janni, W., John, E.M., Jones, M.E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kabisch, M., Kaczmarek, K., Kerin, M.J., Khan, S., Khusnutdinova, E., Kiiski, J.I., Kitahara, C.M., Knight, J.A., Ko, Y.D., Koppert, L.B., Kosma, V.M., Kraft, P., Kristensen, V.N., Kruger, U., Kuhl, T., Lambrechts, D., Marchand, L. le, Lee, E., Lejbkowicz, F., Li, L., Lindblom, A., Lindstrom, S., Linet, M., Lissowska, J., W.Y. lo, Loibl, S., Lubinski, J., Lux, M.P., MacInnis, R.J., Maierthaler, M., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Mavroudis, D., McLean, C., Meindl, A., Middha, P., Miller, N., Milne, R.L., Moreno, F., Mulligan, A.M., Mulot, C., Nassir, R., Neuhausen, S.L., Newman, W.T., Nielsen, S.F., Nordestgaard, B.G., Norman, A., Olsson, H., Orr, N., Pankratz, V.S., Park-Simon, T.W., Perez, J.I.A., Perez-Barrios, C., Peterlongo, P., Petridis, C., Pinchev, M., Prajzendanc, K., Prentice, R., Presneau, N., Prokofieva, D., Pylkas, K., Rack, B., Radice, P., Ramachandran, D., Rennert, G., Rennert, H.S., Rhenius, V., Romero, A., Roylance, R., Saloustros, E., Sawyer, E.J., Schmidt, D.F., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Schumacher, F., Schwentner, L., Scott, R.J., Scott, C., Seynaeve, C., Shah, M., Simard, J., Smeets, A., Sohn, C., Southey, M.C., Swerdlow, A.J., Talhouk, A., Tamimi, R.M., Tapper, W.J., Teixeira, M.R., Tengstrom, M., Terry, M.B., Thone, K., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Truong, T., Turman, C., Turnbull, C., Ulmer, H.U., Untch, M., Vachon, C., Asperen, C.J. van, Ouweland, A.M.W. van den, Veen, E.M. van, Wendt, C., Whittemore, A.S., Willett, W., Winqvist, R., Wolk, A., Yang, X.R., Zhang, Y., Easton, D.F., Fasching, P.A., Nevanlinna, H., Eccles, D.M., Pharoah, P.D.P., Schmidt, M.K., and NBCS Collaborators
Abstract: BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using similar to 10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).RESULTS: We did not find any variant associated with breast cancer-specific mortality at P
Published: 2019

19. Genome-wide association study of germline variants and breast cancer-specific mortality

Author: Escala-Garcia, M. (Maria), Guo, Q. (Qi), Doerk, T. (Thilo), Canisius, S. (Sander), Keeman, R. (Renske), Dennis, J. (Joe), Beesley, J. (Jonathan), Lecarpentier, J. (Julie), Bolla, M. K. (Manjeet K.), Wang, Q. (Qin), Abraham, J. (Jean), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Auer, P. L. (Paul L.), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bernstein, L. (Leslie), Blomqvist, C. (Carl), Boeckx, B. (Bram), Bojesen, S. E. (Stig E.), Bonanni, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brentnall, A. (Adam), Brinton, L. (Louise), Broberg, P. (Per), Brock, I. W. (Ian W.), Brucker, S. Y. (Sara Y.), Burwinkel, B. (Barbara), Caldas, C. (Carlos), Caldes, T. (Trinidad), Campa, D. (Daniele), Canzian, F. (Federico), Carracedo, A. (Angel), Carter, B. D. (Brian D.), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Cheng, T. D. (Ting-Yuan David), Chin, S.-F. (Suet-Feung), Clarke, C. L. (Christine L.), Cordina-Duverger, E. (Emilie), Couch, F. J. (Fergus J.), Cox, D. G. (David G.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Dunn, J. A. (Janet A.), Dunning, A. M. (Alison M.), Durcan, L. (Lorraine), Dwek, M. (Miriam), Earl, H. M. (Helena M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Figueroa, J. (Jonine), Flesch-Janys, D. (Dieter), Flyger, H. (Henrik), Gabrielson, M. (Marike), Gago-Dominguez, M. (Manuela), Galle, E. (Eva), Gapstur, S. M. (Susan M.), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), George, A. (Angela), Georgoulias, V. (Vassilios), Giles, G. G. (Graham G.), Glendon, G. (Gord), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Alnaes, G. I. (Grethe I. Grenaker), Grip, M. (Mervi), Guenel, P. (Pascal), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hankinson, S. (Susan), Harkness, E. F. (Elaine F.), Harrington, P. A. (Patricia A.), Hart, S. N. (Steven N.), Hartikainen, J. M. (Jaana M.), Hein, A. (Alexander), Hillemanns, P. (Peter), Hiller, L. (Louise), Holleczek, B. (Bernd), Hollestelle, A. (Antoinette), Hooning, M. J. (Maartje J.), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Howell, A. (Anthony), Huang, G. (Guanmengqian), Humphreys, K. (Keith), Hunter, D. J. (David J.), Janni, W. (Wolfgang), John, E. M. (Esther M.), Jones, M. E. (Michael E.), Jukkola-Vuorinen, A. (Arja), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kabisch, M. (Maria), Kaczmarek, K. (Katarzyna), Kerin, M. J. (Michael J.), Khan, S. (Sofia), Khusnutdinova, E. (Elza), Kiiski, J. I. (Johanna, I), Kitahara, C. M. (Cari M.), Knight, J. A. (Julia A.), Ko, Y.-D. (Yon-Dschun), Koppert, L. B. (Linetta B.), Kosma, V.-M. (Veli-Matti), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kruger, U. (Ute), Kuehl, T. (Tabea), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lee, E. (Eunjung), Lejbkowicz, F. (Flavio), Li, L. (Lian), Lindblom, A. (Annika), Lindstrom, S. (Sara), Linet, M. (Martha), Lissowska, J. (Jolanta), Lo, W.-Y. (Wing-Yee), Loibl, S. (Sibylle), Lubinski, J. (Jan), Lux, M. P. (Michael P.), MacInnis, R. J. (Robert J.), Maierthaler, M. (Melanie), Maishman, T. (Tom), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martinez, M. E. (Maria Elena), Mavroudis, D. (Dimitrios), McLean, C. (Catriona), Meindl, A. (Alfons), Middha, P. (Pooja), Miller, N. (Nicola), Milne, R. L. (Roger L.), Moreno, F. (Fernando), Mulligan, A. M. (Anna Marie), Mulot, C. (Claire), Nassir, R. (Rami), Neuhausen, S. L. (Susan L.), Newman, W. T. (William T.), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Norman, A. (Aaron), Olsson, H. (Hakan), Orr, N. (Nick), Pankratz, V. S. (V. Shane), Park-Simon, T.-W. (Tjoung-Won), Perez, J. I. (Jose I. A.), Perez-Barrios, C. (Clara), Peterlongo, P. (Paolo), Petridis, C. (Christos), Pinchev, M. (Mila), Prajzendanc, K. (Karoliona), Prentice, R. (Ross), Presneau, N. (Nadege), Prokofieva, D. (Darya), Pylkas, K. (Katri), Rack, B. (Brigitte), Radice, P. (Paolo), Ramachandran, D. (Dhanya), Rennert, G. (Gadi), Rennert, H. S. (Hedy S.), Rhenius, V. (Valerie), Romero, A. (Atocha), Roylance, R. (Rebecca), Saloustros, E. (Emmanouil), Sawyer, E. J. (Elinor J.), Schmidt, D. F. (Daniel F.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Schoemaker, M. J. (Minouk J.), Schumacher, F. (Fredrick), Schwentner, L. (Lukas), Scott, R. J. (Rodney J.), Scott, C. (Christopher), Seynaeve, C. (Caroline), Shah, M. (Mitul), Simard, J. (Jacques), Smeets, A. (Ann), Sohn, C. (Christof), Southey, M. C. (Melissa C.), Swerdlow, A. J. (Anthony J.), Talhouk, A. (Aline), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Teixeira, M. R. (Manuel R.), Tengstrom, M. (Maria), Terry, M. B. (Mary Beth), Thoene, K. (Kathrin), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Torres, D. (Diana), Truong, T. (Therese), Turman, C. (Constance), Turnbull, C. (Clare), Ulmer, H.-U. (Hans-Ulrich), Untch, M. (Michael), Vachon, C. (Celine), van Asperen, C. J. (Christi J.), van den Ouweland, A. M. (Ans M. W.), van Veen, E. M. (Elke M.), Wendt, C. (Camilla), Whittemore, A. S. (Alice S.), Willett, W. (Walter), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Zhang, Y. (Yan), Easton, D. F. (Douglas F.), Fasching, P. A. (Peter A.), Nevanlinna, H. (Heli), Eccles, D. M. (Diana M.), Pharoah, P. D. (Paul D. P.), and Schmidt, M. K. (Marjanka K.)
Abstract: Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10−8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10−7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10−7, HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP
Published: 2019

