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51. Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers

Author

Lachance, J., Vernot, B., Elbers, C.C., Ferwerda, B., Froment, Alain, Bodo, J.M., Lema, G., Fu, W.Q., Nyambo, T.B., Rebbeck, T.R., Zhang, K., Akey, J.M., and Tishkoff, S.A.

Abstract

To reconstruct modern human evolutionary history and identify loci that have shaped hunter-gatherer adaptation, we sequenced the whole genomes of five individuals in each of three different hunter-gatherer populations at >60x coverage: Pygmies from Cameroon and Khoesan-speaking Hadza and Sandawe from Tanzania. We identify 13.4 million variants, substantially increasing the set of known human variation. We found evidence of archaic intro-gression in all three populations, and the distribution of time to most recent common ancestors from these regions is similar to that observed for introgressed regions in Europeans. Additionally, we identify numerous loci that harbor signatures of local adaptation, including genes involved in immunity, metabolism, olfactory and taste perception, reproduction, and wound healing. Within the Pygmy population, we identify multiple highly differentiated loci that play a role in growth and anterior pituitary function and are associated with height.

Published
2012

53. Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

Author

Antoniou, A.C., Beesley, J., McGuffog, L., Sinilnikova, O.M., Healey, S., Neuhausen, S.L., Ding, Y.C., Rebbeck, T.R., Weitzel, J.N., Lynch, H.T., Isaacs, C., Ganz, P.A., Tomlinson, G., Olopade, O.I., Couch, F.J., Wang, X.S., Lindor, N.M., Pankratz, V.S., Radice, P., Manoukian, S., Peissel, B., Zaffaroni, D., Barile, M., Viel, A., Allavena, A., Dall'Olio, V., Peterlongo, P., Szabo, C.I., Zikan, M., Claes, K., Poppe, B., Foretova, L., Mai, P.L., Greene, M.H., Rennert, G., Lejbkowicz, F., Glendon, G., Ozcelik, H., Andrulis, I.L., Thomassen, M., Gerdes, A.M., Sunde, L., Cruger, D., Jensen, U.B., Caligo, M., Friedman, E., Kaufman, B., Laitman, Y., Milgrom, R., Dubrovsky, M., Cohen, S., Borg, A., Jernstrom, H., Lindblom, A., Rantala, J., Stenmark-Askmalm, M., Melin, B., Nathanson, K., Domchek, S., Jakubowska, A., Lubinski, J., Huzarski, T., Osorio, A., Lasa, A., Duran, M., Tejada, M.I., Godino, J., Benitez, J., Hamann, U., Kriege, M., Hoogerbrugge, N., Luijt, R.B. van der, Asperen, C.J. van, Devilee, P., Meijers-Heijboer, E.J., Blok, M.J., Aalfs, C.M., Hogervorst, F., Rookus, M., Cook, M., Oliver, C., Frost, D., Conroy, D., Evans, D.G., Lalloo, F., Pichert, G., Davidson, R., Cole, T., Cook, J., Paterson, J., Hodgson, S., Morrison, P.J., Porteous, M.E., Walker, L., Kennedy, M.J., Dorkins, H., Peock, S., Godwin, A.K., Stoppa-Lyonnet, D., Pauw, A. de, Mazoyer, S., Bonadona, V., Lasset, C., Dreyfus, H., Leroux, D., Hardouin, A., Berthet, P., Faivre, L., Loustalot, C., Noguchi, T., Sobol, H., Rouleau, E., Nogues, C., Frenay, M., Venat-Bouvet, L., Hopper, J.L., Daly, M.B., Terry, M.B., John, E.M., Buys, S.S., Yassin, Y., Miron, A., Goldgar, D., Singer, C.F., Dressler, A.C., Gschwantler-Kaulich, D., Pfeiler, G., Hansen, T.V.O., Jnson, L., Agnarsson, B.A., Kirchhoff, T., Offit, K., Devlin, V., Dutra-Clarke, A., Piedmonte, M., Rodriguez, G.C., Wakeley, K., Boggess, J.F., Basil, J., Schwartz, P.E., Blank, S.V., Toland, A.E., Montagna, M., Casella, C., Imyanitov, E., Tihomirova, L., Blanco, I., Lazaro, C., Ramus, S.J., Sucheston, L., Karlan, B.Y., Gross, J., Schmutzler, R., Wappenschmidt, B., Engel, C., Meindl, A., Lochmann, M., Arnold, N., Heidemann, S., Varon-Mateeva, R., Niederacher, D., Sutter, C., Deissler, H., Gadzicki, D., Preisler-Adams, S., Kast, K., Schonbuchner, I., Caldes, T., Hoya, M. de la, Aittomaki, K., Nevanlinna, H., Simard, J., Spurdle, A.B., Holland, H., Chen, X.Q., Platte, R., Chenevix-Trench, G., Easton, D.F., Ontario Canc Genetics Network, SWE-BRCA, HEBON, EMBRACE, GEMO, Breast Canc Family Registry, kConFab, CIMBA, MUMC+: DA KG Lab Centraal Lab (9), Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Human genetics, CCA - Oncogenesis, Human Genetics, Pathology, Clinical Genetics, Pediatric Surgery, Medical Oncology, and Internal Medicine

Subjects
Oncology, Cancer Research, endocrine system diseases, Vesicular Transport Proteins, Gene mutation, 0302 clinical medicine, Risk Factors, Genotype, skin and connective tissue diseases, Aged, 80 and over, 0303 health sciences, BRCA1 Protein, High Mobility Group Proteins, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Female, Breast disease, Receptors, Progesterone, Adult, Heterozygote, medicine.medical_specialty, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Alleles, Aged, 030304 developmental biology, BRCA2 Protein, Hereditary cancer and cancer-related syndromes [ONCOL 1], Sodium-Bicarbonate Symporters, Haplotype, Cancer, genome-wide association estrogen-receptor loci variants, medicine.disease, Survival Analysis, TOX3, Mutation, Trans-Activators, Cancer research, Apoptosis Regulatory Proteins
Abstract

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03–1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01–1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10−11 − 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers. Cancer Res; 70(23); 9742–54. ©2010 AACR.

Published
2010

54. Association of the Variants CASP8 D302H and CASP10 V410I with Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

Engel, C., Versmold, B., Wappenschmidt, B., Simard, J., Easton, D.F., Peock, S., Cook, M., Oliver, C., Frost, D., Mayes, R., Evans, D.G., Eeles, R., Paterson, J., Brewer, C., McGuffog, L., Antoniou, A.C., Stoppa-Lyonnet, D., Sinilnikova, O.M., Barjhoux, L., Frenay, M., Michel, C., Leroux, D., Dreyfus, H., Toulas, C., Gladieff, L., Uhrhammer, N., Bignon, Y.J., Meindl, A., Arnold, N., Varon-Mateeva, R., Niederacher, D., Preisler-Adams, S., Kast, K., Deissler, H., Sutter, C., Gadzicki, D., Chenevix-Trench, G., Spurdle, A.B., Chen, X.Q., Beesley, J., Olsson, H., Kristoffersson, U., Ehrencrona, H., Liljegren, A., Luijt, R.B. van der, Os, T.A. van, Leeuwen, F.E. van, Domchek, S.M., Rebbeck, T.R., Nathanson, K.L., Osorio, A., Cajal, T.R.Y., Konstantopoulou, I., Benitez, J., Friedman, E., Kaufman, B., Laitman, Y., Mai, P.L., Greene, M.H., Nevanlinna, H., Aittomaki, K., Szabo, C.I., Caldes, T., Couch, F.J., Andrulis, I.L., Godwin, A.K., Hamann, U., Schmutzler, R.K., Epidemiological Study Familial Bre, Kathleen Cuningham Fdn Consortium, Sweden SWE-BRCA, Hereditary Breast Ovarian Canc Grp, Consortium Investigators Modifiers, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - School for Oncology and Reproduction, Human Genetics, Epidemiology and Data Science, CCA - Disease profiling, and EMGO - Quality of care

Subjects
Oncology, medicine.medical_specialty, Genetics and epigenetic pathways of disease [NCMLS 6], Genotype, endocrine system diseases, Epidemiology, Genes, BRCA2, Population, Genes, BRCA1, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Article, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, 0302 clinical medicine, Breast cancer, caspase-8 gene inactivating mutations common variants reduced risk cell-cycle apoptosis susceptibility polymorphisms predisposition carcinomas, Risk Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Caspase 10, education, skin and connective tissue diseases, 030304 developmental biology, Ovarian Neoplasms, Caspase 8, 0303 health sciences, education.field_of_study, Hereditary cancer and cancer-related syndromes [ONCOL 1], Cancer, medicine.disease, 3. Good health, Minor allele frequency, 030220 oncology & carcinogenesis, Cancer and Oncology, Mutation, Cancer research, Female, Breast disease, Ovarian cancer
Abstract

Background: The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population. Methods: To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Results: The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; Ptrend = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; Ptrend = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers. Conclusions: CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers. Impact: The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev; 19(11); 2859–68. ©2010 AACR.

Published
2010

55. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers

Author

Osorio, A., Milne, R.L., Kuchenbaecker, K., Vaclova, T., Pita, G., Alonso, R., Peterlongo, P., Blanco, I., Hoya, M. de la, Duran, M., Diez, O., Ramon, Y.C.T., Konstantopoulou, I., Martinez-Bouzas, C., Conejero, R. Andres, Soucy, P., McGuffog, L., Barrowdale, D., Lee, A., Swe, B., Arver, B., Rantala, J., Loman, N., Ehrencrona, H., Olopade, O.I., Beattie, M.S., Domchek, S.M., Nathanson, K., Rebbeck, T.R., Arun, B.K., Karlan, B.Y., Walsh, C., Lester, J., John, E.M., Whittemore, A.S., Daly, M.B., Southey, M., Hopper, J., Terry, M.B., Buys, S.S., Janavicius, R., Dorfling, C.M., Rensburg, E.J. van, Steele, L., Neuhausen, S.L., Ding, Y.C., Hansen, T.V., Jonson, L., Ejlertsen, B., Gerdes, A.M., Infante, M., Herraez, B., Moreno, L.T., Weitzel, J.N., Herzog, J., Weeman, K., Manoukian, S., Peissel, B., Zaffaroni, D., Scuvera, G., Bonanni, B., Mariette, F., Volorio, S., Viel, A., Varesco, L., Papi, L., Ottini, L., Tibiletti, M.G., Radice, P., Yannoukakos, D., Garber, J., Ellis, S., Frost, D., Platte, R., Fineberg, E., Evans, G., Lalloo, F., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Cole, T., Eccles, D., Cook, J., Hodgson, S., Brewer, C., Tischkowitz, M., Douglas, F., Porteous, M., Side, L., Walker, L., Morrison, P., Donaldson, A., Kennedy, J., Foo, C., Godwin, A.K., Schmutzler, R.K., Wappenschmidt, B., Rhiem, K., Engel, C., Hoogerbrugge-van der Linden, N., et al., Osorio, A., Milne, R.L., Kuchenbaecker, K., Vaclova, T., Pita, G., Alonso, R., Peterlongo, P., Blanco, I., Hoya, M. de la, Duran, M., Diez, O., Ramon, Y.C.T., Konstantopoulou, I., Martinez-Bouzas, C., Conejero, R. Andres, Soucy, P., McGuffog, L., Barrowdale, D., Lee, A., Swe, B., Arver, B., Rantala, J., Loman, N., Ehrencrona, H., Olopade, O.I., Beattie, M.S., Domchek, S.M., Nathanson, K., Rebbeck, T.R., Arun, B.K., Karlan, B.Y., Walsh, C., Lester, J., John, E.M., Whittemore, A.S., Daly, M.B., Southey, M., Hopper, J., Terry, M.B., Buys, S.S., Janavicius, R., Dorfling, C.M., Rensburg, E.J. van, Steele, L., Neuhausen, S.L., Ding, Y.C., Hansen, T.V., Jonson, L., Ejlertsen, B., Gerdes, A.M., Infante, M., Herraez, B., Moreno, L.T., Weitzel, J.N., Herzog, J., Weeman, K., Manoukian, S., Peissel, B., Zaffaroni, D., Scuvera, G., Bonanni, B., Mariette, F., Volorio, S., Viel, A., Varesco, L., Papi, L., Ottini, L., Tibiletti, M.G., Radice, P., Yannoukakos, D., Garber, J., Ellis, S., Frost, D., Platte, R., Fineberg, E., Evans, G., Lalloo, F., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Cole, T., Eccles, D., Cook, J., Hodgson, S., Brewer, C., Tischkowitz, M., Douglas, F., Porteous, M., Side, L., Walker, L., Morrison, P., Donaldson, A., Kennedy, J., Foo, C., Godwin, A.K., Schmutzler, R.K., Wappenschmidt, B., Rhiem, K., Engel, C., Hoogerbrugge-van der Linden, N., and et al.

Abstract

Contains fulltext : 137733.pdf (publisher's version ) (Open Access), Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 x 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 x 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

Published
2014

56. C Modifies Breast Cancer Risk among BRCA2 Mutation Carriers: Results from a Combined Analysis of 19 Studies

Author

Antoniou, A.C., Sinilnikova, O.M., Simard, J., Leone, M., Dumont, M., Neuhausen, S.L., Struewing, J.P., Stoppa-Lyonnet, Dominique, Barjhoux, L., Hughes, D.J., Coupier, I., Belotti, M., Lasset, Christine, Bonadona, Valérie, Bignon, Y.J., Rebbeck, T.R., Wagner, T., Lynch, H.T., Domchek, S.M., Nathanson, K.L., Garber, J.E., Weitzel, J., Narod, S.A., Tomlinson, G., Olopade, O.I., Godwin, A., Isaacs, C., Jakubowska, A., Lubinski, J., Gronwald, J., Gorski, B., Byrski, T., Huzarski, T., Peock, S., Cook, M., Baynes, C., Murray, A., Rogers, M., Daly, P.A., Dorkins, H., Schmutzler, R.K., Versmold, B., Engel, C., Meindl, A., Arnold, N., Niederacher, D., Deissler, H., Spurdle, A.B., Chen, X., Waddell, N., Cloonan, N., Kirchhoff, T., Offit, K., Friedman, E., Kaufmann, B., Laitman, Y., Galore, G., Rennert, G., Lejbkowicz, F., Raskin, L., Andrulis, I.L., Ilyushik, E., Ozcelik, H., Devilee, P., Vreeswijk, M.P., Greene, M.H., Prindiville, S.A., Osorio, A., Benitez, J., Zikan, M., Szabo, C.I., Kilpivaara, O., Nevanlinna, H., Hamann, U., Durocher, F., Arason, A., Couch, F.J., Easton, D.F., Chenevix-Trench, G., Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT]
Published
2007

58. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk.

Author

Couch, F.J., Wang, X., McGuffog, L., Lee, A., Olswold, C., Kuchenbaecker, K.B., Soucy, P., Fredericksen, Z., Barrowdale, D., Dennis, J., Gaudet, M.M., Dicks, E., Kosel, M., Healey, S., Sinilnikova, O.M., Bacot, F., Vincent, D., Hogervorst, F.B., Peock, S., Stoppa-Lyonnet, D., Jakubowska, A., Radice, P., Schmutzler, R.K., Domchek, S.M., Piedmonte, M., Singer, C.F., Friedman, E., Thomassen, M., Hansen, T.V., Neuhausen, S.L., Szabo, C.I., Blanco, I., Greene, M.H., Karlan, B.Y., Garber, J., Phelan, C.M., Weitzel, J.N., Montagna, M., Olah, E., Andrulis, I.L., Godwin, A.K., Yannoukakos, D., Goldgar, D.E., Caldes, T., Nevanlinna, H., Osorio, A., Terry, M.B., Daly, M.B., Rensburg, E.J. van, Hamann, U., Ramus, S.J., Ewart Toland, A., Caligo, M.A., Olopade, O.I., Tung, N., Claes, K., Beattie, M.S., Southey, M.C., Imyanitov, E.N., Tischkowitz, M., Janavicius, R., John, E.M., Kwong, A., Diez, O., Balmana, J., Barkardottir, R.B., Arun, B.K., Rennert, G., Teo, S.H., Ganz, P.A., Campbell, I., Hout, A.H. van der, Deurzen, C.H. van, Seynaeve, C., Gomez Garcia, E.B., Leeuwen, F.E. van, Meijers-Heijboer, H.E., Gille, J.J.P., Ausems, M.G., Blok, M.J., Ligtenberg, M.J.L., Rookus, M.A., Devilee, P., Verhoef, S., Os, T.A. van, Wijnen, J.T., Frost, D., Ellis, S., Fineberg, E., Platte, R., Evans, D.G., Izatt, L., Eeles, R.A., Adlard, J., Eccles, D.M., Cook, J., Brewer, C., Douglas, F., Hodgson, S., Morrison, P.J., Side, L.E., Donaldson, A., Houghton, C., Rogers, M.T., Dorkins, H., Eason, J., Gregory, H., McCann, E., Murray, A., Calender, A., Hardouin, A., Berthet, P., Delnatte, C., Nogues, C., Lasset, C., Houdayer, C., Leroux, D., Rouleau, E., Prieur, F., Damiola, F., Sobol, H., Coupier, I., Venat-Bouvet, L., Castera, L., Gauthier-Villars, M., Leone, M., Pujol, P., Mazoyer, S., Bignon, Y.J., Zlowocka-Perlowska, E., Gronwald, J., Lubinski, J., Durda, K., Jaworska, K., Huzarski, T., Spurdle, A.B., Viel, A., Peissel, B., Bonanni, B., Melloni, G., Ottini, L., Papi, L., Varesco, L., Tibiletti, M.G., Peterlongo, P., Volorio, S., Manoukian, S., Pensotti, V., Arnold, N., Engel, C., Deissler, H., Gadzicki, D., Gehrig, A., Kast, K., Rhiem, K., Meindl, A., Niederacher, D., Ditsch, N., Plendl, H., Preisler-Adams, S., Engert, S., Sutter, C., Varon-Mateeva, R., Wappenschmidt, B., Weber, B.H., Arver, B., Stenmark-Askmalm, M., Loman, N., Rosenquist, R., Einbeigi, Z., Nathanson, K.L., Rebbeck, T.R., Blank, S.V., Cohn, D.E., Rodriguez, G.C., Small, L., Friedlander, M., Bae-Jump, V.L., Fink-Retter, A., Rappaport, C., Gschwantler-Kaulich, D., Pfeiler, G., Tea, M.K., Lindor, N.M., Kaufman, B., Shimon Paluch, S., Laitman, Y., Skytte, A.B., Gerdes, A.M., Pedersen, I.S., Moeller, S.T., Kruse, T.A., Jensen, U.B., Vijai, J., Sarrel, K., Robson, M., Kauff, N., Mulligan, A.M., Glendon, G., Ozcelik, H., Ejlertsen, B., Nielsen, F.C., Jonson, L., Andersen, M.K., Ding, Y.C., Steele, L., Foretova, L., Teule, A., Lazaro, C., Brunet, J., Pujana, M.A., Mai, P.L., Loud, J.T., Walsh, C., Lester, J., Orsulic, S., Narod, S.A., Herzog, J., Sand, S.R., Tognazzo, S., Agata, S., Vaszko, T., Weaver, J., Stavropoulou, A.V., Buys, S.S., Romero, A., Hoya, M. de la, Aittomaki, K., Muranen, T.A., Duran, M., Chung, W.K., Lasa, A., Dorfling, C.M., Miron, A., Benitez, J., Senter, L., Huo, D., Chan, S.B., Sokolenko, A.P., Chiquette, J., Tihomirova, L., Friebel, T.M., Agnarsson, B.A., Lu, K.H., Lejbkowicz, F., James, P.A., Hall, P., Dunning, A.M., Tessier, D., Cunningham, J., Slager, S.L., Wang, C., Hart, S., Stevens, K., Simard, J., Pastinen, T., Pankratz, V.S., Offit, K., Easton, D.F., Chenevix-Trench, G., Antoniou, A.C., et al., Couch, F.J., Wang, X., McGuffog, L., Lee, A., Olswold, C., Kuchenbaecker, K.B., Soucy, P., Fredericksen, Z., Barrowdale, D., Dennis, J., Gaudet, M.M., Dicks, E., Kosel, M., Healey, S., Sinilnikova, O.M., Bacot, F., Vincent, D., Hogervorst, F.B., Peock, S., Stoppa-Lyonnet, D., Jakubowska, A., Radice, P., Schmutzler, R.K., Domchek, S.M., Piedmonte, M., Singer, C.F., Friedman, E., Thomassen, M., Hansen, T.V., Neuhausen, S.L., Szabo, C.I., Blanco, I., Greene, M.H., Karlan, B.Y., Garber, J., Phelan, C.M., Weitzel, J.N., Montagna, M., Olah, E., Andrulis, I.L., Godwin, A.K., Yannoukakos, D., Goldgar, D.E., Caldes, T., Nevanlinna, H., Osorio, A., Terry, M.B., Daly, M.B., Rensburg, E.J. van, Hamann, U., Ramus, S.J., Ewart Toland, A., Caligo, M.A., Olopade, O.I., Tung, N., Claes, K., Beattie, M.S., Southey, M.C., Imyanitov, E.N., Tischkowitz, M., Janavicius, R., John, E.M., Kwong, A., Diez, O., Balmana, J., Barkardottir, R.B., Arun, B.K., Rennert, G., Teo, S.H., Ganz, P.A., Campbell, I., Hout, A.H. van der, Deurzen, C.H. van, Seynaeve, C., Gomez Garcia, E.B., Leeuwen, F.E. van, Meijers-Heijboer, H.E., Gille, J.J.P., Ausems, M.G., Blok, M.J., Ligtenberg, M.J.L., Rookus, M.A., Devilee, P., Verhoef, S., Os, T.A. van, Wijnen, J.T., Frost, D., Ellis, S., Fineberg, E., Platte, R., Evans, D.G., Izatt, L., Eeles, R.A., Adlard, J., Eccles, D.M., Cook, J., Brewer, C., Douglas, F., Hodgson, S., Morrison, P.J., Side, L.E., Donaldson, A., Houghton, C., Rogers, M.T., Dorkins, H., Eason, J., Gregory, H., McCann, E., Murray, A., Calender, A., Hardouin, A., Berthet, P., Delnatte, C., Nogues, C., Lasset, C., Houdayer, C., Leroux, D., Rouleau, E., Prieur, F., Damiola, F., Sobol, H., Coupier, I., Venat-Bouvet, L., Castera, L., Gauthier-Villars, M., Leone, M., Pujol, P., Mazoyer, S., Bignon, Y.J., Zlowocka-Perlowska, E., Gronwald, J., Lubinski, J., Durda, K., Jaworska, K., Huzarski, T., Spurdle, A.B., Viel, A., Peissel, B., Bonanni, B., Melloni, G., Ottini, L., Papi, L., Varesco, L., Tibiletti, M.G., Peterlongo, P., Volorio, S., Manoukian, S., Pensotti, V., Arnold, N., Engel, C., Deissler, H., Gadzicki, D., Gehrig, A., Kast, K., Rhiem, K., Meindl, A., Niederacher, D., Ditsch, N., Plendl, H., Preisler-Adams, S., Engert, S., Sutter, C., Varon-Mateeva, R., Wappenschmidt, B., Weber, B.H., Arver, B., Stenmark-Askmalm, M., Loman, N., Rosenquist, R., Einbeigi, Z., Nathanson, K.L., Rebbeck, T.R., Blank, S.V., Cohn, D.E., Rodriguez, G.C., Small, L., Friedlander, M., Bae-Jump, V.L., Fink-Retter, A., Rappaport, C., Gschwantler-Kaulich, D., Pfeiler, G., Tea, M.K., Lindor, N.M., Kaufman, B., Shimon Paluch, S., Laitman, Y., Skytte, A.B., Gerdes, A.M., Pedersen, I.S., Moeller, S.T., Kruse, T.A., Jensen, U.B., Vijai, J., Sarrel, K., Robson, M., Kauff, N., Mulligan, A.M., Glendon, G., Ozcelik, H., Ejlertsen, B., Nielsen, F.C., Jonson, L., Andersen, M.K., Ding, Y.C., Steele, L., Foretova, L., Teule, A., Lazaro, C., Brunet, J., Pujana, M.A., Mai, P.L., Loud, J.T., Walsh, C., Lester, J., Orsulic, S., Narod, S.A., Herzog, J., Sand, S.R., Tognazzo, S., Agata, S., Vaszko, T., Weaver, J., Stavropoulou, A.V., Buys, S.S., Romero, A., Hoya, M. de la, Aittomaki, K., Muranen, T.A., Duran, M., Chung, W.K., Lasa, A., Dorfling, C.M., Miron, A., Benitez, J., Senter, L., Huo, D., Chan, S.B., Sokolenko, A.P., Chiquette, J., Tihomirova, L., Friebel, T.M., Agnarsson, B.A., Lu, K.H., Lejbkowicz, F., James, P.A., Hall, P., Dunning, A.M., Tessier, D., Cunningham, J., Slager, S.L., Wang, C., Hart, S., Stevens, K., Simard, J., Pastinen, T., Pankratz, V.S., Offit, K., Easton, D.F., Chenevix-Trench, G., Antoniou, A.C., and et al.

