Sir Peter MacCallum Department of Oncology - Research Publications

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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.