20. Genome-wide association study of germline variants and breast cancer-specific mortality.

Author: Garcia-Closas M., Moreno F., Mulligan A.M., Mulot C., Nassir R., Neuhausen S.L., Newman W.T., Nielsen S.F., Nordestgaard B.G., Norman A., Olsson H., Orr N., Pankratz V.S., Park-Simon T.-W., Perez J.I.A., Perez-Barrios C., Peterlongo P., Petridis C., Pinchev M., Prajzendanc K., Prentice R., Presneau N., Prokofieva D., Pylkas K., Rack B., Radice P., Ramachandran D., Rennert G., Rennert H.S., Rhenius V., Romero A., Roylance R., Saloustros E., Sawyer E.J., Schmidt D.F., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Schumacher F., Schwentner L., Scott R.J., Scott C., Seynaeve C., Shah M., Simard J., Smeets A., Sohn C., Southey M.C., Swerdlow A.J., Talhouk A., Tamimi R.M., Tapper W.J., Teixeira M.R., Tengstrom M., Terry M.B., Thone K., Tollenaar R.A.E.M., Tomlinson I., Torres D., Truong T., Turman C., Turnbull C., Ulmer H.-U., Untch M., Vachon C., van Asperen C.J., van den Ouweland A.M.W., van Veen E.M., Wendt C., Whittemore A.S., Willett W., Winqvist R., Wolk A., Yang X.R., Zhang Y., Easton D.F., Fasching P.A., Nevanlinna H., Eccles D.M., Pharoah P.D.P., Schmidt M.K., Escala-Garcia M., Guo Q., Dork T., Canisius S., Keeman R., Dennis J., Beesley J., Lecarpentier J., Bolla M.K., Wang Q., Abraham J., Andrulis I.L., Anton-Culver H., Arndt V., Auer P.L., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bernstein L., Blomqvist C., Boeckx B., Bojesen S.E., Bonanni B., Borresen-Dale A.-L., Brauch H., Brenner H., Brentnall A., Brinton L., Broberg P., Brock I.W., Brucker S.Y., Burwinkel B., Caldas C., Caldes T., Campa D., Canzian F., Carracedo A., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Chenevix-Trench G., Cheng T.-Y.D., Chin S.-F., Clarke C.L., Cordina-Duverger E., Couch F.J., Cox D.G., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Dunn J.A., Dunning A.M., Durcan L., Dwek M., Earl H.M., Ekici A.B., Eliassen A.H., Ellberg C., Engel C., Eriksson M., Evans D.G., Figueroa J., Flesch-Janys D., Flyger H., Gabrielson M., Gago-Dominguez M., Galle E., Gapstur S.M., Garcia-Saenz J.A., Gaudet M.M., George A., Georgoulias V., Giles G.G., Glendon G., Goldgar D.E., Gonzalez-Neira A., Alnaes G.I.G., Grip M., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hankinson S., Harkness E.F., Harrington P.A., Hart S.N., Hartikainen J.M., Hein A., Hillemanns P., Hiller L., Holleczek B., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Howell A., Huang G., Humphreys K., Hunter D.J., Janni W., John E.M., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kabisch M., Kaczmarek K., Kerin M.J., Khan S., Khusnutdinova E., Kiiski J.I., Kitahara C.M., Knight J.A., Ko Y.-D., Koppert L.B., Kosma V.-M., Kraft P., Kristensen V.N., Kruger U., Kuhl T., Lambrechts D., Le Marchand L., Lee E., Lejbkowicz F., Li L., Lindblom A., Lindstrom S., Linet M., Lissowska J., Lo W.-Y., Loibl S., Lubinski J., Lux M.P., MacInnis R.J., Maierthaler M., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Mavroudis D., McLean C., Meindl A., Middha P., Miller N., Milne R.L., Garcia-Closas M., Moreno F., Mulligan A.M., Mulot C., Nassir R., Neuhausen S.L., Newman W.T., Nielsen S.F., Nordestgaard B.G., Norman A., Olsson H., Orr N., Pankratz V.S., Park-Simon T.-W., Perez J.I.A., Perez-Barrios C., Peterlongo P., Petridis C., Pinchev M., Prajzendanc K., Prentice R., Presneau N., Prokofieva D., Pylkas K., Rack B., Radice P., Ramachandran D., Rennert G., Rennert H.S., Rhenius V., Romero A., Roylance R., Saloustros E., Sawyer E.J., Schmidt D.F., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Schumacher F., Schwentner L., Scott R.J., Scott C., Seynaeve C., Shah M., Simard J., Smeets A., Sohn C., Southey M.C., Swerdlow A.J., Talhouk A., Tamimi R.M., Tapper W.J., Teixeira M.R., Tengstrom M., Terry M.B., Thone K., Tollenaar R.A.E.M., Tomlinson I., Torres D., Truong T., Turman C., Turnbull C., Ulmer H.-U., Untch M., Vachon C., van Asperen C.J., van den Ouweland A.M.W., van Veen E.M., Wendt C., Whittemore A.S., Willett W., Winqvist R., Wolk A., Yang X.R., Zhang Y., Easton D.F., Fasching P.A., Nevanlinna H., Eccles D.M., Pharoah P.D.P., Schmidt M.K., Escala-Garcia M., Guo Q., Dork T., Canisius S., Keeman R., Dennis J., Beesley J., Lecarpentier J., Bolla M.K., Wang Q., Abraham J., Andrulis I.L., Anton-Culver H., Arndt V., Auer P.L., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bernstein L., Blomqvist C., Boeckx B., Bojesen S.E., Bonanni B., Borresen-Dale A.-L., Brauch H., Brenner H., Brentnall A., Brinton L., Broberg P., Brock I.W., Brucker S.Y., Burwinkel B., Caldas C., Caldes T., Campa D., Canzian F., Carracedo A., Carter B.D., Castelao J.E., Chang-Claude J., Chanock S.J., Chenevix-Trench G., Cheng T.-Y.D., Chin S.-F., Clarke C.L., Cordina-Duverger E., Couch F.J., Cox D.G., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Dunn J.A., Dunning A.M., Durcan L., Dwek M., Earl H.M., Ekici A.B., Eliassen A.H., Ellberg C., Engel C., Eriksson M., Evans D.G., Figueroa J., Flesch-Janys D., Flyger H., Gabrielson M., Gago-Dominguez M., Galle E., Gapstur S.M., Garcia-Saenz J.A., Gaudet M.M., George A., Georgoulias V., Giles G.G., Glendon G., Goldgar D.E., Gonzalez-Neira A., Alnaes G.I.G., Grip M., Guenel P., Haeberle L., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hankinson S., Harkness E.F., Harrington P.A., Hart S.N., Hartikainen J.M., Hein A., Hillemanns P., Hiller L., Holleczek B., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Howell A., Huang G., Humphreys K., Hunter D.J., Janni W., John E.M., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kabisch M., Kaczmarek K., Kerin M.J., Khan S., Khusnutdinova E., Kiiski J.I., Kitahara C.M., Knight J.A., Ko Y.-D., Koppert L.B., Kosma V.-M., Kraft P., Kristensen V.N., Kruger U., Kuhl T., Lambrechts D., Le Marchand L., Lee E., Lejbkowicz F., Li L., Lindblom A., Lindstrom S., Linet M., Lissowska J., Lo W.-Y., Loibl S., Lubinski J., Lux M.P., MacInnis R.J., Maierthaler M., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Mavroudis D., McLean C., Meindl A., Middha P., Miller N., and Milne R.L.
Abstract: Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Method(s): Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Result(s): We did not find any variant associated with breast cancer-specific mortality at P < 5 x 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 x 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 x 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusion(s): We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.Copyright © 2019, The Author(s).
Published: 2019

