Sir Peter MacCallum Department of Oncology - Research Publications

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    Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk.
    Dareng, EO ; Tyrer, JP ; Barnes, DR ; Jones, MR ; Yang, X ; Aben, KKH ; Adank, MA ; Agata, S ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Aravantinos, G ; Arun, BK ; Augustinsson, A ; Balmaña, J ; Bandera, EV ; Barkardottir, RB ; Barrowdale, D ; Beckmann, MW ; Beeghly-Fadiel, A ; Benitez, J ; Bermisheva, M ; Bernardini, MQ ; Bjorge, L ; Black, A ; Bogdanova, NV ; Bonanni, B ; Borg, A ; Brenton, JD ; Budzilowska, A ; Butzow, R ; Buys, SS ; Cai, H ; Caligo, MA ; Campbell, I ; Cannioto, R ; Cassingham, H ; Chang-Claude, J ; Chanock, SJ ; Chen, K ; Chiew, Y-E ; Chung, WK ; Claes, KBM ; Colonna, S ; GEMO Study Collaborators, ; GC-HBOC Study Collaborators, ; EMBRACE Collaborators, ; Cook, LS ; Couch, FJ ; Daly, MB ; Dao, F ; Davies, E ; de la Hoya, M ; de Putter, R ; Dennis, J ; DePersia, A ; Devilee, P ; Diez, O ; Ding, YC ; Doherty, JA ; Domchek, SM ; Dörk, T ; du Bois, A ; Dürst, M ; Eccles, DM ; Eliassen, HA ; Engel, C ; Evans, GD ; Fasching, PA ; Flanagan, JM ; Fortner, RT ; Machackova, E ; Friedman, E ; Ganz, PA ; Garber, J ; Gensini, F ; Giles, GG ; Glendon, G ; Godwin, AK ; Goodman, MT ; Greene, MH ; Gronwald, J ; OPAL Study Group, ; AOCS Group, ; Hahnen, E ; Haiman, CA ; Håkansson, N ; Hamann, U ; Hansen, TVO ; Harris, HR ; Hartman, M ; Heitz, F ; Hildebrandt, MAT ; Høgdall, E ; Høgdall, CK ; Hopper, JL ; Huang, R-Y ; Huff, C ; Hulick, PJ ; Huntsman, DG ; Imyanitov, EN ; KConFab Investigators, ; HEBON Investigators, ; Isaacs, C ; Jakubowska, A ; James, PA ; Janavicius, R ; Jensen, A ; Johannsson, OT ; John, EM ; Jones, ME ; Kang, D ; Karlan, BY ; Karnezis, A ; Kelemen, LE ; Khusnutdinova, E ; Kiemeney, LA ; Kim, B-G ; Kjaer, SK ; Komenaka, I ; Kupryjanczyk, J ; Kurian, AW ; Kwong, A ; Lambrechts, D ; Larson, MC ; Lazaro, C ; Le, ND ; Leslie, G ; Lester, J ; Lesueur, F ; Levine, DA ; Li, L ; Li, J ; Loud, JT ; Lu, KH ; Lubiński, J ; Mai, PL ; Manoukian, S ; Marks, JR ; Matsuno, RK ; Matsuo, K ; May, T ; McGuffog, L ; McLaughlin, JR ; McNeish, IA ; Mebirouk, N ; Menon, U ; Miller, A ; Milne, RL ; Minlikeeva, A ; Modugno, F ; Montagna, M ; Moysich, KB ; Munro, E ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Yie, JNY ; Nielsen, HR ; Nielsen, FC ; Nikitina-Zake, L ; Odunsi, K ; Offit, K ; Olah, E ; Olbrecht, S ; Olopade, OI ; Olson, SH ; Olsson, H ; Osorio, A ; Papi, L ; Park, SK ; Parsons, MT ; Pathak, H ; Pedersen, IS ; Peixoto, A ; Pejovic, T ; Perez-Segura, P ; Permuth, JB ; Peshkin, B ; Peterlongo, P ; Piskorz, A ; Prokofyeva, D ; Radice, P ; Rantala, J ; Riggan, MJ ; Risch, HA ; Rodriguez-Antona, C ; Ross, E ; Rossing, MA ; Runnebaum, I ; Sandler, DP ; Santamariña, M ; Soucy, P ; Schmutzler, RK ; Setiawan, VW ; Shan, K ; Sieh, W ; Simard, J ; Singer, CF ; Sokolenko, AP ; Song, H ; Southey, MC ; Steed, H ; Stoppa-Lyonnet, D ; Sutphen, R ; Swerdlow, AJ ; Tan, YY ; Teixeira, MR ; Teo, SH ; Terry, KL ; Terry, MB ; OCAC Consortium, ; CIMBA Consortium, ; Thomassen, M ; Thompson, PJ ; Thomsen, LCV ; Thull, DL ; Tischkowitz, M ; Titus, L ; Toland, AE ; Torres, D ; Trabert, B ; Travis, R ; Tung, N ; Tworoger, SS ; Valen, E ; van Altena, AM ; van der Hout, AH ; Van Nieuwenhuysen, E ; van Rensburg, EJ ; Vega, A ; Edwards, DV ; Vierkant, RA ; Wang, F ; Wappenschmidt, B ; Webb, PM ; Weinberg, CR ; Weitzel, JN ; Wentzensen, N ; White, E ; Whittemore, AS ; Winham, SJ ; Wolk, A ; Woo, Y-L ; Wu, AH ; Yan, L ; Yannoukakos, D ; Zavaglia, KM ; Zheng, W ; Ziogas, A ; Zorn, KK ; Kleibl, Z ; Easton, D ; Lawrenson, K ; DeFazio, A ; Sellers, TA ; Ramus, SJ ; Pearce, CL ; Monteiro, AN ; Cunningham, J ; Goode, EL ; Schildkraut, JM ; Berchuck, A ; Chenevix-Trench, G ; Gayther, SA ; Antoniou, AC ; Pharoah, PDP (Springer Science and Business Media LLC, 2022-05)
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    Polygenic risk modeling for prediction of epithelial ovarian cancer risk
    Dareng, EO ; Tyrer, JP ; Barnes, DR ; Jones, MR ; Yang, X ; Aben, KKH ; Adank, MA ; Agata, S ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Aravantinos, G ; Arun, BK ; Augustinsson, A ; Balmana, J ; Bandera, E ; Barkardottir, RB ; Barrowdale, D ; Beckmann, MW ; Beeghly-Fadiel, A ; Benitez, J ; Bermisheva, M ; Bernardini, MQ ; Bjorge, L ; Black, A ; Bogdanova, N ; Bonanni, B ; Borg, A ; Brenton, JD ; Budzilowska, A ; Butzow, R ; Buys, SS ; Cai, H ; Caligo, MA ; Campbell, I ; Cannioto, R ; Cassingham, H ; Chang-Claude, J ; Chanock, SJ ; Chen, K ; Chiew, Y-E ; Chung, WK ; Claes, KBM ; Colonna, S ; Cook, LS ; Couch, FJ ; Daly, MB ; Dao, F ; Davies, E ; de la Hoya, M ; de Putter, R ; Dennis, J ; DePersia, A ; Devilee, P ; Diez, O ; Ding, YC ; Doherty, JA ; Domchek, SM ; Dork, T ; du Bois, A ; Durst, M ; Eccles, DM ; Eliassen, HA ; Engel, C ; Evans, GD ; Fasching, PA ; Flanagan, JM ; Fortner, R ; Machackova, E ; Friedman, E ; Ganz, PA ; Garber, J ; Gensini, F ; Giles, GG ; Glendon, G ; Godwin, AK ; Goodman, MT ; Greene, MH ; Gronwald, J ; Group, OS ; AOCSGroup, ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hamann, U ; Hansen, TVO ; Harris, HR ; Hartman, M ; Heitz, F ; Hildebrandt, MAT ; Hogdall, E ; Hogdall, CK ; Hopper, JL ; Huang, R-Y ; Huff, C ; Hulick, PJ ; Huntsman, DG ; Imyanitov, EN ; Isaacs, C ; Jakubowska, A ; James, PA ; Janavicius, R ; Jensen, A ; Johannsson, OT ; John, EM ; Jones, ME ; Kang, D ; Karlan, BY ; Karnezis, A ; Kelemen, LE ; Khusnutdinova, E ; Kiemeney, LA ; Kim, B-G ; Kjaer, SK ; Komenaka, I ; Kupryjanczyk, J ; Kurian, AW ; Kwong, A ; Lambrechts, D ; Larson, MC ; Lazaro, C ; Le, ND ; Leslie, G ; Lester, J ; Lesueur, F ; Levine, DA ; Li, L ; Li, J ; Loud, JT ; Lu, KH ; Mai, PL ; Manoukian, S ; Marks, JR ; KimMatsuno, R ; Matsuo, K ; May, T ; McGuffog, L ; McLaughlin, JR ; McNeish, IA ; Mebirouk, N ; Menon, U ; Miller, A ; Milne, RL ; Minlikeeva, A ; Modugno, F ; Montagna, M ; Moysich, KB ; Munro, E ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Yie, JNY ; Nielsen, HR ; Nielsen, FC ; Nikitina-Zake, L ; Odunsi, K ; Offit, K ; Olah, E ; Olbrecht, S ; Olopade, O ; Olson, SH ; Olsson, H ; Osorio, A ; Papi, L ; Park, SK ; Parsons, MT ; Pathak, H ; Pedersen, IS ; Peixoto, A ; Pejovic, T ; Perez-Segura, P ; Permuth, JB ; Peshkin, B ; Peterlongo, P ; Piskorz, A ; Prokofyeva, D ; Radice, P ; Rantala, J ; Riggan, MJ ; Risch, HA ; Rodriguez-Antona, C ; Ross, E ; Rossing, MA ; Runnebaum, I ; Sandler, DP ; Santamarina, M ; Soucy, P ; Schmutzler, RK ; Setiawan, VW ; Shan, K ; Sieh, W ; Simard, J ; Singer, CF ; Sokolenko, AP ; Song, H ; Southey, MC ; Steed, H ; Stoppa-Lyonnet, D ; Sutphen, R ; Swerdlow, AJ ; Tan, YY ; Teixeira, MR ; Teo, SH ; Terry, KL ; BethTerry, M ; Thomassen, M ; Thompson, PJ ; Thomsen, LCV ; Thull, DL ; Tischkowitz, M ; Titus, L ; Toland, AE ; Torres, D ; Trabert, B ; Travis, R ; Tung, N ; Tworoger, SS ; Valen, E ; van Altena, AM ; van der Hout, AH ; Nieuwenhuysen, E ; van Rensburg, EJ ; Vega, A ; Edwards, DV ; Vierkant, RA ; Wang, F ; Wappenschmidt, B ; Webb, PM ; Weinberg, CR ; Weitzel, JN ; Wentzensen, N ; White, E ; Whittemore, AS ; Winham, SJ ; Wolk, A ; Woo, Y-L ; Wu, AH ; Yan, L ; Yannoukakos, D ; Zavaglia, KM ; Zheng, W ; Ziogas, A ; Zorn, KK ; Kleibl, Z ; Easton, D ; Lawrenson, K ; DeFazio, A ; Sellers, TA ; Ramus, SJ ; Pearce, CL ; Monteiro, AN ; Cunningham, J ; Goode, EL ; Schildkraut, JM ; Berchuck, A ; Chenevix-Trench, G ; Gayther, SA ; Antoniou, AC ; Pharoah, PDP (SPRINGERNATURE, 2022-01-14)
    Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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    Mendelian randomisation study of smoking exposure in relation to breast cancer risk
    Park, HA ; Neumeyer, S ; Michailidou, K ; Bolla, MK ; Wang, Q ; Dennis, J ; Ahearn, TU ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Aronson, KJ ; Augustinsson, A ; Baten, A ; Freeman, LEB ; Becher, H ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bogdanova, N ; Bojesen, SE ; Brauch, H ; Brenner, H ; Brucker, SY ; Burwinkel, B ; Campa, D ; Canzian, F ; Castelao, JE ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Conroy, DM ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Dork, T ; Dos-Santos-Silva, I ; Dwek, M ; Eccles, DM ; Eliassen, AH ; Engel, C ; Eriksson, M ; Evans, DG ; Fasching, PA ; Flyger, H ; Fritschi, L ; Garcia-Closas, M ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Glendon, G ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Grip, M ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Han, S ; Harkness, EF ; Hart, SN ; He, W ; Heemskerk-Gerritsen, BAM ; Hopper, JL ; Hunter, DJ ; Jager, A ; Jakubowska, A ; John, EM ; Jung, A ; Kaaks, R ; Kapoor, PM ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Koppert, LB ; Koutros, S ; Kristensen, VN ; Kurian, AW ; Lacey, J ; Lambrechts, D ; LeMarchand, L ; Lo, W-Y ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; ElenaMartinez, M ; Mavroudis, D ; Meindl, A ; Menon, U ; Milne, RL ; Muranen, TA ; Nevanlinna, H ; Newman, WG ; Nordestgaard, BG ; Offit, K ; Olshan, AF ; Olsson, H ; Park-Simon, T-W ; Peterlongo, P ; Peto, J ; Plaseska-Karanfilska, D ; Presneau, N ; Radice, P ; Rennert, G ; Rennert, HS ; Romero, A ; Saloustros, E ; Sawyer, EJ ; Schmidt, MK ; Schmutzler, RK ; Schoemaker, MJ ; Schwentner, L ; Scott, C ; Shah, M ; Shu, X-O ; Simard, J ; Smeets, A ; Southey, MC ; Spinelli, JJ ; Stevens, V ; Swerdlow, AJ ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Terry, MB ; Tomlinson, I ; Troester, MA ; Truong, T ; Vachon, CM ; van Veen, EM ; Vijai, J ; Wang, S ; Wendt, C ; Winqvist, R ; Wolk, A ; Ziogas, A ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Zheng, W ; Kraft, P ; Chang-Claude, J (SPRINGERNATURE, 2021-08-02)
    BACKGROUND: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. METHODS: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. RESULTS: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. CONCLUSION: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
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    Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects
    Li, N ; Zethoven, M ; McInerny, S ; Devereux, L ; Huang, Y-K ; Thio, N ; Cheasley, D ; Gutierrez-Enriquez, S ; Moles-Fernandez, A ; Diez, O ; Nguyen-Dumont, T ; Southey, MC ; Hopper, JL ; Simard, J ; Dumont, M ; Soucy, P ; Meindl, A ; Schmutzler, R ; Schmidt, MK ; Adank, MA ; Andrulis, IL ; Hahnen, E ; Engel, C ; Lesueur, F ; Girard, E ; Neuhausen, SL ; Ziv, E ; Allen, J ; Easton, DF ; Scott, RJ ; Gorringe, KL ; James, PA ; Campbell, IG (NATURE RESEARCH, 2021-05-12)
    Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82-1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09-1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
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    CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers
    Johnson, N ; Maguire, S ; Morra, A ; Kapoor, PM ; Tomczyk, K ; Jones, ME ; Schoemaker, MJ ; Gilham, C ; Bolla, MK ; Wang, Q ; Dennis, J ; Ahearn, TU ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Aronson, KJ ; Augustinsson, A ; Baynes, C ; Freeman, LEB ; Beckmann, MW ; Benitez, J ; Bermisheva, M ; Blomqvist, C ; Boeckx, B ; Bogdanova, NV ; Bojesen, SE ; Brauch, H ; Brenner, H ; Burwinkel, B ; Campa, D ; Canzian, F ; Castelao, JE ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Conroy, DM ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Doerk, T ; Eliassen, AH ; Engel, C ; Evans, DG ; Fasching, PA ; Figueroa, J ; Floris, G ; Flyger, H ; Gago-Dominguez, M ; Gapstur, SM ; Garcia-Closas, M ; Gaudet, MM ; Giles, GG ; Goldberg, MS ; Gonzalez-Neira, A ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Harrington, PA ; Hart, SN ; Hooning, MJ ; Hopper, JL ; Howell, A ; Hunter, DJ ; Jager, A ; Jakubowska, A ; John, EM ; Kaaks, R ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Kosma, V-M ; Koutros, S ; Kraft, P ; Kristensen, VN ; Kurian, AW ; Lambrechts, D ; Le Marchand, L ; Linet, M ; Lubinski, J ; Mannermaa, A ; Manoukian, S ; Margolin, S ; Martens, JWM ; Mavroudis, D ; Mayes, R ; Meindl, A ; Milne, RL ; Neuhausen, SL ; Nevanlinna, H ; Newman, WG ; Nielsen, SF ; Nordestgaard, BG ; Obi, N ; Olshan, AF ; Olson, JE ; Olsson, H ; Orban, E ; Park-Simon, T-W ; Peterlongo, P ; Plaseska-Karanfilska, D ; Pylkas, K ; Rennert, G ; Rennert, HS ; Ruddy, KJ ; Saloustros, E ; Sandler, DP ; Sawyer, EJ ; Schmutzler, RK ; Scott, C ; Shu, X-O ; Simard, J ; Smichkoska, S ; Sohn, C ; Southey, MC ; Spinelli, JJ ; Stone, J ; Tamimi, RM ; Taylor, JA ; Tollenaar, RAEM ; Tomlinson, I ; Troester, MA ; Truong, T ; Vachon, CM ; van Veen, EM ; Wang, SS ; Weinberg, CR ; Wendt, C ; Wildiers, H ; Winqvist, R ; Wolk, A ; Zheng, W ; Ziogas, A ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Howie, AF ; Peto, J ; dos-Santos-Silva, I ; Swerdlow, AJ ; Chang-Claude, J ; Schmidt, MK ; Orr, N ; Fletcher, O (SPRINGERNATURE, 2021-01-26)
    BACKGROUND: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. METHODS: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. RESULTS: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8). CONCLUSIONS: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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    Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness
    Patel, VL ; Busch, EL ; Friebel, TM ; Cronin, A ; Leslie, G ; McGuffog, L ; Adlard, J ; Agata, S ; Agnarsson, BA ; Ahmed, M ; Aittomaki, K ; Alducci, E ; Andrulis, IL ; Arason, A ; Arnold, N ; Artioli, G ; Arver, B ; Auber, B ; Azzollini, J ; Balmana, J ; Barkardottir, RB ; Barnes, DR ; Barroso, A ; Barrowdale, D ; Belotti, M ; Benitez, J ; Bertelsen, B ; Blok, MJ ; Bodrogi, I ; Bonadona, V ; Bonanni, B ; Bondavalli, D ; Boonen, SE ; Borde, J ; Borg, A ; Bradbury, AR ; Brady, A ; Brewer, C ; Brunet, J ; Buecher, B ; Buys, SS ; Cabezas-Camarero, S ; Caldes, T ; Caliebe, A ; Caligo, MA ; Calvello, M ; Campbell, IG ; Carnevali, I ; Carrasco, E ; Chan, TL ; Chu, ATW ; Chung, WK ; Claes, KBM ; Cook, J ; Cortesi, L ; Couch, FJ ; Daly, MB ; Damante, G ; Darder, E ; Davidson, R ; de la Hoya, M ; Della Puppa, L ; Dennis, J ; Diez, O ; Ding, YC ; Ditsch, N ; Domchek, SM ; Donaldson, A ; Dworniczak, B ; Easton, DF ; Eccles, DM ; Eeles, RA ; Ehrencrona, H ; Ejlertsen, B ; Engel, C ; Evans, DG ; Faivre, L ; Faust, U ; Feliubadalo, L ; Foretova, L ; Fostira, F ; Fountzilas, G ; Frost, D ; Garcia-Barberan, V ; Garre, P ; Gauthier-Villars, M ; Geczi, L ; Gehrig, A ; Gerdes, A-M ; Gesta, P ; Giannini, G ; Glendon, G ; Godwin, AK ; Goldgar, DE ; Greene, MH ; Gutierrez-Barrera, AM ; Hahnen, E ; Hamann, U ; Hauke, J ; Herold, N ; Hogervorst, FBL ; Honisch, E ; Hopper, JL ; Hulick, PJ ; Izatt, L ; Jager, A ; James, P ; Janavicius, R ; Jensen, UB ; Jensen, TD ; Johannsson, OT ; John, EM ; Joseph, V ; Kang, E ; Kast, K ; Kiiski, J ; Kim, S-W ; Kim, Z ; Ko, K-P ; Konstantopoulou, I ; Kramer, G ; Krogh, L ; Kruse, TA ; Kwong, A ; Larsen, M ; Lasset, C ; Lautrup, C ; Lazaro, C ; Lee, J ; Lee, JW ; Lee, MH ; Lemke, J ; Lesueur, F ; Liljegren, A ; Lindblom, A ; Llovet, P ; Lopez-Fernandez, A ; Lopez-Perolio, I ; Lorca, V ; Loud, JT ; Ma, ESK ; Mai, PL ; Manoukian, S ; Mari, V ; Martin, L ; Matricardi, L ; Mebirouk, N ; Medici, V ; Meijers-Heijboer, HEJ ; Meindl, A ; Mensenkamp, AR ; Miller, C ; Gomes, DM ; Montagna, M ; Mooij, TM ; Moserle, L ; Mouret-Fourme, E ; Mulligan, AM ; Nathanson, KL ; Navratilova, M ; Nevanlinna, H ; Niederacher, D ; Nielsen, FCC ; Nikitina-Zake, L ; Offit, K ; Olah, E ; Olopade, O ; Ong, K-R ; Osorio, A ; Ott, C-E ; Palli, D ; Park, SK ; Parsons, MT ; Pedersen, IS ; Peissel, B ; Peixoto, A ; Perez-Segura, P ; Peterlongo, P ; Petersen, AH ; Porteous, ME ; Angel Pujana, M ; Radice, P ; Ramser, J ; Rantala, J ; Rashid, MU ; Rhiem, K ; Rizzolo, P ; Robson, ME ; Rookus, MA ; Rossing, CM ; Ruddy, KJ ; Santos, C ; Saule, C ; Scarpitta, R ; Schmutzler, RK ; Schuster, H ; Senter, L ; Seynaeve, CM ; Shah, PD ; Sharma, P ; Shin, VY ; Silvestri, V ; Simard, J ; Singer, CF ; Skytte, A-B ; Snape, K ; Solano, AR ; Soucy, P ; Southey, MC ; Spurdle, AB ; Steele, L ; Steinemann, D ; Stoppa-Lyonnet, D ; Stradella, A ; Sunde, L ; Sutter, C ; Tan, YY ; Teixeira, MR ; Teo, SH ; Thomassen, M ; Tibiletti, MG ; Tischkowitz, M ; Tognazzo, S ; Toland, AE ; Tommasi, S ; Torres, D ; Toss, A ; Trainer, AH ; Tung, N ; van Asperen, CJ ; van der Baan, FH ; van der Kolk, LE ; van der Luijt, RB ; van Hest, LP ; Varesco, L ; Varon-Mateeva, R ; Viel, A ; Vierstrate, J ; Villa, R ; von Wachenfeldt, A ; Wagner, P ; Wang-Gohrke, S ; Wappenschmidt, B ; Weitzel, JN ; Wieme, G ; Yadav, S ; Yannoukakos, D ; Yoon, S-Y ; Zanzottera, C ; Zorn, KK ; D'Amico, A ; Freedman, ML ; Pomerantz, MM ; Chenevix-Trench, G ; Antoniou, AC ; Neuhausen, SL ; Ottini, L ; Nielsen, HR ; Rebbeck, TR (AMER ASSOC CANCER RESEARCH, 2020-02-01)
    Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
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    Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
    Fachal, L ; Aschard, H ; Beesley, J ; Barnes, DR ; Allen, J ; Kar, S ; Pooley, KA ; Dennis, J ; Michailidou, K ; Turman, C ; Soucy, P ; Lemacon, A ; Lush, M ; Tyrer, JP ; Ghoussaini, M ; Marjaneh, MM ; Jiang, X ; Agata, S ; Aittomaki, K ; Rosario Alonso, M ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arason, A ; Arndt, V ; Aronson, KJ ; Arun, BK ; Auber, B ; Auer, PL ; Azzollini, J ; Balmana, J ; Barkardottir, RB ; Barrowdale, D ; Beeghly-Fadiel, A ; Benitez, J ; Bermisheva, M ; Bialkowska, K ; Blanco, AM ; Blomqvist, C ; Blot, W ; Bogdanova, N ; Bojesen, SE ; Bolla, MK ; Bonanni, B ; Borg, A ; Bosse, K ; Brauch, H ; Brenner, H ; Briceno, I ; Brock, IW ; Brooks-Wilson, A ; Bruening, T ; Burwinkel, B ; Buys, SS ; Cai, Q ; Caldes, T ; Caligo, MA ; Camp, NJ ; Campbell, I ; Canzian, F ; Carroll, JS ; Carter, BD ; Castelao, JE ; Chiquette, J ; Christiansen, H ; Chung, WK ; Claes, KBM ; Clarke, CL ; Collee, JM ; Cornelissen, S ; Couch, FJ ; Cox, A ; Cross, SS ; Cybulski, C ; Czene, K ; Daly, MB ; de la Hoya, M ; Devilee, P ; Diez, O ; Ding, YC ; Dite, GS ; Domchek, SM ; Doerk, T ; dos-Santos-Silva, I ; Droit, A ; Dubois, S ; Dumont, M ; Duran, M ; Durcan, L ; Dwek, M ; Eccles, DM ; Engel, C ; Eriksson, M ; Evans, DG ; Fasching, PA ; Fletcher, O ; Floris, G ; Flyger, H ; Foretova, L ; Foulkes, WD ; Friedman, E ; Fritschi, L ; Frost, D ; Gabrielson, M ; Gago-Dominguez, M ; Gambino, G ; Ganz, PA ; Gapstur, SM ; Garber, J ; Garcia-Saenz, JA ; Gaudet, MM ; Georgoulias, V ; Giles, GG ; Glendon, G ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Tibiletti, MG ; Greene, MH ; Grip, M ; Gronwald, J ; Grundy, A ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Harrington, PA ; Hartikainen, JM ; Hartman, M ; He, W ; Healey, CS ; Heemskerk-Gerritsen, BAM ; Heyworth, J ; Hillemanns, P ; Hogervorst, FBL ; Hollestelle, A ; Hooning, MJ ; Hopper, JL ; Howell, A ; Huang, G ; Hulick, PJ ; Imyanitov, EN ; Isaacs, C ; Iwasaki, M ; Jager, A ; Jakimovska, M ; Jakubowska, A ; James, PA ; Janavicius, R ; Jankowitz, RC ; John, EM ; Johnson, N ; Jones, ME ; Jukkola-Vuorinen, A ; Jung, A ; Kaaks, R ; Kang, D ; Kapoor, PM ; Karlan, BY ; Keeman, R ; Kerin, MJ ; Khusnutdinova, E ; Kiiski, J ; Kirk, J ; Kitahara, CM ; Ko, Y-D ; Konstantopoulou, I ; Kosma, V-M ; Koutros, S ; Kubelka-Sabit, K ; Kwong, A ; Kyriacou, K ; Laitman, Y ; Lambrechts, D ; Lee, E ; Leslie, G ; Lester, J ; Lesueur, F ; Lindblom, A ; Lo, W-Y ; Long, J ; Lophatananon, A ; Loud, JT ; Lubinski, J ; MacInnis, RJ ; Maishman, T ; Makalic, E ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martinez, ME ; Matsuo, K ; Maurer, T ; Mavroudis, D ; Mayes, R ; McGuffog, L ; McLean, C ; Mebirouk, N ; Meindl, A ; Miller, A ; Miller, N ; Montagna, M ; Moreno, F ; Muir, K ; Mulligan, AM ; Munoz-Garzon, VM ; Muranen, TA ; Narod, SA ; Nassir, R ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Neven, P ; Nielsen, FC ; Nikitina-Zake, L ; Norman, A ; Offit, K ; Olah, E ; Olopade, O ; Olsson, H ; Orr, N ; Osorio, A ; Pankratz, VS ; Papp, J ; Park, SK ; Park-Simon, T-W ; Parsons, MT ; Paul, J ; Pedersen, IS ; Peissel, B ; Peshkin, B ; Peterlongo, P ; Peto, J ; Plaseska-Karanfilska, D ; Prajzendanc, K ; Prentice, R ; Presneau, N ; Prokofyeva, D ; Angel Pujana, M ; Pylkas, K ; Radice, P ; Ramus, SJ ; Rantala, J ; Rau-Murthy, R ; Rennert, G ; Risch, HA ; Robson, M ; Romero, A ; Rossing, M ; Saloustros, E ; Sanchez-Herrero, E ; Sandler, DP ; Santamarina, M ; Saunders, C ; Sawyer, EJ ; Scheuner, MT ; Schmidt, DF ; Schmutzler, RK ; Schneeweiss, A ; Schoemaker, MJ ; Schoettker, B ; Schuermann, P ; Scott, C ; Scott, RJ ; Senter, L ; Seynaeve, CM ; Shah, M ; Sharma, P ; Shen, C-Y ; Shu, X-O ; Singer, CF ; Slavin, TP ; Smichkoska, S ; Southey, MC ; Spinelli, JJ ; Spurdle, AB ; Stone, J ; Stoppa-Lyonnet, D ; Sutter, C ; Swerdlow, AJ ; Tamimi, RM ; Tan, YY ; Tapper, WJ ; Taylor, JA ; Teixeira, MR ; Tengstroem, M ; Teo, SH ; Terry, MB ; Teul, A ; Thomassen, M ; Thull, DL ; Tischkowitz, M ; Toland, AE ; Tollenaar, RAEM ; Tomlinson, I ; Torres, D ; Torres-Mejia, G ; Troester, MA ; Truong, T ; Tung, N ; Tzardi, M ; Ulmer, H-U ; Vachon, CM ; van Asperen, CJ ; van der Kolk, LE ; van Rensburg, EJ ; Vega, A ; Viel, A ; Vijai, J ; Vogel, MJ ; Wang, Q ; Wappenschmidt, B ; Weinberg, CR ; Weitzel, JN ; Wendt, C ; Wildiers, H ; Winqvist, R ; Wolk, A ; Wu, AH ; Yannoukakos, D ; Zhang, Y ; Zheng, W ; Hunter, D ; Pharoah, PDP ; Chang-Claude, J ; Garcia-Closas, M ; Schmidt, MK ; Milne, RL ; Kristensen, VN ; French, JD ; Edwards, SL ; Antoniou, AC ; Chenevix-Trench, G ; Simard, J ; Easton, DF ; Kraft, P ; Dunning, AM ; Mari, V ; Berthet, P ; Castera, L ; Vaur, D ; Lallaoui, H ; Bignon, Y-J ; Uhrhammer, N ; Bonadona, V ; Lasset, C ; Revillion, F ; Vennin, P ; Muller, D ; Gomes, DM ; Ingster, O ; Coupier, I ; Pujol, P ; Collonge-Rame, M-A ; Mortemousque, I ; Bera, O ; Rose, M ; Baurand, A ; Bertolone, G ; Faivre, L ; Dreyfus, H ; Leroux, D ; Venat-Bouvet, L ; Bezieau, S ; Delnatte, C ; Chiesa, J ; Gilbert-Dussardier, B ; Gesta, P ; Prieur, FP ; Bronner, M ; Sokolowska, J ; Coulet, F ; Boutry-Kryza, N ; Calender, A ; Giraud, S ; Leone, M ; Fert-Ferrer, S ; Jiao, Y ; Lesueur, FL ; Barouk-Simonet, E ; Bubien, V ; Longy, M ; Sevenet, N ; Gladieff, L ; Toulas, C ; Reimineras, A ; Sobol, H ; Bressac-de Paillerets, B ; Cabaret, O ; Caron, O ; Guillaud-Bataille, M ; Rouleau, E ; Belotti, M ; Buecher, B ; Caputo, S ; Colas, C ; De Pauw, A ; Fourme, E ; Gauthier-Villars, M ; Golmard, L ; Moncoutier, V ; Saule, C ; Donaldson, A ; Murray, A ; Brady, A ; Brewer, C ; Pottinger, C ; Miller, C ; Gallagher, D ; Gregory, H ; Cook, J ; Eason, J ; Adlard, J ; Barwell, J ; Ong, K-R ; Snape, K ; Walker, L ; Izatt, L ; Side, L ; Rogers, MT ; Porteous, ME ; Ahmed, M ; Morrison, PJ ; Brennan, P ; Eeles, R ; Davidson, R ; Sexton, A ; Christian, A ; Trainer, A ; Spigelman, A ; Fellows, A ; Shelling, A ; De Fazio, A ; Blackburn, A ; Crook, A ; Meiser, B ; Patterson, B ; Clarke, C ; Hunt, C ; Scott, C ; Amor, D ; Marsh, D ; Edkins, E ; Salisbury, E ; Haan, E ; Neidermayr, E ; Macrea, F ; Farshid, G ; Lindeman, G ; Trench, G ; Mann, G ; Giles, G ; Gill, G ; Thorne, H ; Hickie, I ; Winship, I ; Flanagan, J ; Kollias, J ; Visvader, J ; Taylor, J ; Burke, J ; Saunus, J ; Forbes, J ; Hopper, J ; French, J ; Tucker, K ; Wu, K ; Phillips, K ; Lipton, L ; Andrews, L ; Lobb, L ; Walker, L ; Kentwell, M ; Spurdle, M ; Cummings, M ; Gleeson, M ; Harris, M ; Jenkins, M ; Young, MA ; Delatycki, M ; Wallis, M ; Burgess, M ; Price, M ; Brown, M ; Southey, M ; Bogwitz, M ; Field, M ; Friedlander, M ; Gattas, M ; Saleh, M ; Hayward, N ; Pachter, N ; Cohen, P ; Duijf, P ; James, P ; Simpson, P ; Fong, P ; Butow, P ; Williams, R ; Kefford, R ; Scott, R ; Milne, R ; Balleine, R ; Dawson, S ; Lok, S ; O'Connell, S ; Greening, S ; Nightingale, S ; Edwards, S ; Fox, S ; Mclachlan, S-A ; Lakhani, S ; Antill, Y ; Aalfs, C ; Meijers-Heijboer, H ; van Engelen, K ; Gille, H ; Boere, I ; Collee, M ; van Deurzen, C ; Hooning, M ; Obdeijn, I-M ; van den Ouweland, A ; Seynaeve, C ; Siesling, S ; Verloop, J ; van Asperen, C ; van Cronenburg, T ; Blok, R ; de Boer, M ; Garcia, EG ; Adank, M ; Hogervorst, F ; Jenner, D ; van Leeuwen, F ; Rookus, M ; Russell, N ; Schmidt, M ; van den Belt-Dusebout, S ; Kets, C ; Mensenkamp, A ; de Bock, T ; van Der Hout, A ; Mourits, M ; Oosterwijk, J ; Ausems, M ; Koudijs, M ; Marsh, D ; Baxter, R ; Yip, D ; Carpenter, J ; Davis, A ; Pathmanathan, N ; Simpson, P ; Graham, D ; Sachchithananthan, M (NATURE RESEARCH, 2020-01-07)
    Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
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    Transcriptome-wide association study of breast cancer risk by estrogen-receptor status
    Feng, H ; Gusev, A ; Pasaniuc, B ; Wu, L ; Long, J ; Abu-full, Z ; Aittomaki, K ; Andrulis, IL ; Anton-Culver, H ; Antoniou, AC ; Arason, A ; Arndt, V ; Aronson, KJ ; Arun, BK ; Asseryanis, E ; Auer, PL ; Azzollini, J ; Balmana, J ; Barkardottir, RB ; Barnes, DR ; Barrowdale, D ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bialkowska, K ; Blanco, A ; Blomqvist, C ; Boeckx, B ; Bogdanova, NV ; Bojesen, SE ; Bolla, MK ; Bonanni, B ; Borg, A ; Brauch, H ; Brenner, H ; Briceno, I ; Broeks, A ; Bruening, T ; Burwinkel, B ; Cai, Q ; Caldes, T ; Caligo, MA ; Campbell, I ; Canisius, S ; Campa, D ; Carter, BD ; Carter, J ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Christiansen, H ; Chung, WK ; Claes, KBM ; Clarke, CL ; Couch, FJ ; Cox, A ; Cross, SS ; Cybulski, C ; Czene, K ; Daly, MB ; de la Hoya, M ; De Leeneer, K ; Dennis, J ; Devilee, P ; Diez, O ; Domchek, SM ; Doerk, T ; dos-Santos-Silva, I ; Dunning, AM ; Dwek, M ; Eccles, DM ; Ejlertsen, B ; Ellberg, C ; Engel, C ; Eriksson, M ; Fasching, PA ; Fletcher, O ; Flyger, H ; Fostira, F ; Friedman, E ; Fritschi, L ; Frost, D ; Gabrielson, M ; Ganz, PA ; Gapstur, SM ; Garber, J ; Garcia-Closas, M ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Glendon, G ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Greene, MH ; Gronwald, J ; Guenel, P ; Haiman, CA ; Hall, P ; Hamann, U ; Hake, C ; He, W ; Heyworth, J ; Hogervorst, FBL ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Huang, G ; Hulick, PJ ; Humphreys, K ; Imyanitov, EN ; Isaacs, C ; Jakimovska, M ; Jakubowska, A ; James, P ; Janavicius, R ; Jankowitz, RC ; John, EM ; Johnson, N ; Joseph, V ; Jung, A ; Karlan, BY ; Khusnutdinova, E ; Kiiski, J ; Konstantopoulou, I ; Kristensen, VN ; Laitman, Y ; Lambrechts, D ; Lazaro, C ; Leroux, D ; Leslie, G ; Lester, J ; Lesueur, F ; Lindor, N ; Lindstrom, S ; Lo, W-Y ; Loud, JT ; Lubinski, J ; Makalic, E ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martens, JWM ; Martinez, ME ; Matricardi, L ; Maurer, T ; Mavroudis, D ; McGuffog, L ; Meindl, A ; Menon, U ; Michailidou, K ; Kapoor, PM ; Miller, A ; Montagna, M ; Moreno, F ; Moserle, L ; Mulligan, AM ; Muranen, TA ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Nevelsteen, I ; Nielsen, FC ; Nikitina-Zake, L ; Offit, K ; Olah, E ; Olopade, O ; Olsson, H ; Osorio, A ; Papp, J ; Park-Simon, T-W ; Parsons, MT ; Pedersen, IS ; Peixoto, A ; Peterlongo, P ; Peto, J ; Pharoah, PDP ; Phillips, K-A ; Plaseska-Karanfilska, D ; Poppe, B ; Pradhan, N ; Prajzendanc, K ; Presneau, N ; Punie, K ; Pylkas, K ; Radice, P ; Rantala, J ; Rashid, MU ; Rennert, G ; Risch, HA ; Robson, M ; Romero, A ; Saloustros, E ; Sandler, DP ; Santos, C ; Sawyer, EJ ; Schmidt, MK ; Schmidt, DF ; Schmutzler, RK ; Schoemaker, MJ ; Scott, RJ ; Sharma, P ; Shu, X-O ; Simard, J ; Singer, CF ; Skytte, A-B ; Soucy, P ; Southey, MC ; Spinelli, JJ ; Spurdle, AB ; Stone, J ; Swerdlow, AJ ; Tapper, WJ ; Taylor, JA ; Teixeira, MR ; Terry, MB ; Teule, A ; Thomassen, M ; Thoene, K ; Thull, DL ; Tischkowitz, M ; Toland, AE ; Tollenaar, RAEM ; Torres, D ; Truong, T ; Tung, N ; Vachon, CM ; van Asperen, CJ ; van den Ouweland, AMW ; van Rensburg, EJ ; Vega, A ; Viel, A ; Vieiro-Balo, P ; Wang, Q ; Wappenschmidt, B ; Weinberg, CR ; Weitzel, JN ; Wendt, C ; Winqvist, R ; Yang, XR ; Yannoukakos, D ; Ziogas, A ; Milne, RL ; Easton, DF ; Chenevix-Trench, G ; Zheng, W ; Kraft, P ; Jiang, X (WILEY, 2020-03-01)
    Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
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    Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants
    Barnes, DR ; Rookus, MA ; McGuffog, L ; Leslie, G ; Mooij, TM ; Dennis, J ; Mavaddat, N ; Adlard, J ; Ahmed, M ; Aittomaki, K ; Andrieu, N ; Andrulis, IL ; Arnold, N ; Arun, BK ; Azzollini, J ; Balmana, J ; Barkardottir, RB ; Barrowdale, D ; Benitez, J ; Berthet, P ; Bialkowska, K ; Blanco, AM ; Blok, MJ ; Bonanni, B ; Boonen, SE ; Borg, A ; Bozsik, A ; Bradbury, AR ; Brennan, P ; Brewer, C ; Brunet, J ; Buys, SS ; Caldes, T ; Caligo, MA ; Campbell, I ; Christensen, LL ; Chung, WK ; Claes, KBM ; Colas, C ; Collonge-Rame, M-A ; Cook, J ; Daly, MB ; Davidson, R ; de la Hoya, M ; de Putter, R ; Delnatte, C ; Devilee, P ; Diez, O ; Ding, YC ; Domchek, SM ; Dorfling, CM ; Dumont, M ; Eeles, R ; Ejlertsen, B ; Engel, C ; Evans, DG ; Faivre, L ; Foretova, L ; Fostira, F ; Friedlander, M ; Friedman, E ; Frost, D ; Ganz, PA ; Garber, J ; Gehrig, A ; Gerdes, A-M ; Gesta, P ; Giraud, S ; Glendon, G ; Godwin, AK ; Goldgar, DE ; Gonzalez-Neira, A ; Greene, MH ; Gschwantler-Kaulich, D ; Hahnen, E ; Hamann, U ; Hanson, H ; Hentschel, J ; Hogervorst, FBL ; Hooning, MJ ; Horvath, J ; Hu, C ; Hulick, PJ ; Imyanitov, EN ; Isaacs, C ; Izatt, L ; Izquierdo, A ; Jakubowska, A ; James, PA ; Janavicius, R ; John, EM ; Joseph, V ; Karlan, BY ; Kast, K ; Koudijs, M ; Kruse, TA ; Kwong, A ; Laitman, Y ; Lasset, C ; Lazaro, C ; Lester, J ; Lesueur, F ; Liljegren, A ; Loud, JT ; Lubinski, J ; Mai, PL ; Manoukian, S ; Mari, V ; Mebirouk, N ; Meijers-Heijboer, HEJ ; Meindl, A ; Mensenkamp, AR ; Miller, A ; Montagna, M ; Mouret-Fourme, E ; Mukherjee, S ; Mulligan, AM ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Niederacher, D ; Nielsen, FC ; Nikitina-Zake, L ; Nogues, C ; Olah, E ; Olopade, O ; Ong, K-R ; O'Shaughnessy-Kirwan, A ; Osorio, A ; Ott, C-E ; Papi, L ; Park, SK ; Parsons, MT ; Pedersen, IS ; Peissel, B ; Peixoto, A ; Peterlongo, P ; Pfeiler, G ; Phillips, K-A ; Prajzendanc, K ; Pujana, MA ; Radice, P ; Ramser, J ; Ramus, SJ ; Rantala, J ; Rennert, G ; Risch, HA ; Robson, M ; Ronlund, K ; Salani, R ; Schuster, H ; Senter, L ; Shah, PD ; Sharma, P ; Side, LE ; Singer, CF ; Slavin, TP ; Soucy, P ; Southey, MC ; Spurdle, AB ; Steinemann, D ; Steinsnyder, Z ; Stoppa-Lyonnet, D ; Sutter, C ; Tan, YY ; Teixeira, MR ; Teo, SH ; Thull, DL ; Tischkowitz, M ; Tognazzo, S ; Toland, AE ; Trainer, AH ; Tung, N ; van Engelen, K ; van Rensburg, EJ ; Vega, A ; Vierstraete, J ; Wagner, G ; Walker, L ; Wang-Gohrke, S ; Wappenschmidt, B ; Weitzel, JN ; Yadav, S ; Yang, X ; Yannoukakos, D ; Zimbalatti, D ; Offit, K ; Thomassen, M ; Couch, FJ ; Schmutzler, RK ; Simard, J ; Easton, DF ; Chenevix-Trench, G ; Antoniou, AC (SPRINGERNATURE, 2020-07-15)
    PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.