Sir Peter MacCallum Department of Oncology - Research Publications

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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.
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 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.
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.
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

Lawrenson, K ; Kar, S ; McCue, K ; Kuchenbaeker, K ; Michailidou, K ; Tyrer, J ; Beesley, J ; Ramus, SJ ; Li, Q ; Delgado, MK ; Lee, JM ; Aittomaki, K ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Arun, BK ; Arver, B ; Bandera, EV ; Barile, M ; Barkardottir, RB ; Barrowdale, D ; Beckmann, MW ; Benitez, J ; Berchuck, A ; Bisogna, M ; Bjorge, L ; Blomqvist, C ; Blot, W ; Bogdanova, N ; Bojesen, A ; Bojesen, SE ; Bolla, MK ; Bonanni, B ; Borresen-Dale, A-L ; Brauch, H ; Brennan, P ; Brenner, H ; Bruinsma, F ; Brunet, J ; Buhari, SA ; Burwinkel, B ; Butzow, R ; Buys, SS ; Cai, Q ; Caldes, T ; Campbell, I ; Canniotto, R ; Chang-Claude, J ; Chiquette, J ; Choi, J-Y ; Claes, KBM ; Cook, LS ; Cox, A ; Cramer, DW ; Cross, SS ; Cybulski, C ; Czene, K ; Daly, MB ; Damiola, F ; Dansonka-Mieszkowska, A ; Darabi, H ; Dennis, J ; Devilee, P ; Diez, O ; Doherty, JA ; Domchek, SM ; Dorfling, CM ; Doerk, T ; Dumont, M ; Ehrencrona, H ; Ejlertsen, B ; Ellis, S ; Engel, C ; Lee, E ; Evans, DG ; Fasching, PA ; Feliubadalo, L ; Figueroa, J ; Flesch-Janys, D ; Fletcher, O ; Flyger, H ; Foretova, L ; Fostira, F ; Foulkes, WD ; Fridley, BL ; Friedman, E ; Frost, D ; Gambino, G ; Ganz, PA ; Garber, J ; Garcia-Closas, M ; Gentry-Maharaj, A ; Ghoussaini, M ; Giles, GG ; Glasspool, R ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Goode, EL ; Goodman, MT ; Greene, MH ; Gronwald, J ; Guenel, P ; Haiman, CA ; Hall, P ; Hallberg, E ; Hamann, U ; Hansen, TVO ; Harrington, PA ; Hartman, M ; Hassan, N ; Healey, S ; Heitz, F ; Herzog, J ; Hogdall, E ; Hogdall, CK ; Hogervorst, FBL ; Hollestelle, A ; Hopper, JL ; Hulick, PJ ; Huzarski, T ; Imyanitov, EN ; Isaacs, C ; Ito, H ; Jakubowska, A ; Janavicius, R ; Jensen, A ; John, EM ; Johnson, N ; Kabisch, M ; Kang, D ; Kapuscinski, M ; Karlan, BY ; Khan, S ; Kiemeney, LA ; Kjaer, SK ; Knight, JA ; Konstantopoulou, I ; Kosma, V-M ; Kristensen, V ; Kupryjanczyk, J ; Kwong, A ; de la Hoya, M ; Laitman, Y ; Lambrechts, D ; Le, N ; De Leeneer, K ; Lester, J ; Levine, DA ; Li, J ; Lindblom, A ; Long, J ; Lophatananon, A ; Loud, JT ; Lu, K ; Lubinski, J ; Mannermaa, A ; Manoukian, S ; Le Marchand, L ; Margolin, S ; Marme, F ; Massuger, LFAG ; Matsuo, K ; Mazoyer, S ; McGuffog, L ; McLean, C ; McNeish, I ; Meindl, A ; Menon, U ; Mensenkamp, AR ; Milne, RL ; Montagna, M ; Moysich, KB ; Muir, K ; Mulligan, AM ; Nathanson, KL ; Ness, RB ; Neuhausen, SL ; Nevanlinna, H ; Nord, S ; Nussbaum, RL ; Odunsi, K ; Offit, K ; Olah, E ; Olopade, OI ; Olson, JE ; Olswold, C ; O'Malley, D ; Orlow, I ; Orr, N ; Osorio, A ; Park, SK ; Pearce, CL ; Pejovic, T ; Peterlongo, P ; Pfeiler, G ; Phelan, CM ; Poole, EM ; Pylkas, K ; Radice, P ; Rantala, J ; Rashid, MU ; Rennert, G ; Rhenius, V ; Rhiem, K ; Risch, HA ; Rodriguez, G ; Rossing, MA ; Rudolph, A ; Salvesen, HB ; Sangrajrang, S ; Sawyer, EJ ; Schildkraut, JM ; Schmidt, MK ; Schmutzler, RK ; Sellers, TA ; Seynaeve, C ; Shah, M ; Shen, C-Y ; Shu, X-O ; Sieh, W ; Singer, CF ; Sinilnikova, OM ; Slager, S ; Song, H ; Soucy, P ; Southey, MC ; Stenmark-Askmalm, M ; Stoppa-Lyonnet, D ; Sutter, C ; Swerdlow, A ; Tchatchou, S ; Teixeira, MR ; Teo, SH ; Terry, KL ; Terry, MB ; Thomassen, M ; Tibiletti, MG ; Tihomirova, L ; Tognazzo, S ; Toland, AE ; Tomlinson, I ; Torres, D ; Truong, T ; Tseng, C-C ; Tung, N ; Tworoger, SS ; Vachon, C ; van den Ouweland, AMW ; van Doorn, HC ; van Rensburg, EJ ; Van't Veer, LJ ; Vanderstichele, A ; Vergote, I ; Vijai, J ; Wang, Q ; Wang-Gohrke, S ; Weitzel, JN ; Wentzensen, N ; Whittemore, AS ; Wildiers, H ; Winqvist, R ; Wu, AH ; Yannoukakos, D ; Yoon, S-Y ; Yu, J-C ; Zheng, W ; Zheng, Y ; Khanna, KK ; Simard, J ; Monteiro, AN ; French, JD ; Couch, FJ ; Freedman, ML ; Easton, DF ; Dunning, AM ; Pharoah, PD ; Edwards, SL ; Chenevix-Trench, G ; Antoniou, AC ; Gayther, SA (NATURE PORTFOLIO, 2016-09)