21. Genome-wide association study of germline variants and breast cancer-specific mortality

Author: Escala-Garcia, M, Guo, Q, Doerk, T, Canisius, S, Keeman, R, Dennis, J, Beesley, J, Lecarpentier, J, Bolla, MK, Wang, Q, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Boeckx, B, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brentnall, A, Brinton, L, Broberg, P, Brock, IW, Brucker, SY, Burwinkel, B, Caldas, C, Caldes, T, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Cheng, T-YD, Chin, S-F, Clarke, CL, Cordina-Duverger, E, Couch, FJ, Cox, DG, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dunn, JA, Dunning, AM, Durcan, L, Dwek, M, Earl, HM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Figueroa, J, Flesch-Janys, D, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Galle, E, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, George, A, Georgoulias, V, Giles, GG, Glendon, G, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, S, Harkness, EF, Harrington, PA, Hart, SN, Hartikainen, JM, Hein, A, Hillemanns, P, Hiller, L, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Janni, W, John, EM, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, J, Kitahara, CM, Knight, JA, Ko, Y-D, Koppert, LB, Kosma, V-M, Kraft, P, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Li, L, Lindblom, A, Lindstrom, S, Linet, M, Lissowska, J, Lo, W-Y, Loibl, S, Lubinski, J, Lux, MP, MacInnis, RJ, Maierthaler, M, Maishman, T, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Middha, P, Miller, N, Milne, RL, Moreno, F, Mulligan, AM, Mulot, C, Nassir, R, Neuhausen, SL, Newman, WT, Nielsen, SF, Nordestgaard, BG, Norman, A, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Petridis, C, Pinchev, M, Prajzendanc, K, Prentice, R, Presneau, N, Prokofieva, D, Pylkas, K, Rack, B, Radice, P, Ramachandran, D, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Saloustros, E, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schwentner, L, Scott, RJ, Scott, C, Seynaeve, C, Shah, M, Simard, J, Smeets, A, Sohn, C, Southey, MC, Swerdlow, AJ, Talhouk, A, Tamimi, RM, Tapper, WJ, Teixeira, MR, Tengstrom, M, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Turman, C, Turnbull, C, Ulmer, H-U, Untch, M, Vachon, C, van Asperen, CJ, van den Ouweland, AMW, van Veen, EM, Wendt, C, Whittemore, AS, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Zhang, Y, Easton, DF, Fasching, PA, Nevanlinna, H, Eccles, DM, Pharoah, PDP, Schmidt, MK, Escala-Garcia, M, Guo, Q, Doerk, T, Canisius, S, Keeman, R, Dennis, J, Beesley, J, Lecarpentier, J, Bolla, MK, Wang, Q, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Boeckx, B, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brentnall, A, Brinton, L, Broberg, P, Brock, IW, Brucker, SY, Burwinkel, B, Caldas, C, Caldes, T, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Cheng, T-YD, Chin, S-F, Clarke, CL, Cordina-Duverger, E, Couch, FJ, Cox, DG, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dunn, JA, Dunning, AM, Durcan, L, Dwek, M, Earl, HM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Figueroa, J, Flesch-Janys, D, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Galle, E, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, George, A, Georgoulias, V, Giles, GG, Glendon, G, Goldgar, DE, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hankinson, S, Harkness, EF, Harrington, PA, Hart, SN, Hartikainen, JM, Hein, A, Hillemanns, P, Hiller, L, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Janni, W, John, EM, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, J, Kitahara, CM, Knight, JA, Ko, Y-D, Koppert, LB, Kosma, V-M, Kraft, P, Kristensen, VN, Kruger, U, Kuehl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Li, L, Lindblom, A, Lindstrom, S, Linet, M, Lissowska, J, Lo, W-Y, Loibl, S, Lubinski, J, Lux, MP, MacInnis, RJ, Maierthaler, M, Maishman, T, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Middha, P, Miller, N, Milne, RL, Moreno, F, Mulligan, AM, Mulot, C, Nassir, R, Neuhausen, SL, Newman, WT, Nielsen, SF, Nordestgaard, BG, Norman, A, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, T-W, Perez, JIA, Perez-Barrios, C, Peterlongo, P, Petridis, C, Pinchev, M, Prajzendanc, K, Prentice, R, Presneau, N, Prokofieva, D, Pylkas, K, Rack, B, Radice, P, Ramachandran, D, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Saloustros, E, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schwentner, L, Scott, RJ, Scott, C, Seynaeve, C, Shah, M, Simard, J, Smeets, A, Sohn, C, Southey, MC, Swerdlow, AJ, Talhouk, A, Tamimi, RM, Tapper, WJ, Teixeira, MR, Tengstrom, M, Terry, MB, Thoene, K, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Turman, C, Turnbull, C, Ulmer, H-U, Untch, M, Vachon, C, van Asperen, CJ, van den Ouweland, AMW, van Veen, EM, Wendt, C, Whittemore, AS, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Zhang, Y, Easton, DF, Fasching, PA, Nevanlinna, H, Eccles, DM, Pharoah, PDP, and Schmidt, MK
Abstract: BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
Published: 2019

22. Meeting abstracts from the Annual Conference on Hereditary Cancers 2016

Author: Cybulski, C., Kluźniak, W., Huzarski, T., Wokołorczyk, D., Kashyap, A., Jakubowska, A., Szwiec, M., Byrski, T., Dębniak, T., Górski, B., Sopik, V., Akbari, M. R., Sun, P., Gronwald, J., Narod, S. A., Lubiński, J., Dymerska, D., Kurzawski, G., Tutlewska, K., Kuswik, M., Rudnicka, H., Scott, R. J., Billings, R., Pławski, A., Lubinski, J., Gromowski, T., Kąklewski, K., Marciniak, W., Durda, K., Lener, M., Sukiennicki, G., Kaczmarek, K., Jaworska-Bieniek, K., Paszkowska-Szczur, K., Waloszczyk, P., Hemminki, K., Försti, A., Oszurek, O., Gugała, K., Stawicka, M., Morawiec, Z., Mierzwa, T., Falco, M., Janiszewska, H., Kilar, E., Marczyk, E., Kozak-Klonowska, B., Siołek, M., Surdyka, D., Wiśniowski, R., Posmyk, M., Domagała, P., Imyanitov, E. N., Muszyńska, M., Prajzendanc, K., Peruga, N., Morawski, A., Lener, M. R., Baszuk, P., Wiechowska-Kozłowska, A., Kładny, J., Pietrzak, S., Soluch, A., Plawski, A., Rashid, U. R., Naeemi, H., Muhammad, N., Loya, A., Yusuf, M. A., Savanevich, A., Aszurek, O., Mathe, A., Wong-Brown, M., Locke, W., Stirzaker, C., Braye, S. G., Forbes, J. F., Clark, S., Avery-Kiejda, K., Tomiczek-Szwiec, J., Jakubowicz, J., Sibilski, R., and Posmyk, R.
Subjects: Meeting Abstracts
Published: 2017

23. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Author: Rebbeck, TR, Friebel, TM, Friedman, E, Hamann, U, Huo, D, Kwong, A, Olah, E, Olopade, OI, Solano, AR, Teo, S-H, Thomassen, M, Weitzel, JN, Chan, TL, Couch, FJ, Goldgar, DE, Kruse, TA, Palmero, EI, Park, SK, Torres, D, van Rensburg, EJ, McGuffog, L, Parsons, MT, Leslie, G, Aalfs, CM, Abugattas, J, Adlard, J, Agata, S, Aittomaki, K, Andrews, L, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Asseryanis, E, Auerbach, L, Azzollini, J, Balmana, J, Barile, M, Barkardottir, RB, Barrowdale, D, Benitez, J, Berger, A, Berger, R, Blanco, AM, Blazer, KR, Blok, MJ, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campbell, I, Caputo, SM, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Cook, J, Davidson, R, de la Hoya, M, De Leeneer, K, de Pauw, A, Delnatte, C, Diez, O, Ding, YC, Ditsch, N, Domchek, S, Dorfling, CM, Velazquez, C, Dworniczak, B, Eason, J, Easton, DF, Eeles, R, Ehrencrona, H, Ejlertsen, B, Engel, C, Engert, S, Evans, DG, Faivre, L, Feliubadalo, L, Ferrer, SF, Foretova, L, Fowler, J, Frost, D, Galvao, HCR, Ganz, PA, Garber, J, Gauthier-Villars, M, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Giraud, S, Glendon, G, Godwin, AK, Greene, MH, Gronwald, J, Gutierrez-Barrera, A, Hahnen, E, Hauke, J, Henderson, A, Hentschel, J, Hogervorst, FBL, Honisch, E, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Vijai, J, Kaczmarek, K, Karlan, BY, Kast, K, Kim, S-W, Konstantopoulou, I, Korach, J, Laitman, Y, Lasa, A, Lasset, C, Lazaro, C, Lee, A, Lee, MH, Lester, J, Lesueur, F, Liljegren, A, Lindor, NM, Longy, M, Loud, JT, Lu, KH, Lubinski, J, Machackova, E, Manoukian, S, Mari, V, Martinez-Bouzas, C, Matrai, Z, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Mickys, U, Miller, A, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Neuhausen, SL, Nevanlinna, H, Ngeow, J, Nguyen, HP, Niederacher, D, Nielsen, HR, Nielsen, FC, Nussbaum, RL, Offit, K, Ofverholm, A, Ong, K-R, Osorio, A, Papi, L, Papp, J, Pasini, B, Pedersen, IS, Peixoto, A, Peruga, N, Peterlongo, P, Pohl, E, Pradhan, N, Prajzendanc, K, Prieur, F, Pujol, P, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rhiem, K, Robson, M, Rodriguez, GC, Rogers, MT, Rudaitis, V, Schmidt, AY, Schmutzler, RK, Senter, L, Shah, PD, Sharma, P, Side, LE, Simard, J, Singer, CF, Skytte, A-B, Slavin, TP, Snape, K, Sobol, H, Southey, M, Steele, L, Steinemann, D, Sukiennicki, G, Sutter, C, Szabo, CI, Tan, YY, Teixeira, MR, Terry, MB, Teule, A, Thomas, A, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Topka, S, Trainer, AH, Tung, N, van Asperen, CJ, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, Van Heetvelde, M, Varesco, L, Varon-Mateeva, R, Vega, A, Villarreal-Garza, C, von Wachenfeldt, A, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zidan, J, Zorn, KK, Selkirk, CGH, Hulick, PJ, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, Nathanson, KL, Rebbeck, TR, Friebel, TM, Friedman, E, Hamann, U, Huo, D, Kwong, A, Olah, E, Olopade, OI, Solano, AR, Teo, S-H, Thomassen, M, Weitzel, JN, Chan, TL, Couch, FJ, Goldgar, DE, Kruse, TA, Palmero, EI, Park, SK, Torres, D, van Rensburg, EJ, McGuffog, L, Parsons, MT, Leslie, G, Aalfs, CM, Abugattas, J, Adlard, J, Agata, S, Aittomaki, K, Andrews, L, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Asseryanis, E, Auerbach, L, Azzollini, J, Balmana, J, Barile, M, Barkardottir, RB, Barrowdale, D, Benitez, J, Berger, A, Berger, R, Blanco, AM, Blazer, KR, Blok, MJ, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campbell, I, Caputo, SM, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Cook, J, Davidson, R, de la Hoya, M, De Leeneer, K, de Pauw, A, Delnatte, C, Diez, O, Ding, YC, Ditsch, N, Domchek, S, Dorfling, CM, Velazquez, C, Dworniczak, B, Eason, J, Easton, DF, Eeles, R, Ehrencrona, H, Ejlertsen, B, Engel, C, Engert, S, Evans, DG, Faivre, L, Feliubadalo, L, Ferrer, SF, Foretova, L, Fowler, J, Frost, D, Galvao, HCR, Ganz, PA, Garber, J, Gauthier-Villars, M, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Giraud, S, Glendon, G, Godwin, AK, Greene, MH, Gronwald, J, Gutierrez-Barrera, A, Hahnen, E, Hauke, J, Henderson, A, Hentschel, J, Hogervorst, FBL, Honisch, E, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Vijai, J, Kaczmarek, K, Karlan, BY, Kast, K, Kim, S-W, Konstantopoulou, I, Korach, J, Laitman, Y, Lasa, A, Lasset, C, Lazaro, C, Lee, A, Lee, MH, Lester, J, Lesueur, F, Liljegren, A, Lindor, NM, Longy, M, Loud, JT, Lu, KH, Lubinski, J, Machackova, E, Manoukian, S, Mari, V, Martinez-Bouzas, C, Matrai, Z, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Mickys, U, Miller, A, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Neuhausen, SL, Nevanlinna, H, Ngeow, J, Nguyen, HP, Niederacher, D, Nielsen, HR, Nielsen, FC, Nussbaum, RL, Offit, K, Ofverholm, A, Ong, K-R, Osorio, A, Papi, L, Papp, J, Pasini, B, Pedersen, IS, Peixoto, A, Peruga, N, Peterlongo, P, Pohl, E, Pradhan, N, Prajzendanc, K, Prieur, F, Pujol, P, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rhiem, K, Robson, M, Rodriguez, GC, Rogers, MT, Rudaitis, V, Schmidt, AY, Schmutzler, RK, Senter, L, Shah, PD, Sharma, P, Side, LE, Simard, J, Singer, CF, Skytte, A-B, Slavin, TP, Snape, K, Sobol, H, Southey, M, Steele, L, Steinemann, D, Sukiennicki, G, Sutter, C, Szabo, CI, Tan, YY, Teixeira, MR, Terry, MB, Teule, A, Thomas, A, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Topka, S, Trainer, AH, Tung, N, van Asperen, CJ, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, Van Heetvelde, M, Varesco, L, Varon-Mateeva, R, Vega, A, Villarreal-Garza, C, von Wachenfeldt, A, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zidan, J, Zorn, KK, Selkirk, CGH, Hulick, PJ, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, and Nathanson, KL
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
Published: 2018

24. Contribution of constitutional BRCA1 promoter methylation to early-onset and familial breast cancer patients from Pakistan.

Author: Muhammad N, Azeem A, Bakar MA, Prajzendanc K, Loya A, Jakubowska A, Hamann U, and Rashid MU
Subjects: Humans, Male, BRCA1 Protein genetics, Pakistan epidemiology, DNA Methylation, BRCA2 Protein genetics, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Breast Neoplasms pathology, Triple Negative Breast Neoplasms epidemiology, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology
Abstract: Purpose: Constitutional BRCA1 promoter methylation has been identified as a potential risk factor for breast cancer (BC) in the Caucasian population. However, this data is lacking for BC patients of Asian origin. Therefore, we assessed the contribution of constitutional BRCA1 promoter methylation in Pakistani BC patients., Methods: A total of 385 BRCA1/2-negative index BC patients (197 early-onset BC (≤ 30 years), 152 familial BC, 17 familial BC and ovarian cancer, 19 male BC) and 107 healthy controls were screened for the constitutional BRCA1 promoter methylation by methylation-sensitive high-resolution melting assay. Overall, 131 patients displayed triple-negative BC (TNBC) and 254 non-TNBC phenotypes. The prevalence of BRCA1 promoter methylation was calculated based on clinicopathological characteristics using univariable and multivariable logistic regression models., Results: Constitutional BRCA1 promoter methylation was identified in 19.5% (75/385) of BC patients and 13.1% (14/107) of controls. The frequency of methylation was higher in early-onset BC (23.4% vs. 13.1%, P = 0.035) and TNBC patients (29.0% vs. 13.1%, P = 0.004) compared to controls. Methylation was also more prevalent in patients with high-grade than low-grade tumors (21.7% vs. 12.2%, P = 0.034) and progesterone receptor (PR)-negative than PR-positive tumors (26.0% vs. 13.9%, P = 0.004). Constitutional BRCA1 promoter methylation remained independently associated with TNBC phenotype (odds ratio 1.99; 95% CI 1.12-3.54; P = 0.02) after adjusting for BC diagnosis age, tumor grade, ER, and PR status., Conclusion: Constitutional BRCA1 promoter methylation is associated with TNBC and can serve as a non-invasive blood-based biomarker for Pakistani TNBC patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Published: 2023
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25. Association of recurrent mutations in BRCA1, BRCA2, RAD51C, PALB2, and CHEK2 with the risk of borderline ovarian tumor.

Author: Ogrodniczak A, Menkiszak J, Gronwald J, Tomiczek-Szwiec J, Szwiec M, Cybulski C, Dębniak T, Huzarski T, Tołoczko-Grabarek A, Byrski T, Białkowska K, Prajzendanc K, Baszuk P, Lubiński J, and Jakubowska A
Abstract: Background: There are several genes associated with ovarian cancer risk. Molecular changes in borderline ovarian tumor (BOT) indicate linkage of this disease to type I ovarian tumors (low-grade ovarian carcinomas). This study determined the prevalence and association of mutations in BRCA1, BRCA2, PALB2, RAD51C, and CHEK2 with the risk of BOTs., Methods: The study group consisted of 102 patients with histologically confirmed BOT and 1743 healthy controls. In addition, 167 cases with ovarian cancer G1 were analyzed. The analyses included genotyping of 21 founder and recurrent mutations localized in 5 genes (BRCA1, BRCA2, PALB2, RAD51C, and CHEK2). The risk for developing BOT and low-grade ovarian cancer, as well as the association of tested mutations with survival, was estimated., Results: The CHEK2 missense mutation (c.470T>C) was associated with 2-times increased risk of BOT (OR=2.05, p=0.03), at an earlier age at diagnosis and about 10% worse rate of a 10-year survival. Mutations in BRCA1 and PALB2 were associated with a high risk of ovarian cancer G1 (OR=8.53, p=0.005 and OR=7.03, p=0.03, respectively) and were related to worse all-cause survival for BRCA1 carriers (HR=4.73, 95%CI 1.45-15.43, p=0.01)., Conclusions: Results suggest that CHEK2 (c.470T>C) may possibly play a role in the pathogenesis of BOT, but due to the low number of BOT patients, obtained results should be considered as preliminary. Larger more in-depth studies are required., (© 2022. The Author(s).)
Published: 2022
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26. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

Author: Morra A, Escala-Garcia M, Beesley J, Keeman R, Canisius S, Ahearn TU, Andrulis IL, Anton-Culver H, Arndt V, Auer PL, Augustinsson A, Beane Freeman LE, Becher H, Beckmann MW, Behrens S, Bojesen SE, Bolla MK, Brenner H, Brüning T, Buys SS, Caan B, Campa D, Canzian F, Castelao JE, Chang-Claude J, Chanock SJ, Cheng TD, Clarke CL, Colonna SV, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Dennis J, Dörk T, Dossus L, Dunning AM, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Eriksson M, Evans DG, Fasching PA, Flyger H, Fritschi L, Gago-Dominguez M, García-Sáenz JA, Giles GG, Grip M, Guénel P, Gündert M, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Hart SN, Hartikainen JM, Hartmann A, He W, Hooning MJ, Hoppe R, Hopper JL, Howell A, Hunter DJ, Jager A, Jakubowska A, Janni W, John EM, Jung AY, Kaaks R, Keupers M, Kitahara CM, Koutros S, Kraft P, Kristensen VN, Kurian AW, Lacey JV, Lambrechts D, Le Marchand L, Lindblom A, Linet M, Luben RN, Lubiński J, Lush M, Mannermaa A, Manoochehri M, Margolin S, Martens JWM, Martinez ME, Mavroudis D, Michailidou K, Milne RL, Mulligan AM, Muranen TA, Nevanlinna H, Newman WG, Nielsen SF, Nordestgaard BG, Olshan AF, Olsson H, Orr N, Park-Simon TW, Patel AV, Peissel B, Peterlongo P, Plaseska-Karanfilska D, Prajzendanc K, Prentice R, Presneau N, Rack B, Rennert G, Rennert HS, Rhenius V, Romero A, Roylance R, Ruebner M, Saloustros E, Sawyer EJ, Schmutzler RK, Schneeweiss A, Scott C, Shah M, Smichkoska S, Southey MC, Stone J, Surowy H, Swerdlow AJ, Tamimi RM, Tapper WJ, Teras LR, Terry MB, Tollenaar RAEM, Tomlinson I, Troester MA, Truong T, Vachon CM, Wang Q, Hurson AN, Winqvist R, Wolk A, Ziogas A, Brauch H, García-Closas M, Pharoah PDP, Easton DF, Chenevix-Trench G, and Schmidt MK
Subjects: Breast Neoplasms drug therapy, Breast Neoplasms pathology, Female, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Prognosis, Survival Analysis, Breast Neoplasms genetics, Breast Neoplasms mortality, Germ-Line Mutation
Abstract: Background: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients., Methods: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15)., Results: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy., Conclusions: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited., (© 2021. The Author(s).)
Published: 2021
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27. Recurrent Mutations in BRCA1 , BRCA2 , RAD51C , PALB2 and CHEK2 in Polish Patients with Ovarian Cancer.

Author: Łukomska A, Menkiszak J, Gronwald J, Tomiczek-Szwiec J, Szwiec M, Jasiówka M, Blecharz P, Kluz T, Stawicka-Niełacna M, Mądry R, Białkowska K, Prajzendanc K, Kluźniak W, Cybulski C, Dębniak T, Huzarski T, Tołoczko-Grabarek A, Byrski T, Baszuk P, Narod SA, Lubiński J, and Jakubowska A
Abstract: The aim of the study was to analyze the frequency and magnitude of association of 21 recurrent founder germline mutations in BRCA1 , BRCA2 , PALB2 , RAD51C , and CHEK2 genes with ovarian cancer risk among unselected patients in Poland. We genotyped 21 recurrent germline mutations in BRCA1 (9 mutations), BRCA2 (4 mutations), RAD51C (3 mutations), PALB2 (2 mutations), and CHEK2 (3 mutations) among 2270 Polish ovarian cancer patients and 1743 healthy controls, and assessed the odds ratios (OR) for developing ovarian cancer for each gene. Mutations were detected in 369 out of 2095 (17.6%) unselected ovarian cancer cases and 117 out of 1743 (6.7%) unaffected controls. The ovarian cancer risk was associated with mutations in BRCA1 (OR = 40.79, 95% CI: 18.67-114.78; p = 0.29 × 10 -15 ), in BRCA2 (OR = 25.98; 95% CI: 1.55-434.8; p = 0.001), in RAD51C (OR = 6.28; 95% CI 1.77-39.9; p = 0.02), and in PALB2 (OR 3.34; 95% CI: 1.06-14.68; p = 0.06). There was no association found for CHEK2. We found that pathogenic mutations in BRCA1 , BRCA2 , RAD51C or PALB2 are responsible for 12.5% of unselected cases of ovarian cancer. We recommend that all women with ovarian cancer in Poland and first-degree female relatives should be tested for this panel of 18 mutations.
Published: 2021
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28. 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, Aittomäki K, Andrieu N, Andrulis IL, Arnold N, Arun BK, Azzollini J, Balmaña J, Barkardottir RB, Barrowdale D, Benitez J, Berthet P, Białkowska K, Blanco AM, Blok MJ, Bonanni B, Boonen SE, Borg Å, Bozsik A, Bradbury AR, Brennan P, Brewer C, Brunet J, Buys SS, Caldés T, Caligo MA, Campbell I, Christensen LL, Chung WK, Claes KBM, Colas C, Collonge-Rame MA, 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 AM, Gesta P, Giraud S, Glendon G, Godwin AK, Goldgar DE, González-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, Lubiński 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, Noguès C, Olah E, Olopade OI, Ong KR, O'Shaughnessy-Kirwan A, Osorio A, Ott CE, Papi L, Park SK, Parsons MT, Pedersen IS, Peissel B, Peixoto A, Peterlongo P, Pfeiler G, Phillips KA, Prajzendanc K, Pujana MA, Radice P, Ramser J, Ramus SJ, Rantala J, Rennert G, Risch HA, Robson M, Rønlund 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
Subjects: BRCA1 Protein genetics, BRCA2 Protein genetics, Carcinoma, Ovarian Epithelial genetics, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Mutation, Prospective Studies, Retrospective Studies, Risk Factors, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics
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
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29. Polymorphisms in MMP-1 , MMP-2 , MMP-7, MMP-13 and MT2A do not contribute to breast, lung and colon cancer risk in polish population.

