Sir Peter MacCallum Department of Oncology - Research Publications

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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.
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.
GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

Pharoah, PDP ; Tsai, Y-Y ; Ramus, SJ ; Phelan, CM ; Goode, EL ; Lawrenson, K ; Buckley, M ; Fridley, BL ; Tyrer, JP ; Shen, H ; Weber, R ; Karevan, R ; Larson, MC ; Song, H ; Tessier, DC ; Bacot, F ; Vincent, D ; Cunningham, JM ; Dennis, J ; Dicks, E ; Aben, KK ; Anton-Culver, H ; Antonenkova, N ; Armasu, SM ; Baglietto, L ; Bandera, EV ; Beckmann, MW ; Birrer, MJ ; Bloom, G ; Bogdanova, N ; Brenton, JD ; Brinton, LA ; Brooks-Wilson, A ; Brown, R ; Butzow, R ; Campbell, I ; Carney, ME ; Carvalho, RS ; Chang-Claude, J ; Chen, YA ; Chen, Z ; Chow, W-H ; Cicek, MS ; Coetzee, G ; Cook, LS ; Cramer, DW ; Cybulski, C ; Dansonka-Mieszkowska, A ; Despierre, E ; Doherty, JA ; Doerk, T ; du Bois, A ; Duerst, M ; Eccles, D ; Edwards, R ; Ekici, AB ; Fasching, PA ; Fenstermacher, D ; Flanagan, J ; Gao, Y-T ; Garcia-Closas, M ; Gentry-Maharaj, A ; Giles, G ; Gjyshi, A ; Gore, M ; Gronwald, J ; Guo, Q ; Halle, MK ; Harter, P ; Hein, A ; Heitz, F ; Hillemanns, P ; Hoatlin, M ; Hogdall, E ; Hogdall, CK ; Hosono, S ; Jakubowska, A ; Jensen, A ; Kalli, KR ; Karlan, BY ; Kelemen, LE ; Kiemeney, LA ; Kjaer, SK ; Konecny, GE ; Krakstad, C ; Kupryjanczyk, J ; Lambrechts, D ; Lambrechts, S ; Le, ND ; Lee, N ; Lee, J ; Leminen, A ; Lim, BK ; Lissowska, J ; Lubinski, J ; Lundvall, L ; Lurie, G ; Massuger, LFAG ; Matsuo, K ; McGuire, V ; McLaughlin, JR ; Menon, U ; Modugno, F ; Moysich, KB ; Nakanishi, T ; Narod, SA ; Ness, RB ; Nevanlinna, H ; Nickels, S ; Noushmehr, H ; Odunsi, K ; Olson, S ; Orlow, I ; Paul, J ; Pejovic, T ; Pelttari, LM ; Permuth-Wey, J ; Pike, MC ; Poole, EM ; Qu, X ; Risch, HA ; Rodriguez-Rodriguez, L ; Rossing, MA ; Rudolph, A ; Runnebaum, I ; Rzepecka, IK ; Salvesen, HB ; Schwaab, I ; Severi, G ; Shen, H ; Shridhar, V ; Shu, X-O ; Sieh, W ; Southey, MC ; Spellman, P ; Tajima, K ; Teo, S-H ; Terry, KL ; Thompson, PJ ; Timorek, A ; Tworoger, SS ; van Altena, AM ; van den Berg, D ; Vergote, I ; Vierkant, RA ; Vitonis, AF ; Wang-Gohrke, S ; Wentzensen, N ; Whittemore, AS ; Wik, E ; Winterhoff, B ; Woo, YL ; Wu, AH ; Yang, HP ; Zheng, W ; Ziogas, A ; Zulkifli, F ; Goodman, MT ; Hall, P ; Easton, DF ; Pearce, CL ; Berchuck, A ; Chenevix-Trench, G ; Iversen, E ; Monteiro, ANA ; Gayther, SA ; Schildkraut, JM ; Sellers, TA (NATURE PUBLISHING GROUP, 2013-04)

Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

Permuth-Wey, J ; Lawrenson, K ; Shen, HC ; Velkova, A ; Tyrer, JP ; Chen, Z ; Lin, H-Y ; Chen, YA ; Tsai, Y-Y ; Qu, X ; Ramus, SJ ; Karevan, R ; Lee, J ; Lee, N ; Larson, MC ; Aben, KK ; Anton-Culver, H ; Antonenkova, N ; Antoniou, AC ; Armasu, SM ; Bacot, F ; Baglietto, L ; Bandera, EV ; Barnholtz-Sloan, J ; Beckmann, MW ; Birrer, MJ ; Bloom, G ; Bogdanova, N ; Brinton, LA ; Brooks-Wilson, A ; Brown, R ; Butzow, R ; Cai, Q ; Campbell, I ; Chang-Claude, J ; Chanock, S ; Chenevix-Trench, G ; Cheng, JQ ; Cicek, MS ; Coetzee, GA ; Cook, LS ; Couch, FJ ; Cramer, DW ; Cunningham, JM ; Dansonka-Mieszkowska, A ; Despierre, E ; Doherty, JA ; Doerk, T ; du Bois, A ; Duerst, M ; Easton, DF ; Eccles, D ; Edwards, R ; Ekici, AB ; Fasching, PA ; Fenstermacher, DA ; Flanagan, JM ; Garcia-Closas, M ; Gentry-Maharaj, A ; Giles, GG ; Glasspool, RM ; Gonzalez-Bosquet, J ; Goodman, MT ; Gore, M ; Gorski, B ; Gronwald, J ; Hall, P ; Halle, MK ; Harter, P ; Heitz, F ; Hillemanns, P ; Hoatlin, M ; Hogdall, CK ; Hogdall, E ; Hosono, S ; Jakubowska, A ; Jensen, A ; Jim, H ; Kalli, KR ; Karlan, BY ; Kaye, SB ; Kelemen, LE ; Kiemeney, LA ; Kikkawa, F ; Konecny, GE ; Krakstad, C ; Kjaer, SK ; Kupryjanczyk, J ; Lambrechts, D ; Lambrechts, S ; Lancaster, JM ; Le, ND ; Leminen, A ; Levine, DA ; Liang, D ; Lim, BK ; Lin, J ; Lissowska, J ; Lu, KH ; Lubinski, J ; Lurie, G ; Massuger, LFAG ; Matsuo, K ; McGuire, V ; McLaughlin, JR ; Menon, U ; Modugno, F ; Moysich, KB ; Nakanishi, T ; Narod, SA ; Nedergaard, L ; Ness, RB ; Nevanlinna, H ; Nickels, S ; Noushmehr, H ; Odunsi, K ; Olson, SH ; Orlow, I ; Paul, J ; Pearce, CL ; Pejovic, T ; Pelttari, LM ; Pike, MC ; Poole, EM ; Raska, P ; Renner, SP ; Risch, HA ; Rodriguez-Rodriguez, L ; Rossing, MA ; Rudolph, A ; Runnebaum, IB ; Rzepecka, IK ; Salvesen, HB ; Schwaab, I ; Severi, G ; Shridhar, V ; Shu, X-O ; Shvetsov, YB ; Sieh, W ; Song, H ; Southey, MC ; Spiewankiewicz, B ; Stram, D ; Sutphen, R ; Teo, S-H ; Terry, KL ; Tessier, DC ; Thompson, PJ ; Tworoger, SS ; van Altena, AM ; Vergote, I ; Vierkant, RA ; Vincent, D ; Vitonis, AF ; Wang-Gohrke, S ; Weber, RP ; Wentzensen, N ; Whittemore, AS ; Wik, E ; Wilkens, LR ; Winterhoff, B ; Woo, YL ; Wu, AH ; Xiang, Y-B ; Yang, HP ; Zheng, W ; Ziogas, A ; Zulkifli, F ; Phelan, CM ; Iversen, E ; Schildkraut, JM ; Berchuck, A ; Fridley, BL ; Goode, EL ; Pharoah, PDP ; Monteiro, ANA ; Sellers, TA ; Gayther, SA (NATURE RESEARCH, 2013-03)

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).

