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, 2015-09-01)
    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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    Development and validation of a targeted gene sequencing panel for application to disparate cancers
    McCabe, MJ ; Gauthier, M-EA ; Chan, C-L ; Thompson, TJ ; De Sousa, SMC ; Puttick, C ; Grady, JP ; Gayevskiy, V ; Tao, J ; Ying, K ; Cipponi, A ; Deng, N ; Swarbrick, A ; Thomas, ML ; kConFab, ; Lord, RV ; Johns, AL ; Kohonen-Corish, M ; O'Toole, SA ; Clark, J ; Mueller, SA ; Gupta, R ; McCormack, AI ; Dinger, ME ; Cowley, MJ (Nature Publishing Group, 2019-11-19)
    Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour's molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy.
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    Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
    Ferreira, MA ; Gamazon, ER ; Al-Ejeh, F ; Aittomaki, K ; Andrulis, IL ; Anton-Culver, H ; Arason, A ; Arndt, V ; Aronson, KJ ; Arun, BK ; Asseryanis, E ; Azzollini, J ; Balmana, J ; Barnes, DR ; Barrowdale, D ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bialkowska, K ; Blomqvist, C ; Bogdanova, N ; Bojesen, SE ; Bolla, MK ; Borg, A ; Brauch, H ; Brenner, H ; Broeks, A ; Burwinkel, B ; Caldes, T ; Caligo, MA ; Campa, D ; Campbell, I ; Canzian, F ; Carter, J ; Carter, BD ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Christiansen, H ; Chung, WK ; Claes, KBM ; Clarke, CL ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; de la Hoya, M ; Dennis, J ; Devilee, P ; Diez, O ; Doerk, T ; Dunning, AM ; Dwek, M ; Eccles, DM ; Ejlertsen, B ; Ellberg, C ; Engel, C ; Eriksson, M ; Fasching, PA ; Fletcher, O ; Flyger, H ; Friedman, E ; Frost, D ; Gabrielson, M ; Gago-Dominguez, M ; Ganz, PA ; Gapstur, SM ; Garber, J ; Garcia-Closas, M ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Glendon, G ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Greene, MH ; Gronwald, J ; Guenel, P ; Haiman, CA ; Hall, P ; Hamann, U ; He, W ; Heyworth, J ; Hogervorst, FBL ; Hollestelle, A ; Hoover, RN ; Hopper, JL ; Hulick, PJ ; Humphreys, K ; Imyanitov, EN ; Isaacs, C ; Jakimovska, M ; Jakubowska, A ; James, PA ; Janavicius, R ; Jankowitz, RC ; John, EM ; Johnson, N ; Joseph, V ; Karlan, BY ; Khusnutdinova, E ; Kiiski, J ; Ko, Y-D ; Jones, ME ; Konstantopoulou, I ; Kristensen, VN ; Laitman, Y ; Lambrechts, D ; Lazaro, C ; Leslie, G ; Lester, J ; Lesueur, F ; Lindstrom, S ; Long, J ; Loud, JT ; Lubinski, J ; Makalic, E ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; Maurer, T ; Mavroudis, D ; McGuffog, L ; Meindl, A ; Menon, U ; Michailidou, K ; Miller, A ; Montagna, M ; Moreno, F ; Moserle, L ; Mulligan, AM ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Nevelsteen, I ; Nielsen, FC ; Nikitina-Zake, L ; Nussbaum, RL ; Offit, K ; Olah, E ; Olopade, O ; Olsson, H ; Osorio, A ; Papp, J ; Park-Simon, T-W ; Parsons, MT ; Pedersen, IS ; Peixoto, A ; Peterlongo, P ; Pharoah, PDP ; Plaseska-Karanfilska, D ; Poppe, B ; Presneau, N ; Radice, P ; Rantala, J ; Rennert, G ; Risch, HA ; Saloustros, E ; Sanden, K ; Sawyer, EJ ; Schmidt, MK ; Schmutzler, RK ; Sharma, P ; Shu, X-O ; Simard, J ; Singer, CF ; Soucy, P ; Southey, MC ; Spinelli, JJ ; Spurdle, AB ; Stone, J ; Swerdlow, AJ ; Tapper, WJ ; Taylor, JA ; Teixeira, MR ; Terry, MB ; Teule, A ; Thomassen, M ; Thoene, K ; Thull, DL ; Tischkowitz, M ; Toland, AE ; Torres, D ; Truong, T ; Tung, N ; Vachon, CM ; van Asperen, CJ ; van den Ouweland, AMW ; van Rensburg, EJ ; Vega, A ; Viel, A ; Wang, Q ; Wappenschmidt, B ; Weitzel, JN ; Wendt, C ; Winqvist, R ; Yang, XR ; Yannoukakos, D ; Ziogas, A ; Kraft, P ; Antoniou, AC ; Zheng, W ; Easton, DF ; Milne, RL ; Beesley, J ; Chenevix-Trench, G ; Arnold, N ; Auber, B ; Bogdanova-Markov, N ; Borde, J ; Caliebe, A ; Ditsch, N ; Dworniczak, B ; Engert, S ; Faust, U ; Gehrig, A ; Hahnen, E ; Hauke, J ; Hentschel, J ; Herold, N ; Honisch, E ; Just, W ; Kast, K ; Larsen, M ; Lemke, J ; Huu, PN ; Niederacher, D ; Ott, C-E ; Platzer, K ; Pohl-Rescigno, E ; Ramser, J ; Rhiem, K ; Steinemann, D ; Sutter, C ; Varon-Mateeva, R ; Wang-Gohrke, S ; Weber, BHF ; Prieur, F ; Pujol, P ; Sagne, C ; Sevenet, N ; Sobol, H ; Sokolowska, J ; Stoppa-Lyonnet, D ; Venat-Bouvet, L ; Adlard, J ; Ahmed, M ; Barwell, J ; Brady, A ; Brewer, C ; Cook, J ; Davidson, R ; Donaldson, A ; Eason, J ; Eeles, R ; Evans, DG ; Gregory, H ; Hanson, H ; Henderson, A ; Hodgson, S ; Izatt, L ; Kennedy, MJ ; Lalloo, F ; Miller, C ; Morrison, PJ ; Ong, K-R ; Perkins, J ; Porteous, ME ; Rogers, MT ; Side, LE ; Snape, K ; Walker, L ; Harrington, PA ; Heemskerk-Gerritsen, BAM ; Rookus, MA ; Seynaeve, CM ; van der Baan, FH ; van der Hout, AH ; van der Kolk, LE ; van der Luijt, RB ; van Deurzen, CHM ; van Doorn, HC ; van Engelen, K ; van Hest, L ; van Os, TAM ; Verhoef, S ; Vogel, MJ ; Wijnen, JT ; Miron, A ; Kapuscinski, M ; Bane, A ; Ross, E ; Buys, SS ; Conner, TA ; Balleine, R ; Baxter, R ; Braye, S ; Carpenter, J ; Dahlstrom, J ; Forbes, J ; Lee, SC ; Marsh, D ; Morey, A ; Pathmanathan, N ; Simpson, P ; Spigelman, A ; Wilcken, N ; Yip, D (NATURE PUBLISHING GROUP, 2019-04-15)
    Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
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    The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