Abstract

01 maart 2013, Contains fulltext : 115394.pdf (publisher's version ) (Open Access), BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7x10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4x10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4x10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2x10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Published
2013

59. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

Author

Ramus, S.J., Antoniou, A.C., Kuchenbaecker, K.B., Soucy, P., Beesley, J., Chen, X., McGuffog, L., Sinilnikova, O.M., Healey, S., Barrowdale, D., Lee, A., Thomassen, M., Gerdes, A.M., Kruse, T.A., Jensen, U.B., Skytte, A.B., Caligo, M.A., Liljegren, A., Lindblom, A., Olsson, H., Kristoffersson, U., Stenmark-Askmalm, M., Melin, B., Swe, B., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Zlowocka, E., Gronwald, J., Huzarski, T., Byrski, T., Cybulski, C., Toloczko-Grabarek, A., Osorio, A., Benitez, J., Duran, M., Tejada, M.I., Hamann, U., Rookus, M., van Leeuwen, F.E., Aalfs, C.M., Meijers-Heijboer, H.E., Asperen, C.J. van, van Roozendaal, K.E., Hoogerbrugge-van der Linden, N., Collee, J.M., Kriege, M., van der Luijt, R.B., Hebon, ., Embrace, ., Peock, S., Frost, D., Ellis, S.D., Platte, R., Fineberg, E., Evans, D.G., Lalloo, F., Jacobs, C, Eeles, R., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J.L., Paterson, J., Douglas, F., Brewer, C., Hodgson, S., Morrison, P.J., Walker, L., Porteous, M.E., Kennedy, M.J., Pathak, H., Godwin, A.K., Stoppa-Lyonnet, D., Caux-Moncoutier, V., de Pauw, A., Gauthier-Villars, M., Mazoyer, S., Leone, M., Calender, A., Lasset, C., Bonadona, V., Hardouin, A., Berthet, P., Bignon, Y.J., Uhrhammer, N., Faivre, L., Loustalot, C., Gemo, ., Buys, S., Daly, M., Miron, A., Terry, M.B., Chung, W.K., John, E.M., Ligtenberg, M.J., et al., Ramus, S.J., Antoniou, A.C., Kuchenbaecker, K.B., Soucy, P., Beesley, J., Chen, X., McGuffog, L., Sinilnikova, O.M., Healey, S., Barrowdale, D., Lee, A., Thomassen, M., Gerdes, A.M., Kruse, T.A., Jensen, U.B., Skytte, A.B., Caligo, M.A., Liljegren, A., Lindblom, A., Olsson, H., Kristoffersson, U., Stenmark-Askmalm, M., Melin, B., Swe, B., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Zlowocka, E., Gronwald, J., Huzarski, T., Byrski, T., Cybulski, C., Toloczko-Grabarek, A., Osorio, A., Benitez, J., Duran, M., Tejada, M.I., Hamann, U., Rookus, M., van Leeuwen, F.E., Aalfs, C.M., Meijers-Heijboer, H.E., Asperen, C.J. van, van Roozendaal, K.E., Hoogerbrugge-van der Linden, N., Collee, J.M., Kriege, M., van der Luijt, R.B., Hebon, ., Embrace, ., Peock, S., Frost, D., Ellis, S.D., Platte, R., Fineberg, E., Evans, D.G., Lalloo, F., Jacobs, C, Eeles, R., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J.L., Paterson, J., Douglas, F., Brewer, C., Hodgson, S., Morrison, P.J., Walker, L., Porteous, M.E., Kennedy, M.J., Pathak, H., Godwin, A.K., Stoppa-Lyonnet, D., Caux-Moncoutier, V., de Pauw, A., Gauthier-Villars, M., Mazoyer, S., Leone, M., Calender, A., Lasset, C., Bonadona, V., Hardouin, A., Berthet, P., Bignon, Y.J., Uhrhammer, N., Faivre, L., Loustalot, C., Gemo, ., Buys, S., Daly, M., Miron, A., Terry, M.B., Chung, W.K., John, E.M., Ligtenberg, M.J., and et al.

Abstract

Item does not contain fulltext, Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 x 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 x 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 x 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

Published
2012

60. Common genetic variation at BARD1 is not associated with breast cancer risk in BRCA1 or BRCA2 mutation carriers

Author

Spurdle, A.B., Marquart, L., McGuffog, L., Healey, S., Sinilnikova, O., Wan, F., Chen, X., Beesley, J., Singer, C.F., Dressler, A.C., Gschwantler-Kaulich, D., Blum, J.L., Tung, N., Weitzel, J., Lynch, H., Garber, J., Easton, D.F., Peock, S., Cook, M., Oliver, C.T., Frost, D., Conroy, D., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Davidson, R., Chu, C., Eccles, D., Selkirk, C.G., Daly, M., Isaacs, C., Stoppa-Lyonnet, D., Sinilnikova, O.M., Buecher, B., Belotti, M., Mazoyer, S., Barjhoux, L., Verny-Pierre, C., Lasset, C., Dreyfus, H., Pujol, P., Collonge-Rame, M.A., Rookus, M.A., Verhoef, S., Kriege, M., Hoogerbrugge, N., Ausems, M.G., Os, T.A. van, Wijnen, J., Devilee, P., Meijers-Heijboer, H.E., Blok, M.J., Heikkinen, T., Nevanlinna, H., Jakubowska, A., Lubinski, J., Huzarski, T., Byrski, T., Durocher, F., Couch, F.J., Lindor, N.M., Wang, X., Thomassen, M., Domchek, S., Nathanson, K., Caligo, M., Jernstrom, H., Liljegren, A., Ehrencrona, H., Karlsson, P., Ganz, P.A., Olopade, O.I., Tomlinson, G., Neuhausen, S., Antoniou, A.C., Chenevix-Trench, G., Rebbeck, T.R., Spurdle, A.B., Marquart, L., McGuffog, L., Healey, S., Sinilnikova, O., Wan, F., Chen, X., Beesley, J., Singer, C.F., Dressler, A.C., Gschwantler-Kaulich, D., Blum, J.L., Tung, N., Weitzel, J., Lynch, H., Garber, J., Easton, D.F., Peock, S., Cook, M., Oliver, C.T., Frost, D., Conroy, D., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Davidson, R., Chu, C., Eccles, D., Selkirk, C.G., Daly, M., Isaacs, C., Stoppa-Lyonnet, D., Sinilnikova, O.M., Buecher, B., Belotti, M., Mazoyer, S., Barjhoux, L., Verny-Pierre, C., Lasset, C., Dreyfus, H., Pujol, P., Collonge-Rame, M.A., Rookus, M.A., Verhoef, S., Kriege, M., Hoogerbrugge, N., Ausems, M.G., Os, T.A. van, Wijnen, J., Devilee, P., Meijers-Heijboer, H.E., Blok, M.J., Heikkinen, T., Nevanlinna, H., Jakubowska, A., Lubinski, J., Huzarski, T., Byrski, T., Durocher, F., Couch, F.J., Lindor, N.M., Wang, X., Thomassen, M., Domchek, S., Nathanson, K., Caligo, M., Jernstrom, H., Liljegren, A., Ehrencrona, H., Karlsson, P., Ganz, P.A., Olopade, O.I., Tomlinson, G., Neuhausen, S., Antoniou, A.C., Chenevix-Trench, G., and Rebbeck, T.R.

Abstract

Item does not contain fulltext, BACKGROUND: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies. METHODS: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated. RESULTS: The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71-1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59-1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk. CONCLUSION: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers. IMPACT: Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk.

