Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Campbell, Ian × Author: Ramus, Susan × End date: 2019 × Start date: 2018 ×

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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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    Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study
    Dixon-Suen, SC ; Nagle, CM ; Thrift, AP ; Pharoah, PDP ; Ewing, A ; Pearce, CL ; Zheng, W ; Chenevix-Trench, G ; Fasching, PA ; Beckmann, MW ; Lambrechts, D ; Vergote, I ; Lambrechts, S ; Van Nieuwenhuysen, E ; Rossing, MA ; Doherty, JA ; Wicklund, KG ; Chang-Claude, J ; Jung, AY ; Moysich, KB ; Odunsi, K ; Goodman, MT ; Wilkens, LR ; Thompson, PJ ; Shvetsov, YB ; Doerk, T ; Park-Simon, T-W ; Hillemanns, P ; Bogdanova, N ; Butzow, R ; Nevanlinna, H ; Pelttari, LM ; Leminen, A ; Modugno, F ; Ness, RB ; Edwards, RP ; Kelley, JL ; Heitz, F ; du Bois, A ; Harter, P ; Schwaab, I ; Karlan, BY ; Lester, J ; Orsulic, S ; Rimel, BJ ; Kjaer, SK ; Hogdall, E ; Jensen, A ; Goode, EL ; Fridley, BL ; Cunningham, JM ; Winham, SJ ; Giles, GG ; Bruinsma, F ; Milne, RL ; Southey, MC ; Hildebrandt, MAT ; Wu, X ; Lu, KH ; Liang, D ; Levine, DA ; Bisogna, M ; Schildkraut, JM ; Berchuck, A ; Cramer, DW ; Terry, KL ; Bandera, EV ; Olson, SH ; Salvesen, HB ; Thomsen, LCV ; Kopperud, RK ; Bjorge, L ; Kiemeney, LA ; Massuger, LFAG ; Pejovic, T ; Bruegl, A ; Cook, LS ; Le, ND ; Swenerton, KD ; Brooks-Wilson, A ; Kelemen, LE ; Lubinski, J ; Huzarski, T ; Gronwald, J ; Menkiszak, J ; Wentzensen, N ; Brinton, L ; Yang, H ; Lissowska, J ; Hogdall, CK ; Lundvall, L ; Song, H ; Tyrer, JP ; Campbell, I ; Eccles, D ; Paul, J ; Glasspool, R ; Siddiqui, N ; Whittemore, AS ; Sieh, W ; McGuire, V ; Rothstein, JH ; Narod, SA ; Phelan, C ; Risch, HA ; McLaughlin, JR ; Anton-Culver, H ; Ziogas, A ; Menon, U ; Gayther, SA ; Ramus, SJ ; Gentry-Maharaj, A ; Wu, AH ; Pike, MC ; Tseng, C-C ; Kupryjanczyk, J ; Dansonka-Mieszkowska, A ; Budzilowska, A ; Rzepecka, IK ; Webb, PM (NATURE PUBLISHING GROUP, 2018-04)
    BACKGROUND: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. METHODS: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. RESULTS: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. CONCLUSIONS: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.