Jim, HSL ; Lin, H-Y ; Tyrer, JP ; Lawrenson, K ; Dennis, J ; Chornokur, G ; Chen, Z ; Chen, AY ; Permuth-Wey, J ; Aben, KK ; Anton-Culver, H ; Antonenkova, N ; Bruinsma, F ; Bandera, EV ; Bean, YT ; Beckmann, MW ; Bisogna, M ; Bjorge, L ; Bogdanova, N ; Brinton, LA ; Brooks-Wilson, A ; Bunker, CH ; Butzow, R ; Campbell, IG ; Carty, K ; Chang-Claude, J ; Cook, LS ; Cramer, DW ; Cunningham, JM ; Cybulski, C ; Dansonka-Mieszkowska, A ; du Bois, A ; Despierre, E ; Sieh, W ; Doherty, JA ; Dörk, T ; Dürst, M ; Easton, DF ; Eccles, DM ; Edwards, RP ; Ekici, AB ; Fasching, PA ; Fridley, BL ; Gao, Y-T ; Gentry-Maharaj, A ; Giles, GG ; Glasspool, R ; Goodman, MT ; Gronwald, J ; Harter, P ; Hasmad, HN ; Hein, A ; Heitz, F ; Hildebrandt, MAT ; Hillemanns, P ; Hogdall, CK ; Hogdall, E ; Hosono, S ; Iversen, ES ; Jakubowska, A ; Jensen, A ; Ji, B-T ; Karlan, BY ; Kellar, M ; Kiemeney, LA ; Krakstad, C ; Kjaer, SK ; Kupryjanczyk, J ; Vierkant, RA ; Lambrechts, D ; Lambrechts, S ; Le, ND ; Lee, AW ; Lele, S ; Leminen, A ; Lester, J ; Levine, DA ; Liang, D ; Lim, BK ; Lissowska, J ; Lu, K ; Lubinski, J ; Lundvall, L ; Massuger, LFAG ; Matsuo, K ; McGuire, V ; McLaughlin, JR ; McNeish, I ; Menon, U ; Milne, RL ; Modugno, F ; Thomsen, L ; Moysich, KB ; Ness, RB ; Nevanlinna, H ; Eilber, U ; Odunsi, K ; Olson, SH ; Orlow, I ; Orsulic, S ; Palmieri Weber, R ; Paul, J ; Pearce, CL ; Pejovic, T ; Pelttari, LM ; Pike, MC ; Poole, EM ; Schernhammer, E ; Risch, HA ; Rosen, B ; Rossing, MA ; Rothstein, JH ; Rudolph, A ; Runnebaum, IB ; Rzepecka, IK ; Salvesen, HB ; Schwaab, I ; Shu, X-O ; Shvetsov, YB ; Siddiqui, N ; Song, H ; Southey, MC ; Spiewankiewicz, B ; Sucheston-Campbell, L ; Teo, S-H ; Terry, KL ; Thompson, PJ ; Tangen, IL ; Tworoger, SS ; van Altena, AM ; Vergote, I ; Walsh, CS ; Wang-Gohrke, S ; Wentzensen, N ; Whittemore, AS ; Wicklund, KG ; Wilkens, LR ; Wu, AH ; Wu, X ; Woo, Y-L ; Yang, H ; Zheng, W ; Ziogas, A ; Amankwah, E ; Berchuck, A ; Georgia Chenevix-Trench on behalf of the AOCS management group 95,96, ; Schildkraut, JM ; Kelemen, LE ; Ramus, SJ ; Monteiro, ANA ; Goode, EL ; Narod, SA ; Gayther, SA ; Pharoah, PDP ; Sellers, TA ; Phelan, CM (ClinMed International Library, 2015)

Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