Published
2011

61. Exploring the link between MORF4L1 and risk of breast cancer.

Author

Martrat, G., Maxwell, C.M., Tominaga, E., Porta-de-la-Riva, M., Bonifaci, N., Gomez-Baldo, L., Bogliolo, M., Lazaro, C., Blanco, I., Brunet, J., Aguilar, H., Fernandez-Rodriguez, J., Seal, S., Renwick, A., Rahman, N., Kuhl, J., Neveling, K., Schindler, D., Ramirez, M.J., Castella, M., Hernandez, G., Easton, D.F., Peock, S., Cook, M., Oliver, C.T., Frost, D., Platte, R., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Chu, C., Davidson, R., Ong, K.R., Cook, J., Douglas, F., Hodgson, S., Brewer, C., Morrison, P.J., Porteous, M., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., Pasini, B., Ottini, L., Putignano, A.L., Savarese, A., Bernard, L., Radice, P., Healey, S., Spurdle, A., Chen, X., Beesley, J., Rookus, M.A., Verhoef, S., Tilanus-Linthorst, M.A., Vreeswijk, M.P., Asperen, C.J. van, Bodmer, D., Ausems, M.G., Os, T.A. van, Blok, M.J., Meijers-Heijboer, H.E., Hogervorst, F.B.L., Goldgar, D.E., Buys, S., John, E.M., Miron, A., Southey, M., Daly, M.B., Harbst, K., Borg, A., Rantala, J., Barbany-Bustinza, G., Ehrencrona, H., Stenmark-Askmalm, M., Kaufman, B., Laitman, Y., Milgrom, R., Friedman, E., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Johannsson, O.T., Couch, F.J., Wang, X., Fredericksen, Z., Cuadras, D., Moreno, V., Pientka, F.K., Depping, R., Caldes, T., Osorio, A., Benitez, J., Bueren, J., Heikkinen, T., Nevanlinna, H., Hamann, U., Torres, D., Caligo, M.A., Godwin, A.K., Imyanitov, E.N., Janavicius, R., Sinilnikova, O.M., Stoppa-Lyonnet, D., Mazoyer, S., Verny-Pierre, C., Castera, L., Pauw, A. de, Bignon, Y.J., Uhrhammer, N., Peyrat, J.P., Vennin, P., Ferrer, S.F., Collonge-Rame, M.A., Mortemousque, I., McGuffog, L., Chenevix-Trench, G., Pereira-Smith, O.M., Antoniou, A.C., Ceron, J., Tominaga, K., Surralles, J., Pujana, M.A., Martrat, G., Maxwell, C.M., Tominaga, E., Porta-de-la-Riva, M., Bonifaci, N., Gomez-Baldo, L., Bogliolo, M., Lazaro, C., Blanco, I., Brunet, J., Aguilar, H., Fernandez-Rodriguez, J., Seal, S., Renwick, A., Rahman, N., Kuhl, J., Neveling, K., Schindler, D., Ramirez, M.J., Castella, M., Hernandez, G., Easton, D.F., Peock, S., Cook, M., Oliver, C.T., Frost, D., Platte, R., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Chu, C., Davidson, R., Ong, K.R., Cook, J., Douglas, F., Hodgson, S., Brewer, C., Morrison, P.J., Porteous, M., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., Pasini, B., Ottini, L., Putignano, A.L., Savarese, A., Bernard, L., Radice, P., Healey, S., Spurdle, A., Chen, X., Beesley, J., Rookus, M.A., Verhoef, S., Tilanus-Linthorst, M.A., Vreeswijk, M.P., Asperen, C.J. van, Bodmer, D., Ausems, M.G., Os, T.A. van, Blok, M.J., Meijers-Heijboer, H.E., Hogervorst, F.B.L., Goldgar, D.E., Buys, S., John, E.M., Miron, A., Southey, M., Daly, M.B., Harbst, K., Borg, A., Rantala, J., Barbany-Bustinza, G., Ehrencrona, H., Stenmark-Askmalm, M., Kaufman, B., Laitman, Y., Milgrom, R., Friedman, E., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Johannsson, O.T., Couch, F.J., Wang, X., Fredericksen, Z., Cuadras, D., Moreno, V., Pientka, F.K., Depping, R., Caldes, T., Osorio, A., Benitez, J., Bueren, J., Heikkinen, T., Nevanlinna, H., Hamann, U., Torres, D., Caligo, M.A., Godwin, A.K., Imyanitov, E.N., Janavicius, R., Sinilnikova, O.M., Stoppa-Lyonnet, D., Mazoyer, S., Verny-Pierre, C., Castera, L., Pauw, A. de, Bignon, Y.J., Uhrhammer, N., Peyrat, J.P., Vennin, P., Ferrer, S.F., Collonge-Rame, M.A., Mortemousque, I., McGuffog, L., Chenevix-Trench, G., Pereira-Smith, O.M., Antoniou, A.C., Ceron, J., Tominaga, K., Surralles, J., and Pujana, M.A.

Abstract

Contains fulltext : 96909.pdf (publisher's version ) (Open Access), INTRODUCTION: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. METHODS: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. RESULTS: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to gamma-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.

Published
2011

62. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.

Author

Cox, D.G., Simard, J., Sinnett, D., Hamdi, Y., Soucy, P., Ouimet, M., Barjhoux, L., Verny-Pierre, C., McGuffog, L., Healey, S., Szabo, C., Greene, M.H., Mai, P.L., Andrulis, I.L., Thomassen, M., Gerdes, A.M., Caligo, M.A., Friedman, E., Laitman, Y., Kaufman, B., Paluch, S.S., Borg, A., Karlsson, P., Askmalm, M.S., Bustinza, G.B., Nathanson, K.L., Domchek, S.M., Rebbeck, T.R., Benitez, J., Hamann, U., Rookus, M.A., Ouweland, A.M. van den, Ausems, M.G., Aalfs, C.M., Asperen, C.J. van, Devilee, P., Gille, H.J., Peock, S., Frost, D., Evans, D.G., Eeles, R., Izatt, L., Adlard, J., Paterson, J., Eason, J., Godwin, A.K., Remon, M.A., Moncoutier, V., Gauthier-Villars, M., Lasset, C., Giraud, S., Hardouin, A., Berthet, P., Sobol, H., Eisinger, F., Bressac de Paillerets, B., Caron, O., Delnatte, C., Goldgar, D., Miron, A., Ozcelik, H., Buys, S., Southey, M.C., Terry, M.B., Singer, C.F., Dressler, A.C., Tea, M.K., Hansen, T.V., Johannsson, O., Piedmonte, M., Rodriguez, G.C., Basil, J.B., Blank, S., Toland, A.E., Montagna, M., Isaacs, C., Blanco, I., Gayther, S.A., Moysich, K.B., Schmutzler, R.K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Sutter, C., Gadzicki, D., Fiebig, B., Caldes, T., Laframboise, R., Nevanlinna, H., Chen, X., Beesley, J., Spurdle, A.B., Neuhausen, S.L., Ding, Y.C., Couch, F.J., Wang, X., Peterlongo, P., Manoukian, S., Bernard, L., Radice, P., Easton, D.F., Chenevix-Trench, G., Antoniou, A.C., Stoppa-Lyonnet, D., Mazoyer, S., Sinilnikova, O.M., Ligtenberg, M.J.L., Hoogerbrugge, N., et al., Cox, D.G., Simard, J., Sinnett, D., Hamdi, Y., Soucy, P., Ouimet, M., Barjhoux, L., Verny-Pierre, C., McGuffog, L., Healey, S., Szabo, C., Greene, M.H., Mai, P.L., Andrulis, I.L., Thomassen, M., Gerdes, A.M., Caligo, M.A., Friedman, E., Laitman, Y., Kaufman, B., Paluch, S.S., Borg, A., Karlsson, P., Askmalm, M.S., Bustinza, G.B., Nathanson, K.L., Domchek, S.M., Rebbeck, T.R., Benitez, J., Hamann, U., Rookus, M.A., Ouweland, A.M. van den, Ausems, M.G., Aalfs, C.M., Asperen, C.J. van, Devilee, P., Gille, H.J., Peock, S., Frost, D., Evans, D.G., Eeles, R., Izatt, L., Adlard, J., Paterson, J., Eason, J., Godwin, A.K., Remon, M.A., Moncoutier, V., Gauthier-Villars, M., Lasset, C., Giraud, S., Hardouin, A., Berthet, P., Sobol, H., Eisinger, F., Bressac de Paillerets, B., Caron, O., Delnatte, C., Goldgar, D., Miron, A., Ozcelik, H., Buys, S., Southey, M.C., Terry, M.B., Singer, C.F., Dressler, A.C., Tea, M.K., Hansen, T.V., Johannsson, O., Piedmonte, M., Rodriguez, G.C., Basil, J.B., Blank, S., Toland, A.E., Montagna, M., Isaacs, C., Blanco, I., Gayther, S.A., Moysich, K.B., Schmutzler, R.K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Sutter, C., Gadzicki, D., Fiebig, B., Caldes, T., Laframboise, R., Nevanlinna, H., Chen, X., Beesley, J., Spurdle, A.B., Neuhausen, S.L., Ding, Y.C., Couch, F.J., Wang, X., Peterlongo, P., Manoukian, S., Bernard, L., Radice, P., Easton, D.F., Chenevix-Trench, G., Antoniou, A.C., Stoppa-Lyonnet, D., Mazoyer, S., Sinilnikova, O.M., Ligtenberg, M.J.L., Hoogerbrugge, N., and et al.

Abstract

Item does not contain fulltext, Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Published
2011

63. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

Author

Im, K.M., Kirchhoff, T., Wang, X., Green, T., Chow, C.Y., Vijai, J., Korn, J., Gaudet, M.M., Fredericksen, Z., Shane Pankratz, V., Guiducci, C., Crenshaw, A., McGuffog, L., Kartsonaki, C., Morrison, J., Healey, S., Sinilnikova, O.M., Mai, P.L., Greene, M.H., Piedmonte, M., Rubinstein, W.S., Hogervorst, F.B.L., Rookus, M.A., Collee, J.M., Hoogerbrugge, N., Asperen, C.J. van, Meijers-Heijboer, H.E., Roozendaal, C.E.P. van, Caldes, T., Perez-Segura, P., Jakubowska, A., Lubinski, J., Huzarski, T., Blecharz, P., Nevanlinna, H., Aittomaki, K., Lazaro, C., Blanco, I., Barkardottir, R.B., Montagna, M., D'Andrea, E., Devilee, P., Olopade, O.I., Neuhausen, S.L., Peissel, B., Bonanni, B., Peterlongo, P., Singer, C.F., Rennert, G., Lejbkowicz, F., Andrulis, I.L., Glendon, G., Ozcelik, H., Toland, A.E., Caligo, M.A., Beattie, M.S., Chan, S., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Phelan, C., Narod, S., John, E.M., Hopper, J.L., Buys, S.S., Daly, M.B., Southey, M.C., Terry, M.B., Tung, N., Hansen, T.V., Osorio, A., Benitez, J., Duran, M., Weitzel, J.N., Garber, J., Hamann, U., Peock, S., Cook, M., Oliver, C.T., Frost, D., Platte, R., Evans, D.G., Eeles, R., Izatt, L., Paterson, J., Brewer, C., Hodgson, S., Morrison, P.J., Porteous, M., Walker, L., Rogers, M.T., Side, L.E., Godwin, A.K., Schmutzler, R.K., Wappenschmidt, B., Laitman, Y., Meindl, A., Deissler, H., Varon-Mateeva, R., Preisler-Adams, S., Ligtenberg, M.J.L., et al., Im, K.M., Kirchhoff, T., Wang, X., Green, T., Chow, C.Y., Vijai, J., Korn, J., Gaudet, M.M., Fredericksen, Z., Shane Pankratz, V., Guiducci, C., Crenshaw, A., McGuffog, L., Kartsonaki, C., Morrison, J., Healey, S., Sinilnikova, O.M., Mai, P.L., Greene, M.H., Piedmonte, M., Rubinstein, W.S., Hogervorst, F.B.L., Rookus, M.A., Collee, J.M., Hoogerbrugge, N., Asperen, C.J. van, Meijers-Heijboer, H.E., Roozendaal, C.E.P. van, Caldes, T., Perez-Segura, P., Jakubowska, A., Lubinski, J., Huzarski, T., Blecharz, P., Nevanlinna, H., Aittomaki, K., Lazaro, C., Blanco, I., Barkardottir, R.B., Montagna, M., D'Andrea, E., Devilee, P., Olopade, O.I., Neuhausen, S.L., Peissel, B., Bonanni, B., Peterlongo, P., Singer, C.F., Rennert, G., Lejbkowicz, F., Andrulis, I.L., Glendon, G., Ozcelik, H., Toland, A.E., Caligo, M.A., Beattie, M.S., Chan, S., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Phelan, C., Narod, S., John, E.M., Hopper, J.L., Buys, S.S., Daly, M.B., Southey, M.C., Terry, M.B., Tung, N., Hansen, T.V., Osorio, A., Benitez, J., Duran, M., Weitzel, J.N., Garber, J., Hamann, U., Peock, S., Cook, M., Oliver, C.T., Frost, D., Platte, R., Evans, D.G., Eeles, R., Izatt, L., Paterson, J., Brewer, C., Hodgson, S., Morrison, P.J., Porteous, M., Walker, L., Rogers, M.T., Side, L.E., Godwin, A.K., Schmutzler, R.K., Wappenschmidt, B., Laitman, Y., Meindl, A., Deissler, H., Varon-Mateeva, R., Preisler-Adams, S., Ligtenberg, M.J.L., and et al.

Abstract

Item does not contain fulltext, Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.

Published
2011

64. Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Author

Wang, X., Pankratz, V.S., Fredericksen, Z., Tarrell, R., Karaus, M., McGuffog, L., Pharaoh, P.D., Ponder, B.A.J., Dunning, A.M., Peock, S., Cook, M., Oliver, C., Frost, D., Sinilnikova, O.M., Stoppa-Lyonnet, D., Mazoyer, S., Houdayer, C., Hogervorst, F.B.L., Hooning, M.J., Ligtenberg, M.J.L., Spurdle, A., Chenevix-Trench, G., Schmutzler, R.K., Wappenschmidt, B., Engel, C., Meindl, A., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Singer, C.F., Gschwantler-Kaulich, D., Dressler, C., Fink, A., Szabo, C.I., Zikan, M., Foretova, L., Claes, K., Thomas, G., Hoover, R.N., Hunter, D.J., Chanock, S.J., Easton, D.F., Antoniou, A.C., Couch, F.J., Wang, X., Pankratz, V.S., Fredericksen, Z., Tarrell, R., Karaus, M., McGuffog, L., Pharaoh, P.D., Ponder, B.A.J., Dunning, A.M., Peock, S., Cook, M., Oliver, C., Frost, D., Sinilnikova, O.M., Stoppa-Lyonnet, D., Mazoyer, S., Houdayer, C., Hogervorst, F.B.L., Hooning, M.J., Ligtenberg, M.J.L., Spurdle, A., Chenevix-Trench, G., Schmutzler, R.K., Wappenschmidt, B., Engel, C., Meindl, A., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Singer, C.F., Gschwantler-Kaulich, D., Dressler, C., Fink, A., Szabo, C.I., Zikan, M., Foretova, L., Claes, K., Thomas, G., Hoover, R.N., Hunter, D.J., Chanock, S.J., Easton, D.F., Antoniou, A.C., and Couch, F.J.

Abstract

Contains fulltext : 89415.pdf (publisher's version ) (Closed access), Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend) < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69-0.90, P(trend) = 3.6 x 10(-4) and HR = 1.25, 95% CI: 1.10-1.41, P(trend) = 4.2 x 10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25-1.92, P(trend) = 6 x 10(-5) and HR = 1.37, 95% CI: 1.16-1.62, P(trend) = 1.7 x 10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.

Published
2010

65. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.

Author

Antoniou, A.C., Wang, X., Fredericksen, Z., McGuffog, L., Tarrell, R., Sinilnikova, O.M., Healey, S., Morrison, J., Kartsonaki, C., Lesnick, T., Ghoussaini, M., Barrowdale, D., Peock, S., Cook, M., Oliver, C., Frost, D., Eccles, D., Evans, D.G., Eeles, R., Izatt, L., Chu, C., Douglas, F., Paterson, J., Stoppa-Lyonnet, D., Houdayer, C., Mazoyer, S., Giraud, S., Lasset, C., Remenieras, A., Caron, O., Hardouin, A., Berthet, P., Hogervorst, F.B.L., Rookus, M.A., Jager, A., Ouweland, A.M.W. van den, Hoogerbrugge, N., Luijt, R.B. van der, Meijers-Heijboer, H., Gomez Garcia, E.B., Devilee, P., Vreeswijk, M.P., Lubinski, J., Jakubowska, A., Gronwald, J., Huzarski, T., Byrski, T., Gorski, B., Cybulski, C., Spurdle, A.B., Holland, H., Goldgar, D.E., John, E.M., Hopper, J.L., Southey, M.C., Buys, S.S., Daly, M.B., Terry, M.B., Schmutzler, R.K., Wappenschmidt, B., Engel, C., Meindl, A., Preisler-Adams, S., Arnold, N., Niederacher, D., Sutter, C., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Blum, J.L., Piedmonte, M., Rodriguez, G.C., Wakeley, K., Boggess, J.F., Basil, J., Blank, S.V., Friedman, E., Kaufman, B., Laitman, Y., Milgrom, R., Andrulis, I.L., Glendon, G., Ozcelik, H., Kirchhoff, T., Vijai, J., Gaudet, M.M., Altshuler, D., Guiducci, C., Loman, N., Harbst, K., Rantala, J., Ehrencrona, H., Gerdes, A.M., Thomassen, M., Sunde, L., Peterlongo, P., Manoukian, S., Bonanni, B., Viel, A., Antoniou, A.C., Wang, X., Fredericksen, Z., McGuffog, L., Tarrell, R., Sinilnikova, O.M., Healey, S., Morrison, J., Kartsonaki, C., Lesnick, T., Ghoussaini, M., Barrowdale, D., Peock, S., Cook, M., Oliver, C., Frost, D., Eccles, D., Evans, D.G., Eeles, R., Izatt, L., Chu, C., Douglas, F., Paterson, J., Stoppa-Lyonnet, D., Houdayer, C., Mazoyer, S., Giraud, S., Lasset, C., Remenieras, A., Caron, O., Hardouin, A., Berthet, P., Hogervorst, F.B.L., Rookus, M.A., Jager, A., Ouweland, A.M.W. van den, Hoogerbrugge, N., Luijt, R.B. van der, Meijers-Heijboer, H., Gomez Garcia, E.B., Devilee, P., Vreeswijk, M.P., Lubinski, J., Jakubowska, A., Gronwald, J., Huzarski, T., Byrski, T., Gorski, B., Cybulski, C., Spurdle, A.B., Holland, H., Goldgar, D.E., John, E.M., Hopper, J.L., Southey, M.C., Buys, S.S., Daly, M.B., Terry, M.B., Schmutzler, R.K., Wappenschmidt, B., Engel, C., Meindl, A., Preisler-Adams, S., Arnold, N., Niederacher, D., Sutter, C., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Blum, J.L., Piedmonte, M., Rodriguez, G.C., Wakeley, K., Boggess, J.F., Basil, J., Blank, S.V., Friedman, E., Kaufman, B., Laitman, Y., Milgrom, R., Andrulis, I.L., Glendon, G., Ozcelik, H., Kirchhoff, T., Vijai, J., Gaudet, M.M., Altshuler, D., Guiducci, C., Loman, N., Harbst, K., Rantala, J., Ehrencrona, H., Gerdes, A.M., Thomassen, M., Sunde, L., Peterlongo, P., Manoukian, S., Bonanni, B., and Viel, A.

Abstract

Contains fulltext : 89023.pdf (publisher's version ) (Closed access)

Published
2010

66. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Author

Antoniou, A.C., Spurdle, A.B., Sinilnikova, O.M., Healey, S., Pooley, K.A., Schmutzler, R.K., Versmold, B., Engel, C., Meindl, A., Arnold, N., Hofmann, W., Sutter, C., Niederacher, D., Deissler, H., Caldes, T., Kampjarvi, K., Nevanlinna, H., Simard, J., Beesley, J., Chen, X., Neuhausen, S.L., Rebbeck, T.R., Wagner, T., Lynch, H.T., Isaacs, C., Weitzel, J., Ganz, P.A., Daly, M.B., Tomlinson, G., Olopade, O.I., Blum, J.L., Couch, F.J., Peterlongo, P., Manoukian, S., Barile, M., Radice, P., Szabo, C.I., Pereira, L.H., Greene, M.H., Rennert, G., Lejbkowicz, F., Barnett-Griness, O., Andrulis, I.L., Ozcelik, H., Gerdes, A.M., Caligo, M.A., Laitman, Y., Kaufman, B., Milgrom, R., Friedman, E., Domchek, S.M., Nathanson, K.L., Osorio, A., Llort, G., Milne, R.L., Benitez, J., Hamann, U., Hogervorst, F.B.L., Manders, P., Ligtenberg, M.J.L., Ouweland, A.M.W. van den, Peock, S., Cook, M., Platte, R., Evans, D.G., Eeles, R., Pichert, G., Chu, C., Eccles, D., Davidson, R., Douglas, F., Godwin, A.K., Barjhoux, L., Mazoyer, S., Sobol, H., Bourdon, V., Eisinger, F., Chompret, A., Capoulade, C., Bressac-de Paillerets, B., Lenoir, G.M., Gauthier-Villars, M., Houdayer, C., Stoppa-Lyonnet, D., Chenevix-Trench, G., Easton, D.F., Antoniou, A.C., Spurdle, A.B., Sinilnikova, O.M., Healey, S., Pooley, K.A., Schmutzler, R.K., Versmold, B., Engel, C., Meindl, A., Arnold, N., Hofmann, W., Sutter, C., Niederacher, D., Deissler, H., Caldes, T., Kampjarvi, K., Nevanlinna, H., Simard, J., Beesley, J., Chen, X., Neuhausen, S.L., Rebbeck, T.R., Wagner, T., Lynch, H.T., Isaacs, C., Weitzel, J., Ganz, P.A., Daly, M.B., Tomlinson, G., Olopade, O.I., Blum, J.L., Couch, F.J., Peterlongo, P., Manoukian, S., Barile, M., Radice, P., Szabo, C.I., Pereira, L.H., Greene, M.H., Rennert, G., Lejbkowicz, F., Barnett-Griness, O., Andrulis, I.L., Ozcelik, H., Gerdes, A.M., Caligo, M.A., Laitman, Y., Kaufman, B., Milgrom, R., Friedman, E., Domchek, S.M., Nathanson, K.L., Osorio, A., Llort, G., Milne, R.L., Benitez, J., Hamann, U., Hogervorst, F.B.L., Manders, P., Ligtenberg, M.J.L., Ouweland, A.M.W. van den, Peock, S., Cook, M., Platte, R., Evans, D.G., Eeles, R., Pichert, G., Chu, C., Eccles, D., Davidson, R., Douglas, F., Godwin, A.K., Barjhoux, L., Mazoyer, S., Sobol, H., Bourdon, V., Eisinger, F., Chompret, A., Capoulade, C., Bressac-de Paillerets, B., Lenoir, G.M., Gauthier-Villars, M., Houdayer, C., Stoppa-Lyonnet, D., Chenevix-Trench, G., and Easton, D.F.

Abstract

Contains fulltext : 70697.pdf (publisher's version ) (Closed access), Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

Published
2008

67. Association of metabolic gene polymorphisms with tobacco consumption in healthy controls.

Author

Smits, K.M., Benhamou, S., Garte, S., Weijenberg, M.P., Alamanos, Y., Ambrosone, C., Autrup, H., Autrup, J.L., Baranova, H., Bathum, L., Boffetta, P., Bouchardy, C., Brockmoller, J., Butkiewicz, D., Cascorbi, I., Clapper, M.L., Coutelle, C., Daly, A., Muzi, G., Dolzan, V., Duzhak, T.G., Farker, K., Golka, K., Haugen, A., Hein, D.W., Hildesheim, A., Hirvonen, A., Hsieh, L.L., Ingelman-Sundberg, M., Kalina, I., Kang, D., Katoh, T., Kihara, M., Ono-Kihara, M., Kim, H.L., Kiyohara, C., Kremers, P., Lazarus, P., Marchand, L. le, Lechner, M.C., London, S., Manni, J.J., Maugard, C.M., Morgan, G.J., Morita, S., Nazar-Stewart, V., Kristensen, V.N., Oda, Y., Parl, F.F., Peters, W.H.M., Rannug, A., Rebbeck, T.R., Pinto, L.F., Risch, A., Romkes, M., Salagovic, J., Schoket, B., Seidegard, J., Shields, P.G., Sim, E., Sinnett, D., Strange, R.C., Stucker, I., Sugimura, H., To-Figueras, J., Vineis, P., Yu, M.C., Zheng, W., Pedotti, P., Taioli, E., Smits, K.M., Benhamou, S., Garte, S., Weijenberg, M.P., Alamanos, Y., Ambrosone, C., Autrup, H., Autrup, J.L., Baranova, H., Bathum, L., Boffetta, P., Bouchardy, C., Brockmoller, J., Butkiewicz, D., Cascorbi, I., Clapper, M.L., Coutelle, C., Daly, A., Muzi, G., Dolzan, V., Duzhak, T.G., Farker, K., Golka, K., Haugen, A., Hein, D.W., Hildesheim, A., Hirvonen, A., Hsieh, L.L., Ingelman-Sundberg, M., Kalina, I., Kang, D., Katoh, T., Kihara, M., Ono-Kihara, M., Kim, H.L., Kiyohara, C., Kremers, P., Lazarus, P., Marchand, L. le, Lechner, M.C., London, S., Manni, J.J., Maugard, C.M., Morgan, G.J., Morita, S., Nazar-Stewart, V., Kristensen, V.N., Oda, Y., Parl, F.F., Peters, W.H.M., Rannug, A., Rebbeck, T.R., Pinto, L.F., Risch, A., Romkes, M., Salagovic, J., Schoket, B., Seidegard, J., Shields, P.G., Sim, E., Sinnett, D., Strange, R.C., Stucker, I., Sugimura, H., To-Figueras, J., Vineis, P., Yu, M.C., Zheng, W., Pedotti, P., and Taioli, E.

Abstract

Contains fulltext : 58545.pdf (publisher's version ) (Closed access), Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected.

Published
2004

69. Metabolic gene polymorphism frequencies in control populations.

Author

Garte, S., Gaspari, L., Alexandrie, A.K., Ambrosone, C., Autrup, H., Autrup, J.L., Baranova, H., Bathum, L., Benhamou, S., Boffetta, P., Bouchardy, C., Breskvar, K., Brockmoller, J., Cascorbi, I., Clapper, M.L., Coutelle, C., Daly, A., Dell'Omo, M., Dolzan, V., Dresler, C.M., Fryer, A., Haugen, A., Hein, D.W., Hildesheim, A., Hirvonen, A., Hsieh, L.L., Ingelman-Sundberg, M., Kalina, I., Kang, D., Kihara, M., Kiyohara, C., Kremers, P., Lazarus, P., Marchand, L. le, Lechner, M.C., Lieshout, E.M.M. van, London, S., Manni, J.J., Maugard, C.M., Morita, S., Nazar-Stewart, V., Noda, K., Oda, Y., Parl, F.F., Pastorelli, R., Persson, I., Peters, W.H.M., Rannug, A., Rebbeck, T.R., Risch, A., Roelandt, L., Romkes, M., Ryberg, D., Salagovic, J., Schoket, B., Seidegard, J., Shields, P.G., Sim, E., Sinnet, D., Strange, R.C., Stucker, I., Sugimura, H., To-Figueras, J., Vineis, P., Yu, M.C., Taioli, E., Garte, S., Gaspari, L., Alexandrie, A.K., Ambrosone, C., Autrup, H., Autrup, J.L., Baranova, H., Bathum, L., Benhamou, S., Boffetta, P., Bouchardy, C., Breskvar, K., Brockmoller, J., Cascorbi, I., Clapper, M.L., Coutelle, C., Daly, A., Dell'Omo, M., Dolzan, V., Dresler, C.M., Fryer, A., Haugen, A., Hein, D.W., Hildesheim, A., Hirvonen, A., Hsieh, L.L., Ingelman-Sundberg, M., Kalina, I., Kang, D., Kihara, M., Kiyohara, C., Kremers, P., Lazarus, P., Marchand, L. le, Lechner, M.C., Lieshout, E.M.M. van, London, S., Manni, J.J., Maugard, C.M., Morita, S., Nazar-Stewart, V., Noda, K., Oda, Y., Parl, F.F., Pastorelli, R., Persson, I., Peters, W.H.M., Rannug, A., Rebbeck, T.R., Risch, A., Roelandt, L., Romkes, M., Ryberg, D., Salagovic, J., Schoket, B., Seidegard, J., Shields, P.G., Sim, E., Sinnet, D., Strange, R.C., Stucker, I., Sugimura, H., To-Figueras, J., Vineis, P., Yu, M.C., and Taioli, E.

Abstract

Item does not contain fulltext, Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.

Published
2001

75. Predicted germline BRCA1/BRCA2 mutations and second primary ipsilateral breast cancers in young women with pure ductal carcinoma in-situ treated with breast conserving therapy

Author

Kim, C.S, primary, Gumbs, A.A, additional, Komarnicky, L, additional, Carter, D, additional, Hutter, R, additional, Palazzo, J.P, additional, McCue, P.A, additional, Goodman, R, additional, Haffty, B.G, additional, Rebbeck, T.R, additional, Weber, B.L, additional, and Turner, B.C, additional

Published
2000
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78. Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families

Author

Tonin, P., primary, Weber, B., additional, Offit, K., additional, Couch, F., additional, Rebbeck, T.R., additional, Neuhausen, S., additional, Godwin, A.K., additional, Daly, M., additional, Wagner-Costalos, J., additional, Berman, D., additional, Grana, G., additional, Fox, E., additional, Kane, M.F., additional, Kolodner, R.D., additional, Krainer, M., additional, Haber, D.A., additional, Struewing, J.P., additional, Warner, E., additional, Rosen, B., additional, Lerman, C., additional, Peshkin, B., additional, Norton, L., additional, Serova, O., additional, Foulkes, W.D., additional, Lynch, H.T., additional, Lenoir, G.M., additional, Narod, S.A., additional, and Garber, J.E., additional

Published
1996
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80. Increased transcriptional activity of the CYP3A4*1Bpromoter variant

Author

Amirimani, B., Ning, B., Deitz, A.C., Weber, B.L., Kadlubar, F.F., and Rebbeck, T.R.

Abstract

Numerous single nucleotide polymorphisms (SNPs) have been identified in the human genome, yet the functional significance of most is unknown. CYP3A4 is a key enzyme in the metabolism of numerous compounds. An A→G substitution 290 bp upstream of the CYP3A4transcription start site (CYP3A4*1B) has been associated with cancer phenotypes, but its phenotypic effects are unclear. To investigate the functional significance of CYP3A4*1B, we generated two luciferase reporter constructs: 1‐kb (denoted L, long) and 0.5‐kb (denoted S, short) promoter fragments containing either the variant (VL,VS) or the wild‐type (WL, WS) sequences. We evaluated the effect of the variant sequence in the HepG2 and MCF‐7 cell lines, and in primary human hepatocytes from three donors. Reporter constructs with the variant sequence had 1.2‐ to 1.9‐fold higher luciferase activity than constructs with wild‐type sequence in the cell lines (P< 0.0001) and hepatocytes (P= 0.021, P= 0.027, P= 0.061). The ratio of transcriptional activity for VS:WSwas similar to the VL:WLratio in HepG2 cells, but the VS:WSratio was consistently less than the VL:WLratio in MCF‐7 cells. This suggests that CYP3A4expression is higher from the variant promoter and that a repressor sequence may exist in the longer constructs. Electrophoretic mobility shift assays demonstrated specific binding of a component of HepG2 nuclear extract to both wild‐type and variant promoters with consistently higher binding affinities to the wild‐type sequence. This suggests the existence of a transcriptional repressor responsible for the lower CYP3A4*1Aactivity. Therefore, the phenotypic effects of the variant CYP3A4*1Bmay be associated with enhanced CYP3A4 expression due to reduced binding of a transcriptional repressor. Environ. Mol. Mutagen. 42:299–305, 2003. © 2003 Wiley‐Liss, Inc.

Published
2003
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81. Utility of linked markers in genetic counseling: Estimation of carrier risks in X-linked ocular albinism

Author

Rebbeck, T.R., Jordan, H.A., Schnur, R.E., and Rogatko, A.

Abstract

We apply a method proposed by Rogatko et al. [1995: Am J Med Genet 59:24–32] to estimate carrier risks using genetic linkage data. The method is illustrated for X-linked ocular albinism. Linkage data from pedigrees were combined with genome mapping data to compute carrier risks for individuals with unknown carrier status based on pedigree data alone. We considered two situations. First, a linkage map with some ambiguity in the gene order was considered. This analysis allows us to examine the effect of incomplete genetic map information on risk computations. Second, published physical and meiotic mapping information was used to derive a linkage map that could be assumed known without ambiguity. In both situations, the mean and median estimate of carrier risk differed significantly from that obtained using pedigree relationships only, in that the computed risk was significantly different from the a priori value of 0.5. The 95% CI's associated with point estimates of risk made using the known map or a map with ambiguity did not overlap in some cases. These results suggest that the risk estimate and the confidence with which a risk estimate can be imparted may depend on the genetic map and marker data used in the risk estimation procedure. We conclude that the method presented here can be used to estimate genetic risk under a variety of analytical conditions. Am. J. Med. Genet. 70: 58–66, 1997. © Wiley-Liss, Inc.

