Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Bowtell, David × Author: Campbell, Ian × Author: Giles, Graham × Author: Ramus, Susan ×

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    Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
    DeVries, AA ; Dennis, J ; Tyrer, JP ; Peng, P-C ; Coetzee, SG ; Reyes, AL ; Plummer, JT ; Davis, BD ; Chen, SS ; Dezem, FS ; Aben, KKH ; Anton-Culver, H ; Antonenkova, NN ; Beckmann, MW ; Beeghly-Fadiel, A ; Berchuck, A ; Bogdanova, N ; Bogdanova-Markov, N ; Brenton, JD ; Butzow, R ; Campbell, I ; Chang-Claude, J ; Chenevix-Trench, G ; Cook, LS ; DeFazio, A ; Doherty, JA ; Dork, T ; Eccles, DM ; Eliassen, AH ; Fasching, PA ; Fortner, RT ; Giles, GG ; Goode, EL ; Goodman, MT ; Gronwald, J ; Hakansson, N ; Hildebrandt, MAT ; Huff, C ; Huntsman, DG ; Jensen, A ; Kar, S ; Karlan, BY ; Khusnutdinova, EK ; Kiemeney, LA ; Kjaer, SK ; Kupryjanczyk, J ; Labrie, M ; Lambrechts, D ; Le, ND ; Lubinski, J ; May, T ; Menon, U ; Milne, RL ; Modugno, F ; Monteiro, AN ; Moysich, KB ; Odunsi, K ; Olsson, H ; Pearce, CL ; Pejovic, T ; Ramus, SJ ; Riboli, E ; Riggan, MJ ; Romieu, I ; Sandler, DP ; Schildkraut, JM ; Setiawan, VW ; Sieh, W ; Song, H ; Sutphen, R ; Terry, KL ; Thompson, PJ ; Titus, L ; Tworoger, SS ; Van Nieuwenhuysen, E ; Edwards, DV ; Webb, PM ; Wentzensen, N ; Whittemore, AS ; Wolk, A ; Wu, AH ; Ziogas, A ; Freedman, ML ; Lawrenson, K ; Pharoah, PDP ; Easton, DF ; Gayther, SA ; Jones, MR (OXFORD UNIV PRESS INC, 2022-11)
    BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
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    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.
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    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.