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Earp, MA ; Kelemen, LE ; Magliocco, AM ; Swenerton, KD ; Chenevix-Trench, G ; Lu, Y ; Hein, A ; Ekici, AB ; Beckmann, MW ; Fasching, PA ; Lambrechts, D ; Despierre, E ; Vergote, I ; Lambrechts, S ; Doherty, JA ; Rossing, MA ; Chang-Claude, J ; Rudolph, A ; Friel, G ; Moysich, KB ; Odunsi, K ; Sucheston-Campbell, L ; Lurie, G ; Goodman, MT ; Carney, ME ; Thompson, PJ ; Runnebaum, IB ; Duerst, M ; Hillemanns, P ; Doerk, T ; Antonenkova, N ; Bogdanova, N ; Leminen, A ; Nevanlinna, H ; Pelttari, LM ; Butzow, R ; Bunker, CH ; Modugno, F ; Edwards, RP ; Ness, RB ; du Bois, A ; Heitz, F ; Schwaab, I ; Harter, P ; Karlan, BY ; Walsh, C ; Lester, J ; Jensen, A ; Kjaer, SK ; Hogdall, CK ; Hogdall, E ; Lundvall, L ; Sellers, TA ; Fridley, BL ; Goode, EL ; Cunningham, JM ; Vierkant, RA ; Giles, GG ; Baglietto, L ; Severi, G ; Southey, MC ; Liang, D ; Wu, X ; Lu, K ; Hildebrandt, MAT ; Levine, DA ; Bisogna, M ; Schildkraut, JM ; Iversen, ES ; Weber, RP ; Berchuck, A ; Cramer, DW ; Terry, KL ; Poole, EM ; Tworoger, SS ; Bandera, EV ; Chandran, U ; Orlow, I ; Olson, SH ; Wik, E ; Salvesen, HB ; Bjorge, L ; Halle, MK ; van Altena, AM ; Aben, KKH ; Kiemeney, LA ; Massuger, LFAG ; Pejovic, T ; Bean, YT ; Cybulski, C ; Gronwald, J ; Lubinski, J ; Wentzensen, N ; Brinton, LA ; Lissowska, J ; Garcia-Closas, M ; Dicks, E ; Dennis, J ; Easton, DF ; Song, H ; Tyrer, JP ; Pharoah, PDP ; Eccles, D ; Campbell, IG ; Whittemore, AS ; McGuire, V ; Sieh, W ; Rothstein, JH ; Flanagan, JM ; Paul, J ; Brown, R ; Phelan, CM ; Risch, HA ; McLaughlin, JR ; Narod, SA ; Ziogas, A ; Anton-Culver, H ; Gentry-Maharaj, A ; Menon, U ; Gayther, SA ; Ramus, SJ ; Wu, AH ; Pearce, CL ; Pike, MC ; Dansonka-Mieszkowska, A ; Rzepecka, IK ; Szafron, LM ; Kupryjanczyk, J ; Cook, LS ; Le, ND ; Brooks-Wilson, A (SPRINGER, 2014-05)

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome

White, KL ; Vierkant, RA ; Fogarty, ZC ; Charbonneau, B ; Block, MS ; Pharoah, PDP ; Chenevix-Trench, G ; Rossing, MA ; Cramer, DW ; Pearce, CL ; Schildkraut, JM ; Menon, U ; Kjaer, SK ; Levine, DA ; Gronwald, J ; Culver, HA ; Whittemore, AS ; Karlan, BY ; Lambrechts, D ; Wentzensen, N ; Kupryjanczyk, J ; Chang-Claude, J ; Bandera, EV ; Hogdall, E ; Heitz, F ; Kaye, SB ; Fasching, PA ; Campbell, I ; Goodman, MT ; Pejovic, T ; Bean, Y ; Lurie, G ; Eccles, D ; Hein, A ; Beckmann, MW ; Ekici, AB ; Paul, J ; Brown, R ; Flanagan, JM ; Harter, P ; Du Bois, A ; Schwaab, I ; Hogdall, CK ; Lundvall, L ; Olson, SH ; Orlow, I ; Paddock, LE ; Rudolph, A ; Eilber, U ; Dansonka-Mieszkowska, A ; Rzepecka, IK ; Ziolkowska-Seta, I ; Brinton, L ; Yang, H ; Garcia-Closas, M ; Despierre, E ; Lambrechts, S ; Vergote, I ; Walsh, C ; Lester, J ; Sieh, W ; McGuire, V ; Rothstein, JH ; Ziogas, A ; Lubinski, J ; Cybulski, C ; Menkiszak, J ; Jensen, A ; Gayther, SA ; Ramus, SJ ; Gentry-Maharaj, A ; Berchuck, A ; Wu, AH ; Pike, MC ; Van denBerg, D ; Terry, KL ; Vitonis, AF ; Doherty, JA ; Johnatty, SE ; Defazio, A ; Song, H ; Tyrer, J ; Sellers, TA ; Phelan, CM ; Kalli, KR ; Cunningham, JM ; Fridley, BL ; Goode, EL (AMER ASSOC CANCER RESEARCH, 2013-05)

BACKGROUND: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. METHODS: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. RESULTS: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. CONCLUSIONS: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. IMPACT: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed.

Sir Peter MacCallum Department of Oncology - Research Publications

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