Author: Białkowska K, Marciniak W, Muszyńska M, Baszuk P, Gupta S, Jaworska-Bieniek K, Sukiennicki G, Durda K, Gromowski T, Lener M, Prajzendanc K, Łukomska A, Cybulski C, Huzarski T, Gronwald J, Dębniak T, Lubiński J, and Jakubowska A
Abstract: Background: Matrix metalloproteinases (MMPs) and metallothioneins (MTs) are Zinc-related proteins which are involved in processes crucial for carcinogenesis such as angiogenesis, proliferation and apoptosis. Several single nucleotide polymorphisms (SNPs) in MMPs and MTs that affect genes expression have been associated with cancer risk, including breast, lung and colon., Methods: The study group consisted of 648 unselected patients (299 with breast cancer, 199 with lung cancer, 150 with colon cancer) and 648 unaffected individuals. Five SNPs, rs1799750 in MMP-1, rs243865 in MMP-2, rs11568818 in MMP-7, rs2252070 in MMP-13 and rs28366003 in MT2A were genotyped and serum zinc (Zn) level was measured. The cancer risk was calculated using multivariable logistic regression with respect to Zn., Results: None of the 5 tested polymorphisms showed a correlation with cancer risk in studied groups, although for MMP-2 , MMP-7 and MT2A non-significant differences in genotypes frequencies among cases and controls were observed., Conclusions: Analyses of polymorphisms, rs1799750 in MMP-1 , rs243865 in MMP-2 , rs11568818 in MMP-7 , rs2252070 in MMP-13 and rs28366003 in MT2A in relation to serum Zn level did not show significant association with breast, lung and colon cancer risk among polish patients. Further studies are needed to verify this observation., Competing Interests: Competing interestsJL is CEO of Read-Gene S.A. The authors WM, MM are employees of Read-Gene S.A. KB, PB, SG, KJB, GS, KD, TG, ML, KP, AŁ, CC, TH, JG, TD, AJ declare that they have no competing interests., (© The Author(s) 2020.)
Published: 2020
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30. 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, Aittomäki K, Andrulis IL, Anton-Culver H, Antoniou AC, Arason A, Arndt V, Aronson KJ, Arun BK, Asseryanis E, Auer PL, Azzollini J, Balmaña J, Barkardottir RB, Barnes DR, Barrowdale D, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Białkowska 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, Brüning T, Burwinkel B, Cai Q, Caldés 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, Dörk 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, García-Closas M, García-Sáenz JA, Gaudet MM, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Gronwald J, Guénel 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 JI, Konstantopoulou I, Kristensen VN, Laitman Y, Lambrechts D, Lazaro C, Leroux D, Leslie G, Lester J, Lesueur F, Lindor N, Lindström S, Lo WY, Loud JT, Lubiński 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 OI, Olsson H, Osorio A, Papp J, Park-Simon TW, Parsons MT, Pedersen IS, Peixoto A, Peterlongo P, Peto J, Pharoah PDP, Phillips KA, Plaseska-Karanfilska D, Poppe B, Pradhan N, Prajzendanc K, Presneau N, Punie K, Pylkäs 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 XO, Simard J, Singer CF, Skytte AB, Soucy P, Southey MC, Spinelli JJ, Spurdle AB, Stone J, Swerdlow AJ, Tapper WJ, Taylor JA, Teixeira MR, Terry MB, Teulé A, Thomassen M, Thöne 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 JN, Wendt C, Winqvist R, Yang XR, Yannoukakos D, Ziogas A, Milne RL, Easton DF, Chenevix-Trench G, Zheng W, Kraft P, and Jiang X
Subjects: Breast Neoplasms metabolism, Estrogens metabolism, Female, Genetic Predisposition to Disease, Genomics, Humans, Risk Assessment, Transcriptome, Vesicular Transport Proteins genetics, Breast Neoplasms genetics, Genome-Wide Association Study, Receptors, Estrogen metabolism
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., (© 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals, Inc.)
Published: 2020
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31. 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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32. BRCA1 promoter methylation in peripheral blood is associated with the risk of triple-negative breast cancer.

Author: Prajzendanc K, Domagała P, Hybiak J, Ryś J, Huzarski T, Szwiec M, Tomiczek-Szwiec J, Redelbach W, Sejda A, Gronwald J, Kluz T, Wiśniowski R, Cybulski C, Łukomska A, Białkowska K, Sukiennicki G, Kulczycka K, Narod SA, Wojdacz TK, Lubiński J, and Jakubowska A
Subjects: Adult, Aged, Aged, 80 and over, Biomarkers, Tumor blood, Breast pathology, Case-Control Studies, DNA Methylation, Female, Follow-Up Studies, Humans, Middle Aged, Triple Negative Breast Neoplasms blood, Triple Negative Breast Neoplasms pathology, BRCA1 Protein genetics, Biomarkers, Tumor genetics, Genetic Predisposition to Disease, Promoter Regions, Genetic genetics, Triple Negative Breast Neoplasms genetics
Abstract: Methylation of the promoter of the BRCA1 gene in DNA derived from peripheral blood cells is a possible risk factor for breast cancer. It is not clear if this association is restricted to certain types of breast cancer or is a general phenomenon. We evaluated BRCA1 methylation status in peripheral blood cells from 942 breast cancer patients and from 500 controls. We also assessed methylation status in 262 paraffin-embedded breast cancer tissues. Methylation status was assessed using methylation-sensitive high-resolution melting and was categorized as positive or negative. BRCA1 methylation in peripheral blood cells was strongly associated with the risk of triple-negative breast cancer (TNBC) (odds ratio [OR] 4.70; 95% confidence interval [CI]: 3.13-7.07; p < 0.001), but not of estrogen-receptor positive breast cancer (OR 0.80; 95% CI: 0.46-1.42; p = 0.46). Methylation was also overrepresented among patients with high-grade cancers (OR 4.53; 95% CI: 2.91-7.05; p < 0.001) and medullary cancers (OR 3.08; 95% CI: 1.38-6.88; p = 0.006). Moreover, we detected a significant concordance of BRCA1 promoter methylation in peripheral blood and paired tumor tissue (p < 0.001). We found that BRCA1 promoter methylation in peripheral blood cells is associated with approximately five times greater risk of TNBC. We propose that BRCA1 methylation in blood-derived DNA could be a novel biomarker of increased breast cancer susceptibility, in particular for triple-negative tumors., (© 2019 UICC.)
Published: 2020
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33. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Author: Fachal L, Aschard H, Beesley J, Barnes DR, Allen J, Kar S, Pooley KA, Dennis J, Michailidou K, Turman C, Soucy P, Lemaçon A, Lush M, Tyrer JP, Ghoussaini M, Moradi Marjaneh M, Jiang X, Agata S, Aittomäki K, Alonso MR, Andrulis IL, Anton-Culver H, Antonenkova NN, Arason A, Arndt V, Aronson KJ, Arun BK, Auber B, Auer PL, Azzollini J, Balmaña J, Barkardottir RB, Barrowdale D, Beeghly-Fadiel A, Benitez J, Bermisheva M, Białkowska K, Blanco AM, Blomqvist C, Blot W, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Borg A, Bosse K, Brauch H, Brenner H, Briceno I, Brock IW, Brooks-Wilson A, Brüning T, Burwinkel B, Buys SS, Cai Q, Caldés T, Caligo MA, Camp NJ, Campbell I, Canzian F, Carroll JS, Carter BD, Castelao JE, Chiquette J, Christiansen H, Chung WK, Claes KBM, Clarke CL, Collée JM, Cornelissen S, Couch FJ, Cox A, Cross SS, Cybulski C, Czene K, Daly MB, de la Hoya M, Devilee P, Diez O, Ding YC, Dite GS, Domchek SM, Dörk T, Dos-Santos-Silva I, Droit A, Dubois S, Dumont M, Duran M, Durcan L, Dwek M, Eccles DM, Engel C, Eriksson M, Evans DG, Fasching PA, Fletcher O, Floris G, Flyger H, Foretova L, Foulkes WD, Friedman E, Fritschi L, Frost D, Gabrielson M, Gago-Dominguez M, Gambino G, Ganz PA, Gapstur SM, Garber J, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Tibiletti MG, Greene MH, Grip M, Gronwald J, Grundy A, Guénel P, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hartikainen JM, Hartman M, He W, Healey CS, Heemskerk-Gerritsen BAM, Heyworth J, Hillemanns P, Hogervorst FBL, Hollestelle A, Hooning MJ, Hopper JL, Howell A, Huang G, Hulick PJ, Imyanitov EN, Isaacs C, Iwasaki M, Jager A, Jakimovska M, Jakubowska A, James PA, Janavicius R, Jankowitz RC, John EM, Johnson N, Jones ME, Jukkola-Vuorinen A, Jung A, Kaaks R, Kang D, Kapoor PM, Karlan BY, Keeman R, Kerin MJ, Khusnutdinova E, Kiiski JI, Kirk J, Kitahara CM, Ko YD, Konstantopoulou I, Kosma VM, Koutros S, Kubelka-Sabit K, Kwong A, Kyriacou K, Laitman Y, Lambrechts D, Lee E, Leslie G, Lester J, Lesueur F, Lindblom A, Lo WY, Long J, Lophatananon A, Loud JT, Lubiński J, MacInnis RJ, Maishman T, Makalic E, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martinez ME, Matsuo K, Maurer T, Mavroudis D, Mayes R, McGuffog L, McLean C, Mebirouk N, Meindl A, Miller A, Miller N, Montagna M, Moreno F, Muir K, Mulligan AM, Muñoz-Garzon VM, Muranen TA, Narod SA, Nassir R, Nathanson KL, Neuhausen SL, Nevanlinna H, Neven P, Nielsen FC, Nikitina-Zake L, Norman A, Offit K, Olah E, Olopade OI, Olsson H, Orr N, Osorio A, Pankratz VS, Papp J, Park SK, Park-Simon TW, Parsons MT, Paul J, Pedersen IS, Peissel B, Peshkin B, Peterlongo P, Peto J, Plaseska-Karanfilska D, Prajzendanc K, Prentice R, Presneau N, Prokofyeva D, Pujana MA, Pylkäs K, Radice P, Ramus SJ, Rantala J, Rau-Murthy R, Rennert G, Risch HA, Robson M, Romero A, Rossing M, Saloustros E, Sánchez-Herrero E, Sandler DP, Santamariña M, Saunders C, Sawyer EJ, Scheuner MT, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schöttker B, Schürmann P, Scott C, Scott RJ, Senter L, Seynaeve CM, Shah M, Sharma P, Shen CY, Shu XO, Singer CF, Slavin TP, Smichkoska S, Southey MC, Spinelli JJ, Spurdle AB, Stone J, Stoppa-Lyonnet D, Sutter C, Swerdlow AJ, Tamimi RM, Tan YY, Tapper WJ, Taylor JA, Teixeira MR, Tengström M, Teo SH, Terry MB, Teulé A, Thomassen M, Thull DL, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Torres D, Torres-Mejía G, Troester MA, Truong T, Tung N, Tzardi M, Ulmer HU, Vachon CM, van Asperen CJ, van der Kolk LE, van Rensburg EJ, Vega A, Viel A, Vijai J, Vogel MJ, Wang Q, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wildiers H, Winqvist R, Wolk A, Wu AH, Yannoukakos D, Zhang Y, Zheng W, Hunter D, Pharoah PDP, Chang-Claude J, García-Closas M, Schmidt MK, Milne RL, Kristensen VN, French JD, Edwards SL, Antoniou AC, Chenevix-Trench G, Simard J, Easton DF, Kraft P, and Dunning AM
Subjects: Bayes Theorem, Female, Humans, Linkage Disequilibrium, Regulatory Sequences, Nucleic Acid, Risk Factors, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Chromosome Mapping methods, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Quantitative Trait Loci
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.
Published: 2020
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34. Genome-wide association study of germline variants and breast cancer-specific mortality.