    Figlioli, G ; Bogliolo, M ; Catucci, I ; Caleca, L ; Viz Lasheras, S ; Pujol, R ; Kiiski, J ; Muranen, TA ; Barnes, DR ; Dennis, J ; Michailidou, K ; Bolla, MK ; Leslie, G ; Aalfs, CM ; Adank, MA ; Adlard, J ; Agata, S ; Cadoo, K ; Agnarsson, BA ; Ahearn, T ; Aittomaki, K ; Ambrosone, CB ; Andrews, L ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Arnold, N ; Aronson, KJ ; Arun, BK ; Asseryanis, E ; Auber, B ; Auvinen, P ; Azzollini, J ; Balmana, J ; Barkardottir, RB ; Barrowdale, D ; Barwell, J ; Freeman, LEB ; Beauparlant, CJ ; Beckmann, MW ; Behrens, S ; Benitez, J ; Berger, R ; Bermisheva, M ; Blanco, AM ; Blomqvist, C ; Bogdanova, N ; Bojesen, A ; Bojesen, SE ; Bonanni, B ; Borg, A ; Brady, AF ; Brauch, H ; Brenner, H ; Bruening, T ; Burwinkel, B ; Buys, SS ; Caldes, T ; Caliebe, A ; Caligo, MA ; Campa, D ; Campbell, IG ; Canzian, F ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Claes, KBM ; Clarke, CL ; Collavoli, A ; Conner, TA ; Cox, DG ; Cybulski, C ; Czene, K ; Daly, MB ; de la Hoya, M ; Devilee, P ; Diez, O ; Ding, YC ; Dite, GS ; Ditsch, N ; Domchek, SM ; Dorfling, CM ; dos-Santos-Silva, I ; Durda, K ; Dwek, M ; Eccles, DM ; Ekici, AB ; Eliassen, AH ; Ellberg, C ; Eriksson, M ; Evans, DG ; Fasching, PA ; Figueroa, J ; Flyger, H ; Foulkes, WD ; Friebel, TM ; Friedman, E ; Gabrielson, M ; Gaddam, P ; Gago-Dominguez, M ; Gao, C ; Gapstur, SM ; Garber, J ; Garcia-Closas, M ; Garcia-Saenz, JA ; Gaudet, MM ; Gayther, SA ; Giles, GG ; Glendon, G ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Guenel, P ; Gutierrez-Barrera, AM ; Haeberle, L ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Harrington, PA ; Hein, A ; Heyworth, J ; Hillemanns, P ; Hollestelle, A ; Hopper, JL ; Hosgood, HD ; Howell, A ; Hu, C ; Hulick, PJ ; Hunter, DJ ; Imyanitov, EN ; Isaacs, C ; Jakimovska, M ; Jakubowska, A ; James, P ; Janavicius, R ; Janni, W ; John, EM ; Jones, ME ; Jung, A ; Kaaks, R ; Karlan, BY ; Khusnutdinova, E ; Kitahara, CM ; Konstantopoulou, I ; Koutros, S ; Kraft, P ; Lambrechts, D ; Lazaro, C ; Le Marchand, L ; Lester, J ; Lesueur, F ; Lilyquist, J ; Loud, JT ; Lu, KH ; Luben, RN ; Lubinski, J ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martens, JWM ; Maurer, T ; Mavroudis, D ; Mebirouk, N ; Meindl, A ; Menon, U ; Miller, A ; Montagna, M ; Nathanson, KL ; Neuhausen, SL ; Newman, WG ; Nguyen-Dumont, T ; Nielsen, FC ; Nielsen, S ; Nikitina-Zake, L ; Offit, K ; Olah, E ; Olopade, O ; Olshan, AF ; Olson, JE ; Olsson, H ; Osorio, A ; Ottini, L ; Peissel, B ; Peixoto, A ; Peto, J ; Plaseska-Karanfilska, D ; Pocza, T ; Presneau, N ; Angel Pujana, M ; Punie, K ; Rack, B ; Rantala, J ; Rashid, MU ; Rau-Murthy, R ; Rennert, G ; Lejbkowicz, F ; Rhenius, V ; Romero, A ; Rookus, MA ; Ross, EA ; Rossing, M ; Rudaitis, V ; Ruebner, M ; Saloustros, E ; Sanden, K ; Santamarina, M ; Scheuner, MT ; Schmutzler, RK ; Schneider, M ; Scott, C ; Senter, L ; Shah, M ; Sharma, P ; Shu, X-O ; Simard, J ; Singer, CF ; Sohn, C ; Soucy, P ; Southey, MC ; Spinelli, JJ ; Steele, L ; Stoppa-Lyonnet, D ; Tapper, WJ ; Teixeira, MR ; Terry, MB ; Thomassen, M ; Thompson, J ; Thull, DL ; Tischkowitz, M ; Tollenaar, RAEM ; Torres, D ; Troester, MA ; Truong, T ; Tung, N ; Untch, M ; Vachon, CM ; van Rensburg, EJ ; van Veen, EM ; Vega, A ; Viel, A ; Wappenschmidt, B ; Weitzel, JN ; Wendt, C ; Wieme, G ; Wolk, A ; Yang, XR ; Zheng, W ; Ziogas, A ; Zorn, KK ; Dunning, AM ; Lush, M ; Wang, Q ; McGuffog, L ; Parsons, MT ; Pharoah, PDP ; Fostira, F ; Toland, AE ; Andrulis, IL ; Ramus, SJ ; Swerdlow, AJ ; Greene, MH ; Chung, WK ; Milne, RL ; Chenevix-Trench, G ; Doerk, T ; Schmidt, MK ; Easton, DF ; Radice, P ; Hahnen, E ; Antoniou, AC ; Couch, FJ ; Nevanlinna, H ; Surralles, J ; Peterlongo, P ; Balleine, R ; Baxter, R ; Braye, S ; Carpenter, J ; Dahlstrom, J ; Forbes, J ; Lee, CS ; Marsh, D ; Morey, A ; Pathmanathan, N ; Scott, R ; Simpson, P ; Spigelman, A ; Wilcken, N ; Yip, D ; Zeps, N ; Belotti, M ; Bertrand, O ; Birot, A-M ; Buecher, B ; Caputo, S ; Dupre, A ; Fourme, E ; Gauthier-Villars, M ; Golmard, L ; Le Mentec, M ; Moncoutier, V ; de Pauw, A ; Saule, C ; Boutry-Kryza, N ; Calender, A ; Giraud, S ; Leone, M ; Bressac-de-Paillerets, B ; Caron, O ; Guillaud-Bataille, M ; Bignon, Y-J ; Uhrhammer, N ; Bonadona, V ; Lasset, C ; Berthet, P ; Castera, L ; Vaur, D ; Bourdon, V ; Nogues, C ; Noguchi, T ; Popovici, C ; Remenieras, A ; Sobol, H ; Coupier, I ; Pujol, P ; Adenis, C ; Dumont, A ; Revillion, F ; Muller, D ; Barouk-Simonet, E ; Bonnet, F ; Bubien, V ; Longy, M ; Sevenet, N ; Gladieff, L ; Guimbaud, R ; Feillel, V ; Toulas, C ; Dreyfus, H ; Leroux, CD ; Peysselon, M ; Rebischung, C ; Legrand, C ; Baurand, A ; Bertolone, G ; Coron, F ; Faivre, L ; Jacquot, C ; Lizard, S ; Kientz, C ; Lebrun, M ; Prieur, F ; Fert-Ferrer, S ; Mari, V ; Venat-Bouvet, L ; Bezieau, S ; Delnatte, C ; Mortemousque, I ; Colas, C ; Coulet, F ; Soubrier, F ; Warcoin, M ; Bronner, M ; Sokolowska, J ; Collonge-Rame, M-A ; Damette, A ; Gesta, P ; Lallaoui, H ; Chiesa, J ; Molina-Gomes, D ; Ingster, O ; Manouvrier-Hanu, S ; Lejeune, S ; Aghmesheh, M ; Greening, S ; Amor, D ; Gattas, M ; Botes, L ; Buckley, M ; Friedlander, M ; Koehler, J ; Meiser, B ; Saleh, M ; Salisbury, E ; Trainer, A ; Tucker, K ; Antill, Y ; Dobrovic, A ; Fellows, A ; Fox, S ; Harris, M ; Nightingale, S ; Phillips, K ; Sambrook, J ; Thorne, H ; Armitage, S ; Arnold, L ; Kefford, R ; Kirk, J ; Rickard, E ; Bastick, P ; Beesley, J ; Hayward, N ; Spurdle, A ; Walker, L ; Beilby, J ; Saunders, C ; Bennett, I ; Blackburn, A ; Bogwitz, M ; Gaff, C ; Lindeman, G ; Pachter, N ; Scott, C ; Sexton, A ; Visvader, J ; Taylor, J ; Winship, I ; Brennan, M ; Brown, M ; French, J ; Edwards, S ; Burgess, M ; Burke, J ; Patterson, B ; Butow, P ; Culling, B ; Caldon, L ; Callen, D ; Chauhan, D ; Eisenbruch, M ; Heiniger, L ; Chauhan, M ; Christian, A ; Dixon, J ; Kidd, A ; Cohen, P ; Colley, A ; Fenton, G ; Crook, A ; Dickson, R ; Field, M ; Cui, J ; Cummings, M ; Dawson, S-J ; DeFazio, A ; Delatycki, M ; Dudding, T ; Edkins, T ; Farshid, G ; Flanagan, J ; Fong, P ; Forrest, L ; Gallego-Ortega, D ; George, P ; Gill, G ; Kollias, J ; Haan, E ; Hart, S ; Jenkins, M ; Hunt, C ; Lakhani, S ; Lipton, L ; Lobb, L ; Mann, G ; McLachlan, SA ; O'Connell, S ; O'Sullivan, S ; Pieper, E ; Robinson, B ; Saunus, J ; Scott, E ; Shelling, A ; Williams, R ; Young, MA (Springer Nature, 2019-11-01)
    Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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    Shared heritability and functional enrichment across six solid cancers
    Jiang, X ; Finucane, HK ; Schumacher, FR ; Schmit, SL ; Tyrer, JP ; Han, Y ; Michailidou, K ; Lesseur, C ; Kuchenbaecker, KB ; Dennis, J ; Conti, DV ; Casey, G ; Gaudet, MM ; Huyghe, JR ; Albanes, D ; Aldrich, MC ; Andrew, AS ; Andrulis, IL ; Anton-Culver, H ; Antoniou, AC ; Antonenkova, NN ; Arnold, SM ; Aronson, KJ ; Arun, BK ; Bandera, EV ; Barkardottir, RB ; Barnes, DR ; Batra, J ; Beckmann, MW ; Benitez, J ; Benlloch, S ; Berchuck, A ; Berndt, SI ; Bickeboeller, H ; Bien, SA ; Blomqvist, C ; Boccia, S ; Bogdanova, NV ; Bojesen, SE ; Bolla, MK ; Brauch, H ; Brenner, H ; Brenton, JD ; Brook, MN ; Brunet, J ; Brunnstrom, H ; Buchanan, DD ; Burwinkel, B ; Butzow, R ; Cadoni, G ; Caldes, T ; Caligo, MA ; Campbell, I ; Campbell, PT ; Cancel-Tassin, G ; Cannon-Albright, L ; Campa, D ; Caporaso, N ; Carvalho, AL ; Chan, AT ; Chang-Claude, J ; Chanock, SJ ; Chen, C ; Christiani, DC ; Claes, KBM ; Claessens, F ; Clements, J ; Collee, JM ; Correa, MC ; Couch, FJ ; Cox, A ; Cunningham, JM ; Cybulski, C ; Czene, K ; Daly, MB ; defazio, A ; Devilee, P ; Diez, O ; Gago-Dominguez, M ; Donovan, JL ; Doerk, T ; Duell, EJ ; Dunning, AM ; Dwek, M ; Eccles, DM ; Edlund, CK ; Edwards, DRV ; Ellberg, C ; Evans, DG ; Fasching, PA ; Ferris, RL ; Liloglou, T ; Figueiredo, JC ; Fletcher, O ; Fortner, RT ; Fostira, F ; Franceschi, S ; Friedman, E ; Gallinger, SJ ; Ganz, PA ; Garber, J ; Garcia-Saenz, JA ; Gayther, SA ; Giles, GG ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Goode, EL ; Goodman, MT ; Goodman, G ; Grankvist, K ; Greene, MH ; Gronberg, H ; Gronwald, J ; Guenel, P ; Hakansson, N ; Hall, P ; Hamann, U ; Hamdy, FC ; Hamilton, RJ ; Hampe, J ; Haugen, A ; Heitz, F ; Herrero, R ; Hillemanns, P ; Hoffmeister, M ; Hogdall, E ; Hong, Y-C ; Hopper, JL ; Houlston, R ; Hulick, PJ ; Hunter, DJ ; Huntsman, DG ; Idos, G ; Imyanitov, EN ; Ingles, SA ; Isaacs, C ; Jakubowska, A ; James, P ; Jenkins, MA ; Johansson, M ; Johansson, M ; John, EM ; Joshi, AD ; Kaneva, R ; Karlan, BY ; Kelemen, LE ; Kuhl, T ; Khaw, K-T ; Khusnutdinova, E ; Kibel, AS ; Kiemeney, LA ