Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Campbell, Ian × Author: Ramus, Susan × End date: 2023 × Start date: 2020 × Type: Journal Article ×

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    Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8(+) TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas
    Heinze, K ; Nazeran, TM ; Lee, S ; Kramer, P ; Cairns, ES ; Chiu, DS ; Leung, SCY ; Kang, EY ; Meagher, NS ; Kennedy, CJ ; Boros, J ; Kommoss, F ; Vollert, H-W ; Heitze, F ; du Bois, A ; Harter, P ; Grube, M ; Kraemer, B ; Staebler, A ; Kommoss, FKF ; Heublein, S ; Sinn, H-P ; Singh, N ; Laslavic, A ; Elishaev, E ; Olawaiye, A ; Moysich, K ; Modugno, F ; Sharma, R ; Brand, AH ; Harnett, PR ; DeFazio, A ; Fortner, RT ; Lubinski, J ; Lener, M ; Toloczko-Grabarek, A ; Cybulski, C ; Gronwald, H ; Gronwald, J ; Coulson, P ; El-Bahrawy, MA ; Jones, ME ; Schoemaker, MJ ; Swerdlow, AJ ; Gorringe, KL ; Campbell, I ; Cook, L ; Gayther, SA ; Carney, ME ; Shvetsov, YB ; Hernandez, BY ; Wilkens, LR ; Goodman, MT ; Mateoiu, C ; Linder, A ; Sundfeldt, K ; Kelemen, LE ; Gentry-Maharaj, A ; Widschwendter, M ; Menon, U ; Bolton, KL ; Alsop, J ; Shah, M ; Jimenez-Linan, M ; Pharoah, PDP ; Brenton, JD ; Cushing-Haugen, KL ; Harris, HR ; Doherty, JA ; Gilks, B ; Ghatage, P ; Huntsman, DG ; Nelson, GS ; Tinker, A ; Lee, C-H ; Goode, EL ; Nelson, BH ; Ramus, SJ ; Kommoss, S ; Talhouk, A ; Kobel, M ; Anglesio, MS (Wiley, 2022-04)
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    p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study
    Kobel, M ; Kang, E-Y ; Weir, A ; Rambau, PF ; Lee, C-H ; Nelson, GS ; Ghatage, P ; Meagher, NS ; Riggan, MJ ; Alsop, J ; Anglesio, MS ; Beckmann, MW ; Bisinotto, C ; Boisen, M ; Boros, J ; Brand, AH ; Brooks-Wilson, A ; Carney, ME ; Coulson, P ; Courtney-Brooks, M ; Cushing-Haugen, KL ; Cybulski, C ; Deen, S ; El-Bahrawy, MA ; Elishaev, E ; Erber, R ; Fereday, S ; Fischer, A ; Gayther, SA ; Barquin-Garcia, A ; Gentry-Maharaj, A ; Gilks, CB ; Gronwald, H ; Grube, M ; Harnett, PR ; Harris, HR ; Hartkopf, AD ; Hartmann, A ; Hein, A ; Hendley, J ; Hernandez, BY ; Huang, Y ; Jakubowska, A ; Jimenez-Linan, M ; Jones, ME ; Kennedy, CJ ; Kluz, T ; Koziak, JM ; Lesnock, J ; Lester, J ; Lubinski, J ; Longacre, TA ; Lycke, M ; Mateoiu, C ; McCauley, BM ; McGuire, V ; Ney, B ; Olawaiye, A ; Orsulic, S ; Osorio, A ; Paz-Ares, L ; Ramon Y Cajal, T ; Rothstein, JH ; Ruebner, M ; Schoemaker, MJ ; Shah, M ; Sharma, R ; Sherman, ME ; Shvetsov, YB ; Singh, N ; Steed, H ; Storr, SJ ; Talhouk, A ; Traficante, N ; Wang, C ; Whittemore, AS ; Widschwendter, M ; Wilkens, LR ; Winham, SJ ; Benitez, J ; Berchuck, A ; Bowtell, DD ; Candido dos Reis, FJ ; Campbell, I ; Cook, LS ; DeFazio, A ; Doherty, JA ; Fasching, PA ; Fortner, RT ; Garcia, MJ ; Goodman, MT ; Goode, EL ; Gronwald, J ; Huntsman, DG ; Karlan, BY ; Kelemen, LE ; Kommoss, S ; Le, ND ; Martin, SG ; Menon, U ; Modugno, F ; Pharoah, PDP ; Schildkraut, JM ; Sieh, W ; Staebler, A ; Sundfeldt, K ; Swerdlow, AJ ; Ramus, SJ ; Brenton, JD (WILEY, 2023-05)
    Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
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    Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes
    Meagher, NS ; Gorringe, KL ; Wakefield, M ; Bolithon, A ; Pang, CNI ; Chiu, DS ; Anglesio, MS ; Mallitt, K-A ; Doherty, JA ; Harris, HR ; Schildkraut, JM ; Berchuck, A ; Cushing-Haugen, KL ; Chezar, K ; Chou, A ; Tan, A ; Alsop, J ; Barlow, E ; Beckmann, MW ; Boros, J ; Bowtell, DDL ; Brand, AH ; Brenton, JD ; Campbell, I ; Cheasley, D ; Cohen, J ; Cybulski, C ; Elishaev, E ; Erber, R ; Farrell, R ; Fischer, A ; Fu, Z ; Gilks, B ; Gill, AJ ; Gourley, C ; Grube, M ; Harnett, PR ; Hartmann, A ; Hettiaratchi, A ; Hogdall, CK ; Huzarski, T ; Jakubowska, A ; Jimenez-Linan, M ; Kennedy, CJ ; Kim, B-G ; Kim, J-W ; Kim, J-H ; Klett, K ; Koziak, JM ; Lai, T ; Laslavic, A ; Lester, J ; Leung, Y ; Li, N ; Liauw, W ; Lim, BWX ; Linder, A ; Lubinski, J ; Mahale, S ; Mateoiu, C ; McInerny, S ; Menkiszak, J ; Minoo, P ; Mittelstadt, S ; Morris, D ; Orsulic, S ; Park, S-Y ; Pearce, CL ; Pearson, J ; Pike, MC ; Quinn, CM ; Mohan, GR ; Rao, J ; Riggan, MJ ; Ruebner, M ; Salfinger, S ; Scott, CL ; Shah, M ; Steed, H ; Stewart, CJR ; Subramanian, D ; Sung, S ; Tang, K ; Timpson, P ; Ward, RL ; Wiedenhoefer, R ; Thorne, H ; Cohen, PA ; Crowe, P ; Fasching, PA ; Gronwald, J ; Hawkins, NJ ; Hogdall, E ; Huntsman, DG ; James, PA ; Karlan, BY ; Kelemen, LE ; Kommoss, S ; Konecny, GE ; Modugno, F ; Park, SK ; Staebler, A ; Sundfeldt, K ; Wu, AH ; Talhouk, A ; Pharoah, PDP ; Anderson, L ; DeFazio, A ; Kobel, M ; Friedlander, ML ; Ramus, SJ (AMER ASSOC CANCER RESEARCH, 2022-12-15)
    PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
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    Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
    DeVries, AA ; Dennis, J ; Tyrer, JP ; Peng, P-C ; Coetzee, SG ; Reyes, AL ; Plummer, JT ; Davis, BD ; Chen, SS ; Dezem, FS ; Aben, KKH ; Anton-Culver, H ; Antonenkova, NN ; Beckmann, MW ; Beeghly-Fadiel, A ; Berchuck, A ; Bogdanova, N ; Bogdanova-Markov, N ; Brenton, JD ; Butzow, R ; Campbell, I ; Chang-Claude, J ; Chenevix-Trench, G ; Cook, LS ; DeFazio, A ; Doherty, JA ; Dork, T ; Eccles, DM ; Eliassen, AH ; Fasching, PA ; Fortner, RT ; Giles, GG ; Goode, EL ; Goodman, MT ; Gronwald, J ; Hakansson, N ; Hildebrandt, MAT ; Huff, C ; Huntsman, DG ; Jensen, A ; Kar, S ; Karlan, BY ; Khusnutdinova, EK ; Kiemeney, LA ; Kjaer, SK ; Kupryjanczyk, J ; Labrie, M ; Lambrechts, D ; Le, ND ; Lubinski, J ; May, T ; Menon, U ; Milne, RL ; Modugno, F ; Monteiro, AN ; Moysich, KB ; Odunsi, K ; Olsson, H ; Pearce, CL ; Pejovic, T ; Ramus, SJ ; Riboli, E ; Riggan, MJ ; Romieu, I ; Sandler, DP ; Schildkraut, JM ; Setiawan, VW ; Sieh, W ; Song, H ; Sutphen, R ; Terry, KL ; Thompson, PJ ; Titus, L ; Tworoger, SS ; Van Nieuwenhuysen, E ; Edwards, DV ; Webb, PM ; Wentzensen, N ; Whittemore, AS ; Wolk, A ; Wu, AH ; Ziogas, A ; Freedman, ML ; Lawrenson, K ; Pharoah, PDP ; Easton, DF ; Gayther, SA ; Jones, MR (OXFORD UNIV PRESS INC, 2022-11)
    BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
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    Polygenic risk modeling for prediction of epithelial ovarian cancer risk (vol 30, pg 349, 2021)
    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, 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 ; 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, RT ; Machackova, E ; Friedman, E ; Ganz, PA ; Garber, J ; Gensini, F ; Giles, GG ; Glendon, G ; Godwin, AK ; Goodman, MT ; Greene, MH ; Gronwald, J ; 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 ; Lubinski, 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 ; 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 ; Terry, MB ; 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, JM ; Goode, EL ; Schildkraut, JM ; Berchuck, A ; Chenevix-Trench, G ; Gayther, SA ; Antoniou, AC ; Pharoah, PDP (SPRINGERNATURE, 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, 2022-03)
    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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    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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    Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer
    Song, H ; Dicks, EM ; Tyrer, J ; Intermaggio, M ; Chenevix-Trench, G ; Bowtell, DD ; Traficante, N ; Brenton, J ; Goranova, T ; Hosking, K ; Piskorz, A ; van Oudenhove, E ; Doherty, J ; Harris, HR ; Rossing, MA ; Duerst, M ; Dork, T ; Bogdanova, N ; Modugno, F ; Moysich, K ; Odunsi, K ; Ness, R ; Karlan, BY ; Lester, J ; Jensen, A ; Kruger Kjaer, S ; Hogdall, E ; Campbell, IG ; Lazaro, C ; Pujara, MA ; Cunningham, J ; Vierkant, R ; Winham, SJ ; Hildebrandt, M ; Huff, C ; Li, D ; Wu, X ; Yu, Y ; Permuth, JB ; Levine, DA ; Schildkraut, JM ; Riggan, MJ ; Berchuck, A ; Webb, PM ; Cybulski, C ; Gronwald, J ; Jakubowska, A ; Lubinski, J ; Alsop, J ; Harrington, P ; Chan, I ; Menon, U ; Pearce, CL ; Wu, AH ; de Fazio, A ; Kennedy, CJ ; Goode, E ; Ramus, S ; Gayther, S ; Pharoah, P (BMJ PUBLISHING GROUP, 2021-05)
    PURPOSE: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. METHODS: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. RESULTS: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. CONCLUSIONS: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.
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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 (ELSEVIER SCIENCE INC, 2020-10)
    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.