Sir Peter MacCallum Department of Oncology - Research Publications

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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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    Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations
    Rebbeck, TR ; Friebel, TM ; Friedman, E ; Hamann, U ; Huo, D ; Kwong, A ; Olah, E ; Olopade, OI ; Solano, AR ; Teo, S-H ; Thomassen, M ; Weitzel, JN ; Chan, TL ; Couch, FJ ; Goldgar, DE ; Kruse, TA ; Palmero, EI ; Park, SK ; Torres, D ; van Rensburg, EJ ; McGuffog, L ; Parsons, MT ; Leslie, G ; Aalfs, CM ; Abugattas, J ; Adlard, J ; Agata, S ; Aittomaki, K ; Andrews, L ; Andrulis, IL ; Arason, A ; Arnold, N ; Arun, BK ; Asseryanis, E ; Auerbach, L ; Azzollini, J ; Balmana, J ; Barile, M ; Barkardottir, RB ; Barrowdale, D ; Benitez, J ; Berger, A ; Berger, R ; Blanco, AM ; Blazer, KR ; Blok, MJ ; Bonadona, V ; Bonanni, B ; Bradbury, AR ; Brewer, C ; Buecher, B ; Buys, SS ; Caldes, T ; Caliebe, A ; Caligo, MA ; Campbell, I ; Caputo, SM ; Chiquette, J ; Chung, WK ; Claes, KBM ; Collee, JM ; Cook, J ; Davidson, R ; de la Hoya, M ; De Leeneer, K ; de Pauw, A ; Delnatte, C ; Diez, O ; Ding, YC ; Ditsch, N ; Domchek, S ; Dorfling, CM ; Velazquez, C ; Dworniczak, B ; Eason, J ; Easton, DF ; Eeles, R ; Ehrencrona, H ; Ejlertsen, B ; Engel, C ; Engert, S ; Evans, DG ; Faivre, L ; Feliubadalo, L ; Ferrer, SF ; Foretova, L ; Fowler, J ; Frost, D ; Galvao, HCR ; Ganz, PA ; Garber, J ; Gauthier-Villars, M ; Gehrig, A ; Gerdes, A-M ; Gesta, P ; Giannini, G ; Giraud, S ; Glendon, G ; Godwin, AK ; Greene, MH ; Gronwald, J ; Gutierrez-Barrera, A ; Hahnen, E ; Hauke, J ; Henderson, A ; Hentschel, J ; Hogervorst, FBL ; Honisch, E ; Imyanitov, EN ; Isaacs, C ; Izatt, L ; Izquierdo, A ; Jakubowska, A ; James, P ; Janavicius, R ; Jensen, UB ; John, EM ; Vijai, J ; Kaczmarek, K ; Karlan, BY ; Kast, K ; Kim, S-W ; Konstantopoulou, I ; Korach, J ; Laitman, Y ; Lasa, A ; Lasset, C ; Lazaro, C ; Lee, A ; Lee, MH ; Lester, J ; Lesueur, F ; Liljegren, A ; Lindor, NM ; Longy, M ; Loud, JT ; Lu, KH ; Lubinski, J ; Machackova, E ; Manoukian, S ; Mari, V ; Martinez-Bouzas, C ; Matrai, Z ; Mebirouk, N ; Meijers-Heijboer, HEJ ; Meindl, A ; Mensenkamp, AR ; Mickys, U ; Miller, A ; Montagna, M ; Moysich, KB ; Mulligan, AM ; Musinsky, J ; Neuhausen, SL ; Nevanlinna, H ; Ngeow, J ; Nguyen, HP ; Niederacher, D ; Nielsen, HR ; Nielsen, FC ; Nussbaum, RL ; Offit, K ; Ofverholm, A ; Ong, K-R ; Osorio, A ; Papi, L ; Papp, J ; Pasini, B ; Pedersen, IS ; Peixoto, A ; Peruga, N ; Peterlongo, P ; Pohl, E ; Pradhan, N ; Prajzendanc, K ; Prieur, F ; Pujol, P ; Radice, P ; Ramus, SJ ; Rantala, J ; Rashid, MU ; Rhiem, K ; Robson, M ; Rodriguez, GC ; Rogers, MT ; Rudaitis, V ; Schmidt, AY ; Schmutzler, RK ; Senter, L ; Shah, PD ; Sharma, P ; Side, LE ; Simard, J ; Singer, CF ; Skytte, A-B ; Slavin, TP ; Snape, K ; Sobol, H ; Southey, M ; Steele, L ; Steinemann, D ; Sukiennicki, G ; Sutter, C ; Szabo, CI ; Tan, YY ; Teixeira, MR ; Terry, MB ; Teule, A ; Thomas, A ; Thull, DL ; Tischkowitz, M ; Tognazzo, S ; Toland, AE ; Topka, S ; Trainer, AH ; Tung, N ; van Asperen, CJ ; van der Hout, AH ; van der Kolk, LE ; van der Luijt, RB ; Van Heetvelde, M ; Varesco, L ; Varon-Mateeva, R ; Vega, A ; Villarreal-Garza, C ; von Wachenfeldt, A ; Walker, L ; Wang-Gohrke, S ; Wappenschmidt, B ; Weber, BHF ; Yannoukakos, D ; Yoon, S-Y ; Zanzottera, C ; Zidan, J ; Zorn, KK ; Selkirk, CGH ; Hulick, PJ ; Chenevix-Trench, G ; Spurdle, AB ; Antoniou, AC ; Nathanson, KL (WILEY-HINDAWI, 2018-05)
    The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
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    rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology
    Kelemen, LE ; Earp, M ; Fridley, BL ; Chenevix-Trench, G ; Fasching, PA ; Beckmann, MW ; Ekici, AB ; Hein, A ; Lambrechts, D ; Lambrechts, S ; Van Nieuwenhuysen, E ; Vergote, I ; Rossing, MA ; Doherty, JA ; Chang-Claude, J ; Behrens, S ; Moysich, KB ; Cannioto, R ; Lele, S ; Odunsi, K ; Goodman, MT ; Shvetsov, YB ; Thompson, PJ ; Wilkens, LR ; Doerk, T ; Antonenkova, N ; Bogdanova, N ; Hillemanns, P ; Runnebaum, IB ; du Bois, A ; Harter, P ; Heitz, F ; Schwaab, I ; Butzow, R ; Pelttari, LM ; Nevanlinna, H ; Modugno, F ; Edwards, RP ; Kelley, JL ; Ness, RB ; Karlan, BY ; Lester, J ; Orsulic, S ; Walsh, C ; Kjaer, SK ; Jensen, A ; Cunningham, JM ; Vierkant, RA ; Giles, GG ; Bruinsma, F ; Southey, MC ; Hildebrandt, MAT ; Liang, D ; Lu, K ; Wu, X ; Sellers, TA ; Levine, DA ; Schildkraut, JM ; Iversen, ES ; Terry, KL ; Cramer, DW ; Tworoger, SS ; Poole, EM ; Bandera, EV ; Olson, SH ; Orlow, I ; Thomsen, LCV ; Bjorge, L ; Krakstad, C ; Tangen, IL ; Kiemeney, LA ; Aben, KKH ; Massuger, LFAG ; van Altena, AM ; Pejovic, T ; Bean, Y ; Kellar, M ; Cook, LS ; Le, ND ; Brooks-Wilson, A ; Gronwald, J ; Cybulski, C ; Jakubowska, A ; Lubinski, J ; Wentzensen, N ; Brinton, LA ; Lissowska, J ; Hogdall, E ; Engelholm, SA ; Hogdall, C ; Lundvall, L ; Nedergaard, L ; Pharoah, PDP ; Dicks, E ; Song, H ; Tyrer, JP ; McNeish, I ; Siddiqui, N ; Carty, K ; Glasspool, R ; Paul, J ; Campbell, IG ; Eccles, D ; Whittemore, AS ; McGuire, V ; Rothstein, JH ; Sieh, W ; Narod, SA ; Phelan, CM ; McLaughlin, JR ; Risch, HA ; Anton-Culver, H ; Ziogas, A ; Menon, U ; Gayther, SA ; Gentry-Maharaj, A ; Ramus, SJ ; Wu, AH ; Pearce, CL ; Lee, AW ; Pike, MC ; Kupryjanczyk, J ; Podgorska, A ; Plisiecka-Halasa, J ; Sawicki, W ; Goode, EL ; Berchuck, A (MDPI, 2018-09)
    Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
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    Functional Polymorphisms in the TERT Promoter Are Associated with Risk of Serous Epithelial Ovarian and Breast Cancers
    Beesley, J ; Pickett, HA ; Johnatty, SE ; Dunning, AM ; Chen, X ; Li, J ; Michailidou, K ; Lu, Y ; Rider, DN ; Palmieri, RT ; Stutz, MD ; Lambrechts, D ; Despierre, E ; Lambrechts, S ; Vergote, I ; Chang-Claude, J ; Nickels, S ; Vrieling, A ; Flesch-Janys, D ; Wang-Gohrke, S ; Eilber, U ; Bogdanova, N ; Antonenkova, N ; Runnebaum, IB ; Doerk, T ; Goodman, MT ; Lurie, G ; Wilkens, LR ; Matsuno, RK ; Kiemeney, LA ; Aben, KKH ; Marees, T ; Massuger, LFAG ; Fridley, BL ; Vierkant, RA ; Bandera, EV ; Olson, SH ; Orlow, I ; Rodriguez-Rodriguez, L ; Cook, LS ; Le, ND ; Brooks-Wilson, A ; Kelemen, LE ; Campbell, I ; Gayther, SA ; Ramus, SJ ; Gentry-Maharaj, A ; Menon, U ; Ahmed, S ; Baynes, C ; Pharoah, PD ; Muir, K ; Lophatananon, A ; Chaiwerawattana, A ; Wiangnon, S ; Macgregor, S ; Easton, DF ; Reddel, RR ; Goode, EL ; Chenevix-Trench, G ; Zhang, L (PUBLIC LIBRARY SCIENCE, 2011-09-15)
    Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.
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    Identification of six new susceptibility loci for invasive epithelial ovarian cancer
    Kuchenbaecker, KB ; Ramus, SJ ; Tyrer, J ; Lee, A ; Shen, HC ; Beesley, J ; Lawrenson, K ; McGuffog, L ; Healey, S ; Lee, JM ; Spindler, TJ ; Lin, YG ; Pejovic, T ; Bean, Y ; Li, Q ; Coetzee, S ; Hazelett, D ; Miron, A ; Southey, M ; Terry, MB ; Goldgar, DE ; Buys, SS ; Janavicius, R ; Dorfling, CM ; van Rensburg, EJ ; Neuhausen, SL ; Ding, YC ; Hansen, TVO ; Jonson, L ; Gerdes, A-M ; Ejlertsen, B ; Barrowdale, D ; Dennis, J ; Benitez, J ; Osorio, A ; Garcia, MJ ; Komenaka, I ; Weitzel, JN ; Ganschow, P ; Peterlongo, P ; Bernard, L ; Viel, A ; Bonanni, B ; Peissel, B ; Manoukian, S ; Radice, P ; Papi, L ; Ottini, L ; Fostira, F ; Konstantopoulou, I ; Garber, J ; Frost, D ; Perkins, J ; Platte, R ; Ellis, S ; Godwin, AK ; Schmutzler, RK ; Meindl, A ; Engel, C ; Sutter, C ; Sinilnikova, OM ; Damiola, F ; Mazoyer, S ; Stoppa-Lyonnet, D ; Claes, K ; De Leeneer, K ; Kirk, J ; Rodriguez, GC ; Piedmonte, M ; O'Malley, DM ; de la Hoya, M ; Caldes, T ; Aittomaeki, K ; Nevanlinna, H ; Collee, JM ; Rookus, MA ; Oosterwijk, JC ; Tihomirova, L ; Tung, N ; Hamann, U ; Isaccs, C ; Tischkowitz, M ; Imyanitov, EN ; Caligo, MA ; Campbell, IG ; Hogervorst, FBL ; Olah, E ; Diez, O ; Blanco, I ; Brunet, J ; Lazaroso, C ; Angel Pujana, M ; Jakubowska, A ; Gronwald, J ; Lubinski, J ; Sukiennicki, G ; Barkardottir, RB ; Plante, M ; Simard, J ; Soucy, P ; Montagna, M ; Tognazzo, S ; Teixeira, MR ; Pankratz, VS ; Wang, X ; Lindor, N ; Szabo, CI ; Kauff, N ; Vijai, J ; Aghajanian, CA ; Pfeiler, G ; Berger, A ; Singer, CF ; Tea, M-K ; Phelan, CM ; Greene, MH ; Mai, PL ; Rennert, G ; Mulligan, AM ; Tchatchou, S ; Andrulis, IL ; Glendon, G ; Toland, AE ; Jensen, UB ; Kruse, TA ; Thomassen, M ; Bojesen, A ; Zidan, J ; Friedman, E ; Laitman, Y ; Soller, M ; Liljegren, A ; Arver, B ; Einbeigi, Z ; Stenmark-Askmalm, M ; Olopade, OI ; Nussbaum, RL ; Rebbeck, TR ; Nathanson, KL ; Domchek, SM ; Lu, KH ; Karlan, BY ; Walsh, C ; Lester, J ; Hein, A ; Ekici, AB ; Beckmann, MW ; Fasching, PA ; Lambrechts, D ; Van Nieuwenhuysen, E ; Vergote, I ; Lambrechts, S ; Dicks, E ; Doherty, JA ; Wicklund, KG ; Rossing, MA ; Rudolph, A ; Chang-Claude, J ; Wang-Gohrke, S ; Eilber, U ; Moysich, KB ; Odunsi, K ; Sucheston, L ; Lele, S ; Wilkens, LR ; Goodman, MT ; Thompson, PJ ; Shvetsov, YB ; Runnebaum, IB ; Duerst, M ; Hillemanns, P ; Doerk, T ; Antonenkova, N ; Bogdanova, N ; Leminen, A ; Pelttari, LM ; Butzow, R ; Modugno, F ; Kelley, JL ; Edwards, RP ; Ness, RB ; du Bois, A ; Heitz, F ; Schwaab, I ; Harter, P ; Matsuo, K ; Hosono, S ; Orsulic, S ; Jensen, A ; Kjaer, SK ; Hogdall, E ; Hasmad, HN ; Azmi, MAN ; Teo, S-H ; Woo, Y-L ; Fridley, BL ; Goode, EL ; Cunningham, JM ; Vierkant, RA ; Bruinsma, F ; Giles, GG ; Liang, D ; Hildebrandt, MAT ; Wu, X ; Levine, DA ; Bisogna, M ; Berchuck, A ; Iversen, ES ; Schildkraut, JM ; Concannon, P ; Weber, RP ; Cramer, DW ; Terry, KL ; Poole, EM ; Tworoger, SS ; Bandera, EV ; Orlow, I ; Olson, SH ; Krakstad, C ; Salvesen, HB ; Tangen, IL ; Bjorge, L ; van Altena, AM ; Aben, KKH ; Kiemeney, LA ; Massuger, LFAG ; Kellar, M ; Brooks-Wilson, A ; Kelemen, LE ; Cook, LS ; Le, ND ; Cybulski, C ; Yang, H ; Lissowska, J ; Brinton, LA ; Wentzensen, N ; Hogdall, C ; Lundvall, L ; Nedergaard, L ; Baker, H ; Song, H ; Eccles, D ; McNeish, I ; Paul, J ; Carty, K ; Siddiqui, N ; Glasspool, R ; Whittemore, AS ; Rothstein, JH ; McGuire, V ; Sieh, W ; Ji, B-T ; Zheng, W ; Shu, X-O ; Gao, Y-T ; Rosen, B ; Risch, HA ; McLaughlin, JR ; Narod, SA ; Monteiro, AN ; Chen, A ; Lin, H-Y ; Permuth-Wey, J ; Sellers, TA ; Tsai, Y-Y ; Chen, Z ; Ziogas, A ; Anton-Culver, H ; Gentry-Maharaj, A ; Menon, U ; Harrington, P ; Lee, AW ; Wu, AH ; Pearce, CL ; Coetzee, G ; Pike, MC ; Dansonka-Mieszkowska, A ; Timorek, A ; Rzepecka, IK ; Kupryjanczyk, J ; Freedman, M ; Noushmehr, H ; Easton, DF ; Offit, K ; Couch, FJ ; Gayther, S ; Pharoah, PP ; Antoniou, AC ; Chenevix-Trench, G (NATURE PORTFOLIO, 2015-02)
    Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.