Chornokur, G ; Lin, H-Y ; Tyrer, JP ; Lawrenson, K ; Dennis, J ; Amankwah, EK ; Qu, X ; Tsai, Y-Y ; Jim, HSL ; Chen, Z ; Chen, AY ; Permuth-Wey, J ; Aben, KKH ; Anton-Culver, H ; Antonenkova, N ; Bruinsma, F ; Bandera, EV ; Bean, YT ; Beckmann, MW ; Bisogna, M ; Bjorge, L ; Bogdanova, N ; Brinton, LA ; Brooks-Wilson, A ; Bunker, CH ; Butzow, R ; Campbell, IG ; Carty, K ; Chang-Claude, J ; Cook, LS ; Cramer, DW ; Cunningham, JM ; Cybulski, C ; Dansonka-Mieszkowska, A ; du Bois, A ; Despierre, E ; Dicks, E ; Doherty, JA ; Dork, T ; Durst, M ; Easton, DF ; Eccles, DM ; Edwards, RP ; Ekici, AB ; Fasching, PA ; Fridley, BL ; Gao, Y-T ; Gentry-Maharaj, A ; Giles, GG ; Glasspool, R ; Goodman, MT ; Gronwald, J ; Harrington, P ; Harter, P ; Hein, A ; Heitz, F ; Hildebrandt, MAT ; Hillemanns, P ; Hogdall, CK ; Hogdall, E ; Hosono, S ; Jakubowska, A ; Jensen, A ; Ji, B-T ; Karlan, BY ; Kelemen, LE ; Kellar, M ; Kiemeney, LA ; Krakstad, C ; Kjaer, SK ; Kupryjanczyk, J ; Lambrechts, D ; Lambrechts, S ; Le, ND ; Lee, AW ; Lele, S ; Leminen, A ; Lester, J ; Levine, DA ; Liang, D ; Lim, BK ; Lissowska, J ; Lu, K ; Lubinski, J ; Lundvall, L ; Massuger, LFAG ; Matsuo, K ; McGuire, V ; McLaughlin, JR ; McNeish, I ; Menon, U ; Milne, RL ; Modugno, F ; Moysich, KB ; Ness, RB ; Nevanlinna, H ; Eilber, U ; Odunsi, K ; Olson, SH ; Orlow, I ; Orsulic, S ; Weber, RP ; Paul, J ; Pearce, CL ; Pejovic, T ; Pelttari, LM ; Pike, MC ; Poole, EM ; Risch, HA ; Rosen, B ; Rossing, MA ; Rothstein, JH ; Rudolph, A ; Runnebaum, IB ; Rzepecka, IK ; Salvesen, HB ; Schernhammer, E ; Schwaab, I ; Shu, X-O ; Shvetsov, YB ; Siddiqui, N ; Sieh, W ; Song, H ; Southey, MC ; Spiewankiewicz, B ; Sucheston, L ; Teo, S-H ; Terry, KL ; Thompson, PJ ; Thomsen, L ; Tangen, IL ; Tworoger, SS ; van Altena, AM ; Vierkant, RA ; Vergote, I ; Walsh, CS ; Wang-Gohrke, S ; Wentzensen, N ; Whittemore, AS ; Wicklund, KG ; Wilkens, LR ; Wu, AH ; Wu, X ; Woo, Y-L ; Yang, H ; Zheng, W ; Ziogas, A ; Hasmad, HN ; Berchuck, A ; Iversen, ES ; Schildkraut, JM ; Ramus, SJ ; Goode, EL ; Monteiro, ANA ; Gayther, SA ; Narod, SA ; Pharoah, PP ; Sellers, TA ; Phelan, CM ; Agoulnik, IU (PUBLIC LIBRARY SCIENCE, 2015-06-19)

BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. RESULTS: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). CONCLUSION: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.
PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Southey, MC ; Goldgar, DE ; Winqvist, R ; Pylkas, K ; Couch, F ; Tischkowitz, M ; Foulkes, WD ; Dennis, J ; Michailidou, K ; van Rensburg, EJ ; Heikkinen, T ; Nevanlinna, H ; Hopper, JL ; Doerk, T ; Claes, KBM ; Reis-Filho, J ; Teo, ZL ; Radice, P ; Catucci, I ; Peterlongo, P ; Tsimiklis, H ; Odefrey, FA ; Dowty, JG ; Schmidt, MK ; Broeks, A ; Hogervorst, FB ; Verhoef, S ; Carpenter, J ; Clarke, C ; Scott, RJ ; Fasching, PA ; Haeberle, L ; Ekici, AB ; Beckmann, MW ; Peto, J ; dos-Santos-Silva, I ; Fletcher, O ; Johnson, N ; Bolla, MK ; Sawyer, EJ ; Tomlinson, I ; Kerin, MJ ; Miller, N ; Marme, F ; Burwinkel, B ; Yang, R ; Guenel, P ; Therese, T ; Menegaux, F ; Sanchez, M ; Bojesen, S ; Nielsen, SF ; Flyger, H ; Benitez, J ; Pilar Zamora, M ; Arias Perez, JI ; Menendez, P ; Anton-Culver, H ; Neuhausen, S ; Ziogas, A ; Clarke, CA ; Brenner, H ; Arndt, V ; Stegmaier, C ; Brauch, H ; Bruening, T ; Ko, Y-D ; Muranen, TA ; Aittomaki, K ; Blomqvist, C ; Bogdanova, NV ; Antonenkova, NN ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, JM ; Spurdle, AB ; Wauters, E ; Smeets, D ; Beuselinck, B ; Floris, G ; Chang-Claude, J ; Rudolph, A ; Seibold, P ; Flesch-Janys, D ; Olson, JE ; Vachon, C ; Pankratz, VS ; McLean, C ; Haiman, CA ; Henderson, BE ; Schumacher, F ; Le Marchand, L ; Kristensen, V ; Alnaes, GG ; Zheng, W ; Hunter, DJ ; Lindstrom, S ; Hankinson, SE ; Kraft, P ; Andrulis, I ; Knight, JA ; Glendon, G ; Mulligan, AM ; Jukkola-Vuorinen, A ; Grip, M ; Kauppila, S ; Devilee, P ; Tollenaar, RAEM ; Seynaeve, C ; Hollestelle, A ; Garcia-Closas, M ; Figueroa, J ; Chanock, SJ ; Lissowska, J ; Czene, K ; Darabi, H ; Eriksson, M ; Eccles, DM ; Rafiq, S ; Tapper, WJ ; Gerty, SM ; Hooning, MJ ; Martens, JWM ; Collee, JM ; Tilanus-Linthorst, M ; Hall, P ; Li, J ; Brand, JS ; Humphreys, K ; Cox, A ; Reed, MWR ; Luccarini, C ; Baynes, C ; Dunning, AM ; Hamann, U ; Torres, D ; Ulmer, HU ; Ruediger, T ; Jakubowska, A ; Lubinski, J ; Jaworska, K ; Durda, K ; Slager, S ; Toland, AE ; Ambrosone, CB ; Yannoukakos, D ; Swerdlow, A ; Ashworth, A ; Orr, N ; Jones, M ; Gonzalez-Neira, A ; Pita, G ; Rosario Alonso, M ; Alvarez, N ; Herrero, D ; Tessier, DC ; Vincent, D ; Bacot, F ; Simard, J ; Dumont, M ; Soucy, P ; Eeles, R ; Muir, K ; Wiklund, F ; Gronberg, H ; Schleutker, J ; Nordestgaard, BG ; Weischer, M ; Travis, RC ; Neal, D ; Donovan, JL ; Hamdy, FC ; Khaw, K-T ; Stanford, JL ; Blot, WJ ; Thibodeau, S ; Schaid, DJ ; Kelley, JL ; Maier, C ; Kibel, AS ; Cybulski, C ; Cannon-Albright, L ; Butterbach, K ; Park, J ; Kaneva, R ; Batra, J ; Teixeira, MR ; Kote-Jarai, Z ; Al Olama, AA ; Benlloch, S ; Renner, SP ; Hartmann, A ; Hein, A ; Ruebner, M ; Lambrechts, D ; Van Nieuwenhuysen, E ; Vergote, I ; Lambretchs, S ; Doherty, JA ; Rossing, MA ; Nickels, S ; Eilber, U ; Wang-Gohrke, S ; Odunsi, K ; Sucheston-Campbell, LE ; Friel, G ; Lurie, G ; Killeen, JL ; Wilkens, LR ; Goodman, MT ; Runnebaum, I ; Hillemanns, PA ; Pelttari, LM ; Butzow, R ; Modugno, F ; Edwards, RP ; Ness, RB ; Moysich, KB ; du Bois, A ; Heitz, F ; Harter, P ; Kommoss, S ; Karlan, BY ; Walsh, C ; Lester, J ; Jensen, A ; Kjaer, SK ; Hogdall, E ; Peissel, B ; Bonanni, B ; Bernard, L ; Goode, EL ; Fridley, BL ; Vierkant, RA ; Cunningham, JM ; Larson, MC ; Fogarty, ZC ; Kalli, KR ; Liang, D ; Lu, KH ; Hildebrandt, MAT ; Wu, X ; Levine, DA ; Dao, F ; Bisogna, M ; Berchuck, A ; Iversen, ES ; Marks, JR ; Akushevich, L ; Cramer, DW ; Schildkraut, J ; Terry, KL ; Poole, EM ; Stampfer, M ; Tworoger, SS ; Bandera, EV ; Orlow, I ; Olson, SH ; Bjorge, L ; Salvesen, HB ; van Altena, AM ; Aben, KKH ; Kiemeney, LA ; Massuger, LFAG ; Pejovic, T ; Bean, Y ; Brooks-Wilson, A ; Kelemen, LE ; Cook, LS ; Le, ND ; Grski, B ; Gronwald, J ; Menkiszak, J ; Hogdall, CK ; Lundvall, L ; Nedergaard, L ; Engelholm, SA ; Dicks, E ; Tyrer, J ; Campbell, I ; McNeish, I ; Paul, J ; Siddiqui, N ; Glasspool, R ; Whittemore, AS ; Rothstein, JH ; McGuire, V ; Sieh, W ; Cai, H ; Shu, X-O ; Teten, RT ; Sutphen, R ; McLaughlin, JR ; Narod, SA ; Phelan, CM ; Monteiro, AN ; Fenstermacher, D ; Lin, H-Y ; Permuth, JB ; Sellers, TA ; Chen, YA ; Tsai, Y-Y ; Chen, Z ; Gentry-Maharaj, A ; Gayther, SA ; Ramus, SJ ; Menon, U ; Wu, AH ; Pearce, CL ; Van den Berg, D ; Pike, MC ; Dansonka-Mieszkowska, A ; Plisiecka-Halasa, J ; Moes-Sosnowska, J ; Kupryjanczyk, J ; Pharoah, PDP ; Song, H ; Winship, I ; Chenevix-Trench, G ; Giles, GG ; Tavtigian, SV ; Easton, DF ; Milne, RL (BMJ PUBLISHING GROUP, 2016-12)

BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Lawrenson, K ; Li, Q ; Kar, S ; Seo, J-H ; Tyrer, J ; Spindler, TJ ; Lee, J ; Chen, Y ; Karst, A ; Drapkin, R ; Aben, KKH ; Anton-Culver, H ; Antonenkova, N ; Baker, H ; Bandera, EV ; Bean, Y ; Beckmann, MW ; Berchuck, A ; Bisogna, M ; Bjorge, L ; Bogdanova, N ; Brinton, LA ; Brooks-Wilson, A ; Bruinsma, F ; Butzow, R ; Campbell, IG ; Carty, K ; Chang-Claude, J ; Chenevix-Trench, G ; Chen, A ; Chen, Z ; Cook, LS ; Cramer, DW ; Cunningham, JM ; Cybulski, C ; Dansonka-Mieszkowska, A ; Dennis, J ; Dicks, E ; Doherty, JA ; Doerk, T ; Du Bois, A ; Duerst, M ; Eccles, D ; Easton, DT ; Edwards, RP ; Eilber, U ; Ekici, AB ; Fasching, PA ; Fridley, BL ; Gao, Y-T ; Gentry-Maharaj, A ; Giles, GG ; Glasspool, R ; Goode, EL ; Goodman, MT ; Grownwald, J ; Harrington, P ; Harter, P ; Hasmad, HN ; Hein, A ; Heitz, F ; Hildebrandt, MAT ; Hillemanns, P ; Hogdall, E ; Hogdall, C ; Hosono, S ; Iversen, ES ; Jakubowska, A ; James, P ; Jensen, A ; Ji, B-T ; Karlan, BY ; Kjaer, SK ; Kelemen, LE ; Kellar, M ; Kelley, JL ; Kiemeney, LA ; Krakstad, C ; Kupryjanczyk, J ; Lambrechts, D ; Lambrechts, S ; Le, ND ; Lee, AW ; Lele, S ; Leminen, A ; Lester, J ; Levine, DA ; Liang, D ; Lissowska, J ; Lu, K ; Lubinski, J ; Lundvall, L ; Massuger, LFAG ; Matsuo, K ; McGuire, V ; McLaughlin, JR ; Nevanlinna, H ; McNeish, I ; Menon, U ; Modugno, F ; Moysich, KB ; Narod, SA ; Nedergaard, L ; Ness, RB ; Azmi, MAN ; Odunsi, K ; Olson, SH ; Orlow, I ; Orsulic, S ; Weber, RP ; Pearce, CL ; Pejovic, T ; Pelttari, LM ; Permuth-Wey, J ; Phelan, CM ; Pike, MC ; Poole, EM ; Ramus, SJ ; Risch, HA ; Rosen, B ; Rossing, MA ; Rothstein, JH ; Rudolph, A ; Runnebaum, IB ; Rzepecka, IK ; Salvesen, HB ; Schildkraut, JM ; Schwaab, I ; Sellers, TA ; Shu, X-O ; Shvetsov, YB ; Siddiqui, N ; Sieh, W ; Song, H ; Southey, MC ; Sucheston, L ; Tangen, IL ; Teo, S-H ; Terry, KL ; Thompson, PJ ; Timorek, A ; Tsai, Y-Y ; Tworoger, SS ; Van Altena, AM ; Van Nieuwenhuysen, E ; Vergote, I ; Vierkant, RA ; Wang-Gohrke, S ; Walsh, C ; Wentzensen, N ; Whittemore, AS ; Wicklund, KG ; Wilkens, LR ; Woo, Y-L ; Wu, X ; Wu, AH ; Yang, H ; Zheng, W ; Ziogas, A ; Monteiro, A ; Pharoah, PD ; Gayther, SA ; Freedman, ML ; Grp, AOCS ; Bowtell, D ; Webb, PM ; Defazio, A (NATURE RESEARCH, 2015-09)

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Hampras, SS ; Sucheston-Campbell, LE ; Cannioto, R ; Chang-Claude, J ; Modugno, F ; Doerk, T ; Hillemanns, P ; Preus, L ; Knutson, KL ; Wallace, PK ; Hong, C-C ; Friel, G ; Davis, W ; Nesline, M ; Pearce, CL ; Kelemen, LE ; Goodman, MT ; Bandera, EV ; Terry, KL ; Schoof, N ; Eng, KH ; Clay, A ; Singh, PK ; Joseph, JM ; Aben, KKH ; Anton-Culver, H ; Antonenkova, N ; Baker, H ; Bean, Y ; Beckmann, MW ; Bisogna, M ; Bjorge, L ; Bogdanova, N ; Brinton, LA ; Brooks-Wilson, A ; Bruinsma, F ; Butzow, R ; Campbell, IG ; Carty, K ; Cook, LS ; Cramer, DW ; Cybulski, C ; Dansonka-Mieszkowska, A ; Dennis, J ; Despierre, E ; Dicks, E ; Doherty, JA ; du Bois, A ; Duerst, M ; Easton, D ; Eccles, D ; Edwards, RP ; Ekici, AB ; Fasching, PA ; Fridley, BL ; Gao, Y-T ; Gentry-Maharaj, A ; Giles, GG ; Glasspool, R ; Gronwald, J ; Harrington, P ; Harter, P ; Hasmad, HN ; Hein, A ; Heitz, F ; Hildebrandt, MAT ; Hogdall, C ; Hogdall, E ; Hosono, S ; Iversen, ES ; Jakubowska, A ; Jensen, A ; Ji, B-T ; Karlan, BY ; Kellar, M ; Kelley, JL ; Kiemeney, LA ; Klapdor, R ; Kolomeyevskaya, N ; Krakstad, C ; Kjaer, SK ; Kruszka, B ; Kupryjanczyk, J ; Lambrechts, D ; Lambrechts, S ; Le, ND ; Lee, AW ; Lele, S ; Leminen, A ; Lester, J ; Levine, DA ; Liang, D ; Lissowska, J ; Liu, S ; Lu, K ; Lubinski, J ; Lundvall, L ; Massuger, LFAG ; Matsuo, K ; McGuire, V ; McLaughlin, JR ; McNeish, I ; Menon, U ; Moes-Sosnowska, J ; Narod, SA ; Nedergaard, L ; Nevanlinna, H ; Nickels, S ; Olson, SH ; Orlow, I ; Weber, RP ; Paul, J ; Pejovic, T ; Pelttari, LM ; Perkins, B ; Permuth-Wey, J ; Pike, MC ; Plisiecka-Halasa, J ; Poole, EM ; Risch, HA ; Rossing, MA ; Rothstein, JH ; Rudolph, A ; Runnebaum, IB ; Rzepecka, IK ; Salvesen, HB ; Schernhammer, E ; Schmitt, K ; Schwaab, I ; Shu, X-O ; Shvetsov, YB ; Siddiqui, N ; Sieh, W ; Song, H ; Southey, MC ; Tangen, IL ; Teo, S-H ; Thompson, PJ ; Timorek, A ; Tsai, Y-Y ; Tworoger, SS ; Tyrer, J ; van Altena, AM ; Vergote, I ; Vierkant, RA ; Walsh, C ; Wang-Gohrke, S ; Wentzensen, N ; Whittemore, AS ; Wicklund, KG ; Wilkens, LR ; Wu, AH ; Wu, X ; Woo, Y-L ; Yang, H ; Zheng, W ; Ziogas, A ; Gayther, SA ; Ramus, SJ ; Sellers, TA ; Schildkraut, JM ; Phelan, CM ; Berchuck, A ; Chenevix-Trench, G ; Cunningham, JM ; Pharoah, PP ; Ness, RB ; Odunsi, K ; Goode, EL ; Moysich, KB (IMPACT JOURNALS LLC, 2016-10-25)

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.
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.

Sir Peter MacCallum Department of Oncology - Research Publications

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