Published
1997
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82. Exploring the link between MORF4L1 and risk of breast cancer

Author

Martrat, G., Maxwell, C.A., Tominaga, E., Porta-de-la-Riva, M., Bonifaci, N., Gomez-Baldo, L., Bogliolo, M., Lazaro, C., Blanco, I., Brunet, J., Aguilar, H., Fernandez-Rodriguez, J., Seal, S., Renwick, A., Rahman, N., Kuhl, J., Neveling, K., Schindler, D., Ramirez, M.J., Castella, M., Hernandez, G., Easton, D.F., Peock, S., Cook, M., Oliver, C.T., Frost, D., Platte, R., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Chu, C., Davidson, R., Ong, K.R., Cook, J., Douglas, F., Hodgson, S., Brewer, C., Morrison, P.J., Porteous, M., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., Pasini, B., Ottini, L., Putignano, A.L., Savarese, A., Bernard, L., Radice, P., Healey, S., Spurdle, A., Chen, X.Q., Beesley, J., Rookus, M.A., Verhoef, S., Tilanus-Linthorst, M.A., Vreeswijk, M.P., Asperen, C.J., Bodmer, D., Ausems, M.G.E.M., Os, T.A. van, Blok, M.J., Meijers-Heijboer, H.E.J., Hogervorst, F.B.L., Goldgar, D.E., Buys, S., John, E.M., Miron, A., Southey, M., Daly, M.B., Harbst, K., Borg, A., Rantala, J., Barbany-Bustinza, G., Ehrencrona, H., Stenmark-Askmalm, M., Kaufman, B., Laitman, Y., Milgrom, R., Friedman, E., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Oskar, T., Couch, F.J., Wang, X.S., Fredericksen, Z., Cuadras, D., Moreno, V., Pientka, F.K., Depping, R., Caldes, T., Osorio, A., Benitez, J., Bueren, J., Heikkinen, T., Nevanlinna, H., Hamann, U., Torres, D., Caligo, M.A., Godwin, A.K., Imyanitov, E.N., Janavicius, R., Sinilnikova, O.M., Stoppa-Lyonnet, D., Mazoyer, S., Verny-Pierre, C., Castera, L., Pauw, A. de, Bignon, Y.J., Uhrhammer, N., Peyrat, J.P., Vennin, P., Ferrer, S.F., Collonge-Rame, M.A., Mortemousque, I., McGuffog, L., Chenevix-Trench, G., Pereira-Smith, O.M., Antoniou, A.C., Ceron, J., Tominaga, K., Surralles, J., Pujana, M.A., EMBRACE, kConFab, HEBON, BCFR, SWE-BRCA, GEMO Study Collaborators, Human Genetics, BMC, Ed., Translational Research Laboratory, Catalan Institute of Oncology-Bellvitge Institute for Biomedical Research, Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Catalan Institute of Oncology, Department of Cellular and Structural Biology, The University of Texas Health Science Center at Houston (UTHealth)-Sam and Ann Barshop Institute for Longevity and Aging Studies, Chemoresistance and Predictive Factors of Tumor Response and Stromal Microenvironment, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Biomarkers and Susceptibility Unit, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona (UAB), Biomedical Research Centre Network for Rare Diseases (CIBERER), Genetic Counseling and Hereditary Cancer Programme, Section of Cancer Genetics, Institute of cancer research, Department of Human Genetics, Julius-Maximilians-Universität Würzburg (JMU), Strangeways Research Laboratory, University of Cambridge [UK] (CAM)-Department of Public Health and Primary Care-Centre for Cancer Genetic Epidemiology, Centre for Cancer Genetic Epidemiology [Cambridge], University of Cambridge [UK] (CAM)-Department of Oncology, Genetic Medicine, St Mary's Hospital-NHS Foundation Trust-Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics Department, Guy's and St Thomas NHS Foundation Trust, Yorkshire Regional Genetics Service, St James's hospital, Ferguson-Smith Centre for Clinical Genetics, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Institute of Human Genetics, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Queen Mary University of London (QMUL)-St George's Hospital, Department of Clinical Genetics, Royal Devon & Exeter Hospital, Northern Ireland Regional Genetics Centre, Belfast City Hospital, South East of Scotland Regional Genetics Service, Western General Hospital, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine-Fondazione IRCCS Istituto Nazionale Tumori (INT), Department of Preventive and Predictive Medicine, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Unit of Medical Genetics, Fondazione IRCCS INT, Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Division of Experimental Oncology 1, Centro di Riferimento Oncologico (CRO), Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Department of Molecular Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Firenze = University of Florence (UniFI), Fiorgen Foundation for Pharmacogenomics, Division of Medical Oncology, Regina Elena Cancer Institute, Department of Experimental Oncology, IEO, Division of Genetics and Population Health, Queensland Institute of Medical Research, Department of Epidemiology, The Netherlands Cancer Institute, Family Cancer Clinic, Department of Surgical Oncology, Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), DNA Diagnostics, Radboud University Medical Center [Nijmegen], Department of Medical Genetics, University Medical Center [Utrecht], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), University Hospital Maastricht, VU Medical Center, Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Department of Internal Medicine, Huntsman Cancer Institute, Cancer Prevention Institute of California, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] (HMS), Centre for Molecular, Environmental, Genetic and Analytic Epidemiology (MEGA), University of Melbourne-Melbourne School of Population Health, Division of Population Science, Fox Chase Cancer Center, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Karolinska University Hospital [Stockholm], Department of Genetics and Pathology, Uppsala University, Department of Oncology, University Hospital-Hälsouniversitetet Universitetssjukhuset, The Institute of Oncology, Chaim Sheba Medical Center, The Susanne Levy Gertner Oncogenetics Unit, Sackler Faculty of Medicine, Tel Aviv University (TAU), Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Department of Medicine, Medical Genetics, Abramson Cancer Center-Perelman School of Medicine, Center for Clinical Epidemiology and Biostatistics, Faculty of Medicine, University of Iceland [Reykjavik], Department of Laboratory Medicine and Pathology, Mayo Clinic, Department of Health Sciences Research, Statistical Assessment Service, Department of Physiology, Universität zu Lübeck = University of Lübeck [Lübeck]-Center for Structural and Cell Biology in Medicine, Medical Oncology Branch, Hospital Clínico San Carlos, Human Cancer Genetics Programme, CIBER de Enfermedades Raras (CIBERER)-Spanish National Cancer Research Centre, Division of Hematopoiesis and Gene Therapy, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas [Madrid] (CIEMAT), Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Instituto de Genética Humana, Pontificia Universidad Javeriana (PUJ), Section of Genetic Oncology, University of Pisa - Università di Pisa, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Kansas City, KS, USA], Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion, Vilnius University [Vilnius]-Hospital Santariskiu Clinics, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Oncologique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncogénétique, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, Consultation d'Oncogénétique, Laboratoire de Génétique Chromosomique, CH Chambéry, Département de Génétique et Reproduction, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, The CIMBA data management is supported by Cancer Research - UK., kConFab, HEBON, BCFR, SWE-BRCA, GEMO Study Collaborators, Autonomous University of Barcelona, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Department of Oncology-University of Cambridge [UK] (CAM), University of Turin, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Tel Aviv University [Tel Aviv], University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Universität zu Lübeck [Lübeck]-Center for Structural and Cell Biology in Medicine, University of Kansas Medical Center [Lawrence], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Universiteit Leiden-Universiteit Leiden, Skåne University Hospital-Lund University [Lund], University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Abramson Cancer Center, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical Genetics, Faculteit der Geneeskunde, Klinische Genetica, RS: GROW - School for Oncology and Reproduction, Genetica & Celbiologie, Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Martrat, G, Maxwell, C, Tominaga, E, Porta de la Riva, M, Bonifaci, N, Gómez Baldó, L, Bogliolo, M, Lázaro, C, Blanco, I, Brunet, J, Aguilar, H, Fernández Rodríguez, J, Seal, S, Renwick, A, Rahman, N, Kühl, J, Neveling, K, Schindler, D, Ramírez, M, Castellà, M, Hernández, G, Embrace, Easton, D, Peock, S, Cook, M, Oliver, C, Frost, D, Platte, R, Evans, D, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Ong, K, Cook, J, Douglas, F, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Pasini, B, Ottini, L, Putignano, A, Savarese, A, Bernard, L, Radice, P, Healey, S, Spurdle, A, Chen, X, Beesley, J, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Asperen, C, Bodmer, D, Ausems, M, van Os, T, Blok, M, Meijers Heijboer, H, Hogervorst, F, Goldgar, D, Buys, S, John, E, Miron, A, Southey, M, Daly, M, Harbst, K, Borg, A, Rantala, J, Barbany Bustinza, G, Ehrencrona, H, Stenmark Askmalm, M, Kaufman, B, Laitman, Y, Milgrom, R, Friedman, E, Domchek, S, Nathanson, K, Rebbeck, T, Johannsson, O, Couch, F, Wang, X, Fredericksen, Z, Cuadras, D, Moreno, V, Pientka, F, Depping, R, Caldés, T, Osorio, A, Benítez, J, Bueren, J, Heikkinen, T, Nevanlinna, H, Hamann, U, Torres, D, Caligo, M, Godwin, A, Imyanitov, E, Janavicius, R, Sinilnikova, O, Stoppa Lyonnet, D, Mazoyer, S, Verny Pierre, C, Castera, L, de Pauw, A, Bignon, Y, Uhrhammer, N, Peyrat, J, Vennin, P, Ferrer, S, Collonge Rame, M, Mortemousque, I, Mcguffog, L, Chenevix Trench, G, Pereira Smith, O, Antoniou, A, Cerón, J, Tominaga, K, Surrallés, J, Pujana, M, Human genetics, CCA - Oncogenesis, Biomedical Research Centre Network for Epidemiology and Public Health ( CIBERESP ), The University of Texas Health Science Center at San Antonio-Sam and Ann Barshop Institute for Longevity and Aging Studies, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] ( IDIBELL ), Biomedical Research Centre Network for Rare Diseases ( CIBERER ), University of Würzburg, University of Cambridge [UK] ( CAM ) -Department of Public Health and Primary Care-Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] ( CAM ) -Department of Oncology, Birmingham Women's Hospital Healthcare NHS Trust, Sheffield Children's Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Queen Mary University of London ( QMUL ) -St George's Hospital, IFOM, Istituto FIRC di Oncologia Molecolare ( IFOM ), Università degli Studi di Roma 'La Sapienza' [Rome], University of Florence, Erasmus MC-Daniel den Hoed Cancer Center-Family Cancer Clinic, University Medical Center Utrecht, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ), Harvard Medical School [Boston] ( HMS ), Centre for Molecular, Environmental, Genetic and Analytic Epidemiology ( MEGA ), University of Pennsylvania School of Medicine, University of Pennsylvania School of Medicine-Abramson Cancer Center, Centro de Investigaciones Energéticas, Deutsches Krebsforschungszentrum ( DKFZ ), Pontificia Universidad Javeriana, University of Pisa [Pisa], University of Kansas Medical Center, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CRLCC Jean Perrin, CRLCC Oscar Lambret, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Saint-Jacques, Hôpital Bretonneau-CHRU Tours, and Universitat de Barcelona

Subjects
DNA Repair, Genes, BRCA2, RAD51, Genes, BRCA1, Germ-Cell, Helicase Brip1, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 0302 clinical medicine, Breast cancer, Fanconi anemia, Risk Factors, Replication Protein A, Teknik och teknologier, Homologous Recombination, skin and connective tissue diseases, C-Elegans, Genetics, Medicine(all), ddc:616, 0303 health sciences, Mutation, Fanconi Anemia Complementation Group D2 Protein, Nuclear Proteins, Anèmia aplàstica, 3. Good health, 030220 oncology & carcinogenesis, Chromodomain Protein, Engineering and Technology, Female, RNA Interference, Fanconi Anemia Complementation Group N Protein, Aplastic anemia, Research Article, BRCA2 Mutation Carrier, DNA repair, PALB2, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Cell Line, Càncer de mama, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, SDG 3 - Good Health and Well-being, [SDV.CAN] Life Sciences [q-bio]/Cancer, Two-Hybrid System Techniques, medicine, Genetic predisposition, Animals, Humans, Genetic Predisposition to Disease, Caenorhabditis elegans, Gene, 030304 developmental biology, Phenocopy, Caenorhabditis-Elegan, Tumor Suppressor Proteins, medicine.disease, BRCA1, BRCA2, Pancreatic-Cancer, Fanconi Anemia, Genes, Cancer and Oncology, Fanconi-Anemia, Cancer research, Rad51 Recombinase, Susceptibility Gene, DNA Damage, Transcription Factors
Abstract

Introduction Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. Conclusions While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

83. Polymorphisms in PTEN in breast cancer families

Author

Carroll, B.T., Weber, B.L., Couch, F.J., and Rebbeck, T.R.