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    MyD88 and TLR4 Expression in Epithelial Ovarian Cancer
    Block, MS ; Vierkant, RA ; Rambau, PF ; Winham, SJ ; Wagner, P ; Traficante, N ; Toloczko, A ; Tiezzi, DG ; Taran, FA ; Sinn, P ; Sieh, W ; Sharma, R ; Rothstein, JH ; Ramon y Cajal, T ; Paz-Ares, L ; Oszurek, O ; Orsulic, S ; Ness, RB ; Nelson, G ; Modugno, F ; Menkiszak, J ; McGuire, V ; McCauley, BM ; Mack, M ; Lubinski, J ; Longacre, TA ; Li, Z ; Lester, J ; Kennedy, CJ ; Kalli, KR ; Jung, AY ; Johnatty, SE ; Jimenez-Linan, M ; Jensen, A ; Intermaggio, MP ; Hung, J ; Herpel, E ; Hernandez, BY ; Hartkopf, AD ; Harnett, PR ; Ghatage, P ; Garcia-Bueno, JM ; Gao, B ; Fereday, S ; Eilber, U ; Edwards, RP ; de Sousa, CB ; de Andrade, JM ; Chudecka-Glaz, A ; Chenevix-Trench, G ; Cazorla, A ; Brucker, SY ; Alsop, J ; Whittemore, AS ; Steed, H ; Staebler, A ; Moysich, KB ; Menon, U ; Koziak, JM ; Kommoss, S ; Kjaer, SK ; Kelemen, LE ; Karlan, BY ; Huntsman, DG ; Hogdall, E ; Gronwald, J ; Goodman, MT ; Gilks, B ; Jose Garcia, M ; Fasching, PA ; de Fazio, A ; Deen, S ; Chang-Claude, J ; dos Reis, FJC ; Campbell, IG ; Brenton, JD ; Bowtell, DD ; Benitez, J ; Pharoah, PDP ; Kobel, M ; Ramus, SJ ; Goode, EL (ELSEVIER SCIENCE INC, 2018-03)
    OBJECTIVE: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. PATIENTS AND METHODS: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). CONCLUSION: Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.
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    Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers
    Qian, F ; Rookus, MA ; Leslie, G ; Risch, HA ; Greene, MH ; Aalfs, CM ; Adank, MA ; Adlard, J ; Agnarsson, BA ; Ahmed, M ; Aittomaki, K ; Andrulis, IL ; Arnold, N ; Arun, BK ; Ausems, MGEM ; Azzollini, J ; Barrowdale, D ; Barwell, J ; Benitez, J ; Bialkowska, K ; Bonadona, V ; Borde, J ; Borg, A ; Bradbury, AR ; Brunet, J ; Buys, SS ; Caldes, T ; Caligo, MA ; Campbell, I ; Carter, J ; Chiquette, J ; Chung, WK ; Claes, KBM ; Collee, JM ; Collonge-Rame, M-A ; Couch, FJ ; Daly, MB ; Delnatte, C ; Diez, O ; Domchek, SM ; Dorfling, CM ; Eason, J ; Easton, DF ; Eeles, R ; Engel, C ; Evans, DG ; Faivre, L ; Feliubado, L ; Foretova, L ; Friedman, E ; Frost, D ; Ganz, PA ; Garber, J ; Garcia-Barberan, V ; Gehrig, A ; Glendon, G ; Godwin, AK ; Garcia, EBG ; Hamann, U ; Hauke, J ; Hopper, JL ; Hulick, PJ ; Imyanitov, EN ; Isaacs, C ; Izatt, L ; Jakubowska, A ; Janavicius, R ; John, EM ; Karlan, BY ; Kets, CM ; Laitman, Y ; Lazaro, C ; Leroux, D ; Lester, J ; Lesueur, F ; Loud, JT ; Lubinski, J ; Lukomska, A ; McGuffog, L ; Mebirouk, N ; Meijers-Heijboer, HEJ ; Meindl, A ; Miller, A ; Montagna, M ; Mooij, TM ; Mouret-Fourme, E ; Nathanson, KL ; Nehoray, B ; Neuhausen, SL ; Nevanlinna, H ; Nielsen, FC ; Offit, K ; Olah, E ; Ong, K-R ; Oosterwijk, JC ; Ottini, L ; Parsons, MT ; Peterlongo, P ; Pfeiler, G ; Pradhan, N ; Radice, P ; Ramus, SJ ; Rantala, J ; Rennert, G ; Robson, M ; Rodriguez, GC ; Salani, R ; Scheuner, MT ; Schmutzler, RK ; Shah, PD ; Side, LE ; Simard, J ; Singer, CF ; Steinemann, D ; Stoppa-Lyonnet, D ; Tan, YY ; Teixeira, MR ; Terry, MB ; Thomassen, M ; Tischkowitz, M ; Tognazzo, S ; Toland, AE ; Tung, N ; van Asperen, CJ ; van Engelen, K ; van Rensburg, EJ ; Venat-Bouvet, L ; Vierstraete, J ; Wagner, G ; Walker, L ; Weitze, JN ; Yannoukakos, D ; Antoniou, AC ; Goldgar, DE ; Olopade, O ; Chenevix-Trench, G ; Rebbeck, TR ; Huo, D (SPRINGERNATURE, 2019-07-16)
    BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.