Author: Escala-Garcia M, Guo Q, Dörk T, Canisius S, Keeman R, Dennis J, Beesley J, Lecarpentier J, Bolla MK, Wang Q, Abraham J, Andrulis IL, Anton-Culver H, Arndt V, Auer PL, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bernstein L, Blomqvist C, Boeckx B, Bojesen SE, Bonanni B, Børresen-Dale AL, Brauch H, Brenner H, Brentnall A, Brinton L, Broberg P, Brock IW, Brucker SY, Burwinkel B, Caldas C, Caldés T, Campa D, Canzian F, Carracedo A, Carter BD, Castelao JE, Chang-Claude J, Chanock SJ, Chenevix-Trench G, Cheng TD, Chin SF, Clarke CL, Cordina-Duverger E, Couch FJ, Cox DG, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dunn JA, Dunning AM, Durcan L, Dwek M, Earl HM, Ekici AB, Eliassen AH, Ellberg C, Engel C, Eriksson M, Evans DG, Figueroa J, Flesch-Janys D, Flyger H, Gabrielson M, Gago-Dominguez M, Galle E, Gapstur SM, García-Closas M, García-Sáenz JA, Gaudet MM, George A, Georgoulias V, Giles GG, Glendon G, Goldgar DE, González-Neira A, Alnæs GIG, Grip M, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Hankinson S, Harkness EF, Harrington PA, Hart SN, Hartikainen JM, Hein A, Hillemanns P, Hiller L, Holleczek B, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Howell A, Huang G, Humphreys K, Hunter DJ, Janni W, John EM, Jones ME, Jukkola-Vuorinen A, Jung A, Kaaks R, Kabisch M, Kaczmarek K, Kerin MJ, Khan S, Khusnutdinova E, Kiiski JI, Kitahara CM, Knight JA, Ko YD, Koppert LB, Kosma VM, Kraft P, Kristensen VN, Krüger U, Kühl T, Lambrechts D, Le Marchand L, Lee E, Lejbkowicz F, Li L, Lindblom A, Lindström S, Linet M, Lissowska J, Lo WY, Loibl S, Lubiński J, Lux MP, MacInnis RJ, Maierthaler M, Maishman T, Makalic E, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martinez ME, Mavroudis D, McLean C, Meindl A, Middha P, Miller N, Milne RL, Moreno F, Mulligan AM, Mulot C, Nassir R, Neuhausen SL, Newman WT, Nielsen SF, Nordestgaard BG, Norman A, Olsson H, Orr N, Pankratz VS, Park-Simon TW, Perez JIA, Pérez-Barrios C, Peterlongo P, Petridis C, Pinchev M, Prajzendanc K, Prentice R, Presneau N, Prokofieva D, Pylkäs K, Rack B, Radice P, Ramachandran D, Rennert G, Rennert HS, Rhenius V, Romero A, Roylance R, Saloustros E, Sawyer EJ, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schumacher F, Schwentner L, Scott RJ, Scott C, Seynaeve C, Shah M, Simard J, Smeets A, Sohn C, Southey MC, Swerdlow AJ, Talhouk A, Tamimi RM, Tapper WJ, Teixeira MR, Tengström M, Terry MB, Thöne K, Tollenaar RAEM, Tomlinson I, Torres D, Truong T, Turman C, Turnbull C, Ulmer HU, Untch M, Vachon C, van Asperen CJ, van den Ouweland AMW, van Veen EM, Wendt C, Whittemore AS, Willett W, Winqvist R, Wolk A, Yang XR, Zhang Y, Easton DF, Fasching PA, Nevanlinna H, Eccles DM, Pharoah PDP, and Schmidt MK
Subjects: Bayes Theorem, Breast Neoplasms metabolism, Chromosomes, Human, Pair 7, Female, Genetic Variation, Genome-Wide Association Study, Humans, Prognosis, Proportional Hazards Models, Receptors, Estrogen genetics, Receptors, Estrogen metabolism, White People genetics, Breast Neoplasms genetics, Breast Neoplasms mortality
Abstract: Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry., Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP)., Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 -8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 -7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 -7 , HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster., Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
Published: 2019
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35. Iron levels, genes involved in iron metabolism and antioxidative processes and lung cancer incidence.

Author: Sukiennicki GM, Marciniak W, Muszyńska M, Baszuk P, Gupta S, Białkowska K, Jaworska-Bieniek K, Durda K, Lener M, Pietrzak S, Gromowski T, Prajzendanc K, Łukomska A, Waloszczyk P, Wójcik JZ, Scott R, Lubiński J, and Jakubowska A
Subjects: Genetic Variation, Humans, Incidence, Lung Neoplasms blood, Lung Neoplasms pathology, Neoplasm Staging, Risk Factors, Survival Analysis, Antioxidants metabolism, Iron blood, Iron metabolism, Lung Neoplasms epidemiology, Lung Neoplasms genetics
Abstract: Background: Lung cancer is the most common adult malignancy accounting for the largest proportion of cancer related deaths. Iron (Fe) is an essential trace element and is a component of several major metabolic pathways playing an important role in many physiological processes. In this study we evaluated the association between Fe concentration in serum, iron metabolism parameters and genetic variaton in 7 genes involved in iron metabolism and anti-oxidative processes with the incidence of lung cancer in Poland., Materials and Methods: The study included 200 lung cancer patients and 200 matched healthy control subjects. We analyzed serum iron concentration and iron metabolism parameters (TIBC, UIBC, serum ferritin and transferrin saturation), and genotyped seven variants in seven genes: HFE, TFR1, HAMP, TF, SOD2, CAT and GPX1., Results: Lung cancer patients compared to their matched controls had significantly higher mean serum iron level (p = 0.01), ferritin level (p = 0.007) and TIBC (p = 0.006). Analysis revealed that higher concentration of iron and ferritin (IVth quartile) compared to the lower concentration (Ist quartile) was associated with over 2-fold increased lung cancer incidence. We also found that higher transferrin saturation (p = 0.01) and lower TIBC (p<0.01) are associated with better survival of lung cancer patients. The analysis of polymorphisms in iron related genes did not reveal a significant difference between lung cancer patients and controls. However, rs10421768 in HAMP showed a borderline statistically significant correlation with lung cancer risk (OR = 2.83, p = 0.05)., Conclusions: The results of this case control study indicate that higher body iron represented by higher Fe and ferritin levels may be associated with lung cancer incidence. Rs10421768 in HAMP may be associated with about 3-times higher lung cancer risk. Higher Fe body content may be associated with better survival of lung cancer patients., Competing Interests: The authors have read the journal's policy and have the following conflicts: The authors WM, MM, and JL are employed by Read-Gene S.A.; SG is employed by Strand Life Sciences; and PW is employed by an Independent Laboratory of Pathology. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.
Published: 2019
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36. Association of zinc level and polymorphism in MMP-7 gene with prostate cancer in Polish population.

Author: Białkowska K, Marciniak W, Muszyńska M, Baszuk P, Gupta S, Jaworska-Bieniek K, Sukiennicki G, Durda K, Gromowski T, Prajzendanc K, Cybulski C, Huzarski T, Gronwald J, Dębniak T, Scott RJ, Lubiński J, and Jakubowska A
Subjects: Case-Control Studies, Genetic Predisposition to Disease, Humans, Incidence, Male, Matrix Metalloproteinase 1 genetics, Matrix Metalloproteinase 13 genetics, Matrix Metalloproteinase 2 genetics, Metallothionein genetics, Poland epidemiology, Prostatic Neoplasms epidemiology, Retrospective Studies, White People genetics, Matrix Metalloproteinase 7 genetics, Polymorphism, Single Nucleotide, Prostatic Neoplasms blood, Prostatic Neoplasms genetics, Zinc blood
Abstract: Introduction: Prostate cancer is one of the most commonly diagnosed malignancies among men in Western populations. Evidence reported in the literature suggests that zinc may be related to prostate cancer. In this study we evaluated the association of serum zinc levels and polymorphisms in genes encoding zinc-dependent proteins with prostate cancer in Poland., Methods: The study group consisted of 197 men affected with prostate cancer and 197 healthy men. Serum zinc levels were measured and 5 single nucleotide polymorphisms in MMP-1, MMP-2, MMP-7, MMP-13, MT2A genes were genotyped., Results: The mean serum zinc level was higher in prostate cancer patients than in healthy controls (898.9±12.01 μg/l vs. 856.6±13.05 μg/l, p<0.01). When compared in quartiles a significant association of higher zinc concentration with the incidence of prostate cancer was observed. The highest OR (OR = 4.41, 95%CI 2.07-9.37, p<0.01) was observed in 3rd quartile (>853.0-973.9 μg/l). Among five analyzed genetic variants, rs11568818 in MMP-7 appeared to be correlated with 2-fold increased prostate cancer risk (OR = 2.39, 95% CI = 1.19-4.82, p = 0.015)., Conclusion: Our results suggest a significant correlation of higher serum zinc levels with the diagnosis of prostate cancer. The polymorphism rs11568818 in MMP-7 gene was also associated with an increased prostate cancer risk in Poland., Competing Interests: JL is CEO of Read-Gene S.A. The authors WM, MM are employees of Read-Gene S.A. KB, PB, GS, KD, TG, KP, CC, TH, JG, TD, RJS, AJ declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Published: 2018
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37. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Author: Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH, Thomassen M, Weitzel JN, Chan TL, Couch FJ, Goldgar DE, Kruse TA, Palmero EI, Park SK, Torres D, van Rensburg EJ, McGuffog L, Parsons MT, Leslie G, Aalfs CM, Abugattas J, Adlard J, Agata S, Aittomäki K, Andrews L, Andrulis IL, Arason A, Arnold N, Arun BK, Asseryanis E, Auerbach L, Azzollini J, Balmaña J, Barile M, Barkardottir RB, Barrowdale D, Benitez J, Berger A, Berger R, Blanco AM, Blazer KR, Blok MJ, Bonadona V, Bonanni B, Bradbury AR, Brewer C, Buecher B, Buys SS, Caldes T, Caliebe A, Caligo MA, Campbell I, Caputo SM, Chiquette J, Chung WK, Claes KBM, Collée JM, Cook J, Davidson R, de la Hoya M, De Leeneer K, de Pauw A, Delnatte C, Diez O, Ding YC, Ditsch N, Domchek SM, Dorfling CM, Velazquez C, Dworniczak B, Eason J, Easton DF, Eeles R, Ehrencrona H, Ejlertsen B, Engel C, Engert S, Evans DG, Faivre L, Feliubadaló L, Ferrer SF, Foretova L, Fowler J, Frost D, Galvão HCR, Ganz PA, Garber J, Gauthier-Villars M, Gehrig A, Gerdes AM, Gesta P, Giannini G, Giraud S, Glendon G, Godwin AK, Greene MH, Gronwald J, Gutierrez-Barrera A, Hahnen E, Hauke J, Henderson A, Hentschel J, Hogervorst FBL, Honisch E, Imyanitov EN, Isaacs C, Izatt L, Izquierdo A, Jakubowska A, James P, Janavicius R, Jensen UB, John EM, Vijai J, Kaczmarek K, Karlan BY, Kast K, Investigators K, Kim SW, Konstantopoulou I, Korach J, Laitman Y, Lasa A, Lasset C, Lázaro C, Lee A, Lee MH, Lester J, Lesueur F, Liljegren A, Lindor NM, Longy M, Loud JT, Lu KH, Lubinski J, Machackova E, Manoukian S, Mari V, Martínez-Bouzas C, Matrai Z, Mebirouk N, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Mickys U, Miller A, Montagna M, Moysich KB, Mulligan AM, Musinsky J, Neuhausen SL, Nevanlinna H, Ngeow J, Nguyen HP, Niederacher D, Nielsen HR, Nielsen FC, Nussbaum RL, Offit K, Öfverholm A, Ong KR, Osorio A, Papi L, Papp J, Pasini B, Pedersen IS, Peixoto A, Peruga N, Peterlongo P, Pohl E, Pradhan N, Prajzendanc K, Prieur F, Pujol P, Radice P, Ramus SJ, Rantala J, Rashid MU, Rhiem K, Robson M, Rodriguez GC, Rogers MT, Rudaitis V, Schmidt AY, Schmutzler RK, Senter L, Shah PD, Sharma P, Side LE, Simard J, Singer CF, Skytte AB, Slavin TP, Snape K, Sobol H, Southey M, Steele L, Steinemann D, Sukiennicki G, Sutter C, Szabo CI, Tan YY, Teixeira MR, Terry MB, Teulé A, Thomas A, Thull DL, Tischkowitz M, Tognazzo S, Toland AE, Topka S, Trainer AH, Tung N, van Asperen CJ, van der Hout AH, van der Kolk LE, van der Luijt RB, Van Heetvelde M, Varesco L, Varon-Mateeva R, Vega A, Villarreal-Garza C, von Wachenfeldt A, Walker L, Wang-Gohrke S, Wappenschmidt B, Weber BHF, Yannoukakos D, Yoon SY, Zanzottera C, Zidan J, Zorn KK, Hutten Selkirk CG, Hulick PJ, Chenevix-Trench G, Spurdle AB, Antoniou AC, and Nathanson KL
Subjects: Databases, Genetic, Family, Geography, Humans, BRCA1 Protein genetics, BRCA2 Protein genetics, Internationality, Mutation genetics
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations., (© 2018 Wiley Periodicals, Inc.)
Published: 2018
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