Abstract

Germline mutations in PTEN are the underlying genetic defect in Cowden disease, which is associated with a lifetime risk of 25-50% of developing breast cancer. To investigate the role of PTEN in inherited breast cancer in the absence of manifestations of Cowden disease, we screened 177 unrelated subjects with breast cancer who also had a family history of breast cancer in at least one relative. We found no disease associated PTEN mutations in this cohort, supporting previous studies suggesting that PTEN mutations do not contribute to inherited susceptibility to breast cancer without associated manifestations of Cowden disease. We did identify an association between a common polymorphism in intron 4 and lower mean age of diagnosis of breast cancer. While preliminary, these findings suggest that further study is warranted to determine whether this allelic variant of PTEN could function as a low penetrance breast cancer susceptibility allele.

Published
1999

85. Genome-Wide Association Studies, Field Synopses, and the Development of the Knowledge Base on Genetic Variation and Human Diseases

Author

Roberta A Pagon, Thomas R. O'Brien, Paolo Boffetta, Ryan P. Owen, Paolo Vineis, Muin J. Khoury, Jonine L. Bernstein, Julian P T Higgins, Adam S. Butterworth, A. Cecile J.W. Janssens, Daniela Seminara, Timothy R. Rebbeck, Helena Furberg, Lars Bertram, Stephen J. Chanock, Marta Gwinn, Siobhan M. Dolan, Anand Chockalingam, James M. Ostell, Harry Campbell, Deborah M. Winn, Julian Little, Isabel Fortier, Montserrat Garcia-Closas, Nathaniel Rothman, John P. A. Ioannidis, Paul Burton, Wei Yu, Khoury, M.J., Bertram, L., Boffetta, P., Butterworth, A.S., Chanock, S.J., Dolan, S.M., Fortier, I., Garcia-Closas, M., Gwinn, M., Higgins, J.P.T., Janssens, A.C.J.W., Ostell, J., Owen, R.P., Pagon, R.A., Rebbeck, T.R., Rothman, N., Bernstein, J.L., Burton, P.R., Campbell, H., Chockalingam, A., Furberg, H., Little, J., O'Brien, T.R., Seminara, D., Vineis, P., Winn, D.M., Yu, W., Ioannidis, J.P.A., and Epidemiology

Subjects
human diseases, Candidate gene, Pathology, Schizophrenia/genetics, Epidemiology, epidemiologic methods, Genome-wide association study, Pilot Projects, Disease, Epidemiologic Methods, 0302 clinical medicine, Medicine, Genome-Wide Association Study, Genome-wide, database, 0303 health sciences, synopse, Genetic Variation, field, 3. Good health, Phenotype, 030220 oncology & carcinogenesis, Meta-analysis, Bias (Epidemiology), Practice Guidelines as Topic, Disease Susceptibility, medicine.medical_specialty, Evidence-based practice, Georgia, Genomics, Computational biology, association studie, 03 medical and health sciences, Special Article, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, genomics, Humans, Genetic Predisposition to Disease, 030304 developmental biology, genome-wide association study, business.industry, Genome, Human, association, Bayes Theorem, meta-analysis, genetic variation, Disease/*genetics, Human genome, Interdisciplinary Communication, Knowledge Bases, encyclopedias, genome, human, business, Candidate Disease Gene
Abstract

Genome-wide association studies (GWAS) have led to a rapid increase in available data on common genetic variants and phenotypes and numerous discoveries of new loci associated with susceptibility to common complex diseases. Integrating the evidence from GWAS and candidate gene studies depends on concerted efforts in data production, online publication, database development, and continuously updated data synthesis. Here the authors summarize current experience and challenges on these fronts, which were discussed at a 2008 multidisciplinary workshop sponsored by the Human Genome Epidemiology Network. Comprehensive field synopses that integrate many reported gene-disease associations have been systematically developed for several fields, including Alzheimer's disease, schizophrenia, bladder cancer, coronary heart disease, preterm birth, and DNA repair genes in various cancers. The authors summarize insights from these field synopses and discuss remaining unresolved issues - especially in the light of evidence from GWAS, for which they summarize empirical P-value and effect-size data on 223 discovered associations for binary outcomes (142 with P

Published
2009

86. Cancer prevention for global health: A report from the ASPO international cancer prevention interest group

Author

Timothy R. Rebbeck, Dejana Braithwaite, Paolo Boffetta, Frank L. Meyskens, Braithwaite, D., Boffetta, P., Rebbeck, T.R., and Meyskens, F.

Subjects
medicine.medical_specialty, Epidemiology, International Cooperation, Population, Smoking Prevention, Global Health, Causes of cancer, Neoplasms, Occupational Exposure, Epidemiology of cancer, Global health, medicine, Humans, Hepatitis B Vaccines, Nutritional Physiological Phenomena, education, Reproductive health, Gynecology, education.field_of_study, Cancer prevention, cancer prevention, business.industry, Public health, Cancer, medicine.disease, Oncology, Family medicine, business
Abstract

As cancer incidence and mortality rates increase in low- and middle-income countries, the need for cancer prevention and control research directed to these countries becomes increasingly important. The American Society of Preventive Oncology (ASPO) is a community of professionals in cancer prevention and control whose mission is to “foster the continuing development of investigators and the exchange and translation of scientific information to reduce the cancer burden.” In the session presented at the ASPO 36th Annual Meeting in Washington, DC in March 2012, chaired by Drs. Frank Meyskens and Dejana Braithwaite, Dr. Paolo Boffetta discussed some of the achievements in global cancer prevention and suggested that future efforts focus on three major causes of cancer: tobacco-use, infections, and overweight/obesity. Dr. Timothy Rebbeck presented an overview of prostate cancer research in sub-Saharan Africa and highlighted how the complex nature of prostate cancer etiology and outcomes can be addressed through capacity-building research partnerships. Cancer is an emerging public health challenge in developing countries because of the aging and expansion of the population and increased prevalence of cancer risk factors such as smoking, obesity, physical inactivity, and reproductive factors. There are opportunities to reduce the growing cancer burden through the development of research capacity and the application of resource-appropriate interventions. Cancer Epidemiol Biomarkers Prev; 21(9); 1606–10. ©2012 AACR.

Published
2012

87. Assessment of cumulative evidence on genetic associations: interim guidelines

Author

Daniela Seminara, Julian P T Higgins, Anand P. Chokkalingam, Muin J. Khoury, Timothy R. Rebbeck, Thomas R. O'Brien, Julian Little, Paolo Boffetta, Grier P. Page, André G. Uitterlinden, W. Dana Flanders, John P. A. Ioannidis, Siobhan M. Dolan, Paolo Vineis, David H. McDermott, David J. Balding, Mark I. McCarthy, Ioannidis, J.P.A., Boffetta, P., Little, J., O'Brien, T.R., Uitterlinden, A.G., Vineis, P., Balding, D.J., Chokkalingam, A., Dolan, S.M., Flanders, W.D., Higgins, J.P.T., Mccarthy, M.I., McDermott, D.H., Page, G.P., Rebbeck, T.R., Seminara, D., Khoury, M.J., and Internal Medicine

Subjects
Male, causality, genetic association, Epidemiology, epidemiologic methods, Genetic Heterogeneity, Genome-wide association study, Guidelines as Topic, Epidemiologic Studies, Assessment, Heterozygote Detection, Sensitivity and Specificity, Empirical research, Interim, Credibility, genomics, Medicine, Humans, genetics, Genetic Predisposition to Disease, Genetic Predisposition to Disease/*epidemiology, Biological data, Actuarial science, Evidence-Based Medicine, business.industry, evidence, Genetic Carrier Screening, General Medicine, Evidence-based medicine, Causality, cumulative evidence, Evaluation Studies as Topic, Causal inference, Female, business
Abstract

Established guidelines for causal inference in epidemiological studies may be inappropriate for genetic associations. A consensus process was used to develop guidance criteria for assessing cumulative epidemiologic evidence in genetic associations. A proposed semi-quantitative index assigns three levels for the amount of evidence, extent of replication, and protection from bias, and also generates a composite assessment of 'strong', 'moderate' or 'weak' epidemiological credibility. In addition, we discuss how additional input and guidance can be derived from biological data. Future empirical research and consensus development are needed to develop an integrated model for combining epidemiological and biological evidence in the rapidly evolving field of investigation of genetic factors. This work was partly supported by ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program (Contract No 513943). This research was also supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and National Institute of Allergy and Infectious Diseases, Laboratory of Molecular Immunology. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Published
2008

88. Glutathione S-transferases M1, T1, and P1 and breast cancer: A pooled analysis

Author

Vogl, F. D., Taioli, E., Maugard, C., Zheng, W., Luis Felipe Ribeiro Pinto, Ambrosone, C., Parl, F. F., Nedelcheva-Kristensen, V., Rebbeck, T. R., Brennan, P., Boffetta, P., Vogl, F.D., Taioli, E., Maugard, C., Zheng, W., Ribeiro Pinto, L.F., Ambrosone, C., Parl, F.F., Nedelcheva-Kristensen, V., Rebbeck, T.R., Brennan, P., and Boffetta, P.

Subjects
Polymorphism, Genetic, Base Sequence, Genotype, Epidemiology, Genetic Carrier Screening, DNA Mutational Analysis, Glutathione S-transferases M1 T1 P1 breast cancer pooled analysis, Breast Neoplasms, Carcinogens, Environmental, Oncology, Meta-Analysis as Topic, Risk Factors, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Chromosome Deletion, Codon, Acyltransferases, Glutathione Transferase
Abstract

The glutathione S-transferase (GST) genes are involved in the metabolism of various carcinogens. Deletion polymorphisms in the genes GSTM1 and GSTT1 and a base transition polymorphism at codon 105 (Ile→Val) in GSTP1 were investigated in relation to breast cancer risk. Tobacco smoking and reproductive factors were examined as potential effect modifiers. Individual data from seven case-control studies were pooled within the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens. To measure the effect of GSTs on breast cancer risk, odds ratios and 95% confidence intervals were computed adjusting for study center and age. The modifying effect was investigated by stratification on variables of smoking habits and reproductive history. A total of 2,048 cases with breast cancer and 1,969 controls were analyzed. The relative odds ratio (95% confidence interval) of breast cancer was 0.98 (0.86–1.12) with the GSTM1 null, 1.11 (0.87–1.41) with the GSTT1 null, 1.01 (0.79–1.28) with GSTP1 heterozygous mutants, and 0.93 (0.62–1.38) with GSTP1 homozygous mutants. Stratification by smoking or reproductive factors did not reveal a modifying effect of these variables, nor was there any association between GSTM1 and age at diagnosis of breast cancer. This is the largest study investigating susceptibility to breast cancer due to polymorphisms in the GST genes. The results conclusively show that single gene GST polymorphisms do not confer a substantial risk of breast cancer to its carriers. Furthermore, GSTs did not interact with smoking or reproductive history to modify cancer risk.

Published
2004

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