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    Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women
    Grant, DJ ; Manichaikul, A ; Alberg, AJ ; Bandera, E ; Barnholtz-Sloan, J ; Bondy, M ; Cote, ML ; Funkhouser, E ; Moorman, PG ; Peres, LC ; Peters, ES ; Schwartz, AG ; Terry, PD ; Wang, X-Q ; Keku, TO ; Hoyo, C ; Berchuck, A ; Sandler, DP ; Taylor, JA ; O'Brien, KM ; Edwards, DRV ; Edwards, TL ; Beeghly-Fadiel, A ; Wentzensen, N ; Pearce, CL ; Wu, AH ; Whittemore, AS ; McGuire, V ; Sieh, W ; Rothstein, JH ; Modugno, F ; Ness, R ; Moysich, K ; Rossing, MA ; Doherty, JA ; Sellers, TA ; Permuth-Way, JB ; Monteiro, AN ; Levine, DA ; Setiawan, VW ; Haiman, CA ; LeMarchand, L ; Wilkens, LR ; Karlan, BY ; Menon, U ; Ramus, S ; Gayther, S ; Gentry-Maharaj, A ; Terry, KL ; Cramer, DW ; Goode, EL ; Larson, MC ; Kaufmann, SH ; Cannioto, R ; Odunsi, K ; Etter, JL ; Huang, R-Y ; Bernardini, MQ ; Tone, AA ; May, T ; Goodman, MT ; Thompson, PJ ; Carney, ME ; Tworoger, SS ; Poole, EM ; Lambrechts, D ; Vergote, I ; Vanderstichele, A ; Van Nieuwenhuysen, E ; Anton-Culver, H ; Ziogas, A ; Brenton, JD ; Bjorge, L ; Salvensen, HB ; Kiemeney, LA ; Massuger, LFAG ; Pejovic, T ; Bruegl, A ; Moffitt, M ; Cook, L ; Le, ND ; Brooks-Wilson, A ; Kelemen, LE ; Pharoah, PDP ; Song, H ; Campbell, I ; Eccles, D ; DeFazio, A ; Kennedy, CJ ; Schildkraut, JM (WILEY, 2019-05)
    An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.
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    The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
    Figlioli, G ; Bogliolo, M ; Catucci, I ; Caleca, L ; Viz Lasheras, S ; Pujol, R ; Kiiski, J ; Muranen, TA ; Barnes, DR ; Dennis, J ; Michailidou, K ; Bolla, MK ; Leslie, G ; Aalfs, CM ; Adank, MA ; Adlard, J ; Agata, S ; Cadoo, K ; Agnarsson, BA ; Ahearn, T ; Aittomaki, K ; Ambrosone, CB ; Andrews, L ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Arnold, N ; Aronson, KJ ; Arun, BK ; Asseryanis, E ; Auber, B ; Auvinen, P ; Azzollini, J ; Balmana, J ; Barkardottir, RB ; Barrowdale, D ; Barwell, J ; Freeman, LEB ; Beauparlant, CJ ; Beckmann, MW ; Behrens, S ; Benitez, J ; Berger, R ; Bermisheva, M ; Blanco, AM ; Blomqvist, C ; Bogdanova, N ; Bojesen, A ; Bojesen, SE ; Bonanni, B ; Borg, A ; Brady, AF ; Brauch, H ; Brenner, H ; Bruening, T ; Burwinkel, B ; Buys, SS ; Caldes, T ; Caliebe, A ; Caligo, MA ; Campa, D ; Campbell, IG ; Canzian, F ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Claes, KBM ; Clarke, CL ; Collavoli, A ; Conner, TA ; Cox, DG ; Cybulski, C ; Czene, K ; Daly, MB ; de la Hoya, M ; Devilee, P ; Diez, O ; Ding, YC ; Dite, GS ; Ditsch, N ; Domchek, SM ; Dorfling, CM ; dos-Santos-Silva, I ; Durda, K ; Dwek, M ; Eccles, DM ; Ekici, AB ; Eliassen, AH ; Ellberg, C ; Eriksson, M ; Evans, DG ; Fasching, PA ; Figueroa, J ; Flyger, H ; Foulkes, WD ; Friebel, TM ; Friedman, E ; Gabrielson, M ; Gaddam, P ; Gago-Dominguez, M ; Gao, C ; Gapstur, SM ; Garber, J ; Garcia-Closas, M ; Garcia-Saenz, JA ; Gaudet, MM ; Gayther, SA ; Giles, GG ; Glendon, G ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Guenel, P ; Gutierrez-Barrera, AM ; Haeberle, L ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Harrington, PA ; Hein, A ; Heyworth, J ; Hillemanns, P ; Hollestelle, A ; Hopper, JL ; Hosgood, HD ; Howell, A ; Hu, C ; Hulick, PJ ; Hunter, DJ ; Imyanitov, EN ; Isaacs, C ; Jakimovska, M ; Jakubowska, A ; James, P ; Janavicius, R ; Janni, W ; John, EM ; Jones, ME ; Jung, A ; Kaaks, R ; Karlan, BY ; Khusnutdinova, E ; Kitahara, CM ; Konstantopoulou, I ; Koutros, S ; Kraft, P ; Lambrechts, D ; Lazaro, C ; Le Marchand, L ; Lester, J ; Lesueur, F ; Lilyquist, J ; Loud, JT ; Lu, KH ; Luben, RN ; Lubinski, J ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martens, JWM ; Maurer, T ; Mavroudis, D ; Mebirouk, N ; Meindl, A ; Menon, U ; Miller, A ; Montagna, M ; Nathanson, KL ; Neuhausen, SL ; Newman, WG ; Nguyen-Dumont, T ; Nielsen, FC ; Nielsen, S ; Nikitina-Zake, L ; Offit, K ; Olah, E ; Olopade, O ; Olshan, AF ; Olson, JE ; Olsson, H ; Osorio, A ; Ottini, L ; Peissel, B ; Peixoto, A ; Peto, J ; Plaseska-Karanfilska, D ; Pocza, T ; Presneau, N ; Angel Pujana, M ; Punie, K ; Rack, B ; Rantala, J ; Rashid, MU ; Rau-Murthy, R ; Rennert, G ; Lejbkowicz, F ; Rhenius, V ; Romero, A ; Rookus, MA ; Ross, EA ; Rossing, M ; Rudaitis, V ; Ruebner, M ; Saloustros, E ; Sanden, K ; Santamarina, M ; Scheuner, MT ; Schmutzler, RK ; Schneider, M ; Scott, C ; Senter, L ; Shah, M ; Sharma, P ; Shu, X-O ; Simard, J ; Singer, CF ; Sohn, C ; Soucy, P ; Southey, MC ; Spinelli, JJ ; Steele, L ; Stoppa-Lyonnet, D ; Tapper, WJ ; Teixeira, MR ; Terry, MB ; Thomassen, M ; Thompson, J ; Thull, DL ; Tischkowitz, M ; Tollenaar, RAEM ; Torres, D ; Troester, MA ; Truong, T ; Tung, N ; Untch, M ; Vachon, CM ; van Rensburg, EJ ; van Veen, EM ; Vega, A ; Viel, A ; Wappenschmidt, B ; Weitzel, JN ; Wendt, C ; Wieme, G ; Wolk, A ; Yang, XR ; Zheng, W ; Ziogas, A ; Zorn, KK ; Dunning, AM ; Lush, M ; Wang, Q ; McGuffog, L ; Parsons, MT ; Pharoah, PDP ; Fostira, F ; Toland, AE ; Andrulis, IL ; Ramus, SJ ; Swerdlow, AJ ; Greene, MH ; Chung, WK ; Milne, RL ; Chenevix-Trench, G ; Doerk, T ; Schmidt, MK ; Easton, DF ; Radice, P ; Hahnen, E ; Antoniou, AC ; Couch, FJ ; Nevanlinna, H ; Surralles, J ; Peterlongo, P ; Balleine, R ; Baxter, R ; Braye, S ; Carpenter, J ; Dahlstrom, J ; Forbes, J ; Lee, CS ; Marsh, D ; Morey, A ; Pathmanathan, N ; Scott, R ; Simpson, P ; Spigelman, A ; Wilcken, N ; Yip, D ; Zeps, N ; Belotti, M ; Bertrand, O ; Birot, A-M ; Buecher, B ; Caputo, S ; Dupre, A ; Fourme, E ; Gauthier-Villars, M ; Golmard, L ; Le Mentec, M ; Moncoutier, V ; de Pauw, A ; Saule, C ; Boutry-Kryza, N ; Calender, A ; Giraud, S ; Leone, M ; Bressac-de-Paillerets, B ; Caron, O ; Guillaud-Bataille, M ; Bignon, Y-J ; Uhrhammer, N ; Bonadona, V ; Lasset, C ; Berthet, P ; Castera, L ; Vaur, D ; Bourdon, V ; Nogues, C ; Noguchi, T ; Popovici, C ; Remenieras, A ; Sobol, H ; Coupier, I ; Pujol, P ; Adenis, C ; Dumont, A ; Revillion, F ; Muller, D ; Barouk-Simonet, E ; Bonnet, F ; Bubien, V ; Longy, M ; Sevenet, N ; Gladieff, L ; Guimbaud, R ; Feillel, V ; Toulas, C ; Dreyfus, H ; Leroux, CD ; Peysselon, M ; Rebischung, C ; Legrand, C ; Baurand, A ; Bertolone, G ; Coron, F ; Faivre, L ; Jacquot, C ; Lizard, S ; Kientz, C ; Lebrun, M ; Prieur, F ; Fert-Ferrer, S ; Mari, V ; Venat-Bouvet, L ; Bezieau, S ; Delnatte, C ; Mortemousque, I ; Colas, C ; Coulet, F ; Soubrier, F ; Warcoin, M ; Bronner, M ; Sokolowska, J ; Collonge-Rame, M-A ; Damette, A ; Gesta, P ; Lallaoui, H ; Chiesa, J ; Molina-Gomes, D ; Ingster, O ; Manouvrier-Hanu, S ; Lejeune, S ; Aghmesheh, M ; Greening, S ; Amor, D ; Gattas, M ; Botes, L ; Buckley, M ; Friedlander, M ; Koehler, J ; Meiser, B ; Saleh, M ; Salisbury, E ; Trainer, A ; Tucker, K ; Antill, Y ; Dobrovic, A ; Fellows, A ; Fox, S ; Harris, M ; Nightingale, S ; Phillips, K ; Sambrook, J ; Thorne, H ; Armitage, S ; Arnold, L ; Kefford, R ; Kirk, J ; Rickard, E ; Bastick, P ; Beesley, J ; Hayward, N ; Spurdle, A ; Walker, L ; Beilby, J ; Saunders, C ; Bennett, I ; Blackburn, A ; Bogwitz, M ; Gaff, C ; Lindeman, G ; Pachter, N ; Scott, C ; Sexton, A ; Visvader, J ; Taylor, J ; Winship, I ; Brennan, M ; Brown, M ; French, J ; Edwards, S ; Burgess, M ; Burke, J ; Patterson, B ; Butow, P ; Culling, B ; Caldon, L ; Callen, D ; Chauhan, D ; Eisenbruch, M ; Heiniger, L ; Chauhan, M ; Christian, A ; Dixon, J ; Kidd, A ; Cohen, P ; Colley, A ; Fenton, G ; Crook, A ; Dickson, R ; Field, M ; Cui, J ; Cummings, M ; Dawson, S-J ; DeFazio, A ; Delatycki, M ; Dudding, T ; Edkins, T ; Farshid, G ; Flanagan, J ; Fong, P ; Forrest, L ; Gallego-Ortega, D ; George, P ; Gill, G ; Kollias, J ; Haan, E ; Hart, S ; Jenkins, M ; Hunt, C ; Lakhani, S ; Lipton, L ; Lobb, L ; Mann, G ; McLachlan, SA ; O'Connell, S ; O'Sullivan, S ; Pieper, E ; Robinson, B ; Saunus, J ; Scott, E ; Shelling, A ; Williams, R ; Young, MA (Springer Nature, 2019-11-01)
    Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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    Shared heritability and functional enrichment across six solid cancers
    Jiang, X ; Finucane, HK ; Schumacher, FR ; Schmit, SL ; Tyrer, JP ; Han, Y ; Michailidou, K ; Lesseur, C ; Kuchenbaecker, KB ; Dennis, J ; Conti, DV ; Casey, G ; Gaudet, MM ; Huyghe, JR ; Albanes, D ; Aldrich, MC ; Andrew, AS ; Andrulis, IL ; Anton-Culver, H ; Antoniou, AC ; Antonenkova, NN ; Arnold, SM ; Aronson, KJ ; Arun, BK ; Bandera, EV ; Barkardottir, RB ; Barnes, DR ; Batra, J ; Beckmann, MW ; Benitez, J ; Benlloch, S ; Berchuck, A ; Berndt, SI ; Bickeboeller, H ; Bien, SA ; Blomqvist, C ; Boccia, S ; Bogdanova, NV ; Bojesen, SE ; Bolla, MK ; Brauch, H ; Brenner, H ; Brenton, JD ; Brook, MN ; Brunet, J ; Brunnstrom, H ; Buchanan, DD ; Burwinkel, B ; Butzow, R ; Cadoni, G ; Caldes, T ; Caligo, MA ; Campbell, I ; Campbell, PT ; Cancel-Tassin, G ; Cannon-Albright, L ; Campa, D ; Caporaso, N ; Carvalho, AL ; Chan, AT ; Chang-Claude, J ; Chanock, SJ ; Chen, C ; Christiani, DC ; Claes, KBM ; Claessens, F ; Clements, J ; Collee, JM ; Correa, MC ; Couch, FJ ; Cox, A ; Cunningham, JM ; Cybulski, C ; Czene, K ; Daly, MB ; defazio, A ; Devilee, P ; Diez, O ; Gago-Dominguez, M ; Donovan, JL ; Doerk, T ; Duell, EJ ; Dunning, AM ; Dwek, M ; Eccles, DM ; Edlund, CK ; Edwards, DRV ; Ellberg, C ; Evans, DG ; Fasching, PA ; Ferris, RL ; Liloglou, T ; Figueiredo, JC ; Fletcher, O ; Fortner, RT ; Fostira, F ; Franceschi, S ; Friedman, E ; Gallinger, SJ ; Ganz, PA ; Garber, J ; Garcia-Saenz, JA ; Gayther, SA ; Giles, GG ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Goode, EL ; Goodman, MT ; Goodman, G ; Grankvist, K ; Greene, MH ; Gronberg, H ; Gronwald, J ; Guenel, P ; Hakansson, N ; Hall, P ; Hamann, U ; Hamdy, FC ; Hamilton, RJ ; Hampe, J ; Haugen, A ; Heitz, F ; Herrero, R ; Hillemanns, P ; Hoffmeister, M ; Hogdall, E ; Hong, Y-C ; Hopper, JL ; Houlston, R ; Hulick, PJ ; Hunter, DJ ; Huntsman, DG ; Idos, G ; Imyanitov, EN ; Ingles, SA ; Isaacs, C ; Jakubowska, A ; James, P ; Jenkins, MA ; Johansson, M ; Johansson, M ; John, EM ; Joshi, AD ; Kaneva, R ; Karlan, BY ; Kelemen, LE ; Kuhl, T ; Khaw, K-T ; Khusnutdinova, E ; Kibel, AS ; Kiemeney, LA ; Kim, J ; Kjaer, SK ; Knight, JA ; Kogevinas, M ; Kote-Jarai, Z ; Koutros, S ; Kristensen, VN ; Kupryjanczyk, J ; Lacko, M ; Lam, S ; Lambrechts, D ; Landi, MT ; Lazarus, P ; Le, ND ; Lee, E ; Lejbkowicz, F ; Lenz, H-J ; Leslie, G ; Lessel, D ; Lester, J ; Levine, DA ; Li, L ; Li, CI ; Lindblom, A ; Lindor, NM ; Liu, G ; Loupakis, F ; Lubinski, J ; Maehle, L ; Maier, C ; Mannermaa, A ; Le Marchand, L ; Margolin, S ; May, T ; McGuffog, L ; Meindl, A ; Middha, P ; Miller, A ; Milne, RL ; MacInnis, RJ ; Modugno, F ; Montagna, M ; Moreno, V ; Moysich, KB ; Mucci, L ; Muir, K ; Mulligan, AM ; Nathanson, KL ; Neal, DE ; Ness, AR ; Neuhausen, SL ; Nevanlinna, H ; Newcomb, PA ; Newcomb, LF ; Nielsen, FC ; Nikitina-Zake, L ; Nordestgaard, BG ; Nussbaum, RL ; Offit, K ; Olah, E ; Al Olama, AA ; Olopade, OI ; Olshan, AF ; Olsson, H ; Osorio, A ; Pandha, H ; Park, JY ; Pashayan, N ; Parsons, MT ; Pejovic, T ; Penney, KL ; Peters, WHM ; Phelan, CM ; Phipps, AI ; Plaseska-Karanfilska, D ; Pring, M ; Prokofyeva, D ; Radice, P ; Stefansson, K ; Ramus, SJ ; Raskin, L ; Rennert, G ; Rennert, HS ; van Rensburg, EJ ; Riggan, MJ ; Risch, HA ; Risch, A ; Roobol, MJ ; Rosenstein, BS ; Rossing, MA ; De Ruyck, K ; Saloustros, E ; Sandler, DP ; Sawyer, EJ ; Schabath, MB ; Schleutker, J ; Schmidt, MK ; Setiawan, VW ; Shen, H ; Siegel, EM ; Sieh, W ; Singer, CF ; Slattery, ML ; Sorensen, KD ; Southey, MC ; Spurdle, AB ; Stanford, JL ; Stevens, VL ; Stintzing, S ; Stone, J ; Sundfeldt, K ; Sutphen, R ; Swerdlow, AJ ; Tajara, EH ; Tangen, CM ; Tardon, A ; Taylor, JA ; Teare, MD ; Teixeira, MR ; Terry, MB ; Terry, KL ; Thibodeau, SN ; Thomassen, M ; Bjorge, L ; Tischkowitz, M ; Toland, AE ; Torres, D ; Townsend, PA ; Travis, RC ; Tung, N ; Tworoger, SS ; Ulrich, CM ; Usmani, N ; Vachon, CM ; Van Nieuwenhuysen, E ; Vega, A ; Aguado-Barrera, ME ; Wang, Q ; Webb, PM ; Weinberg, CR ; Weinstein, S ; Weissler, MC ; Weitzel, JN ; West, CML ; White, E ; Whittemore, AS ; Wichmann, H-E ; Wiklund, F ; Winqvist, R ; Wolk, A ; Woll, P ; Woods, M ; Wu, AH ; Wu, X ; Yannoukakos, D ; Zheng, W ; Zienolddiny, S ; Ziogas, A ; Zorn, KK ; Lane, JM ; Saxena, R ; Thomas, D ; Hung, RJ ; Diergaarde, B ; Mckay, J ; Peters, U ; Hsu, L ; Garcia-Closas, M ; Eeles, RA ; Chenevix-Trench, G ; Brennan, PJ ; Haiman, CA ; Simard, J ; Easton, DF ; Gruber, SB ; Pharoah, PDP ; Price, AL ; Pasaniuc, B ; Amos, CI ; Kraft, P ; Lindstrom, S (NATURE PORTFOLIO, 2019-01-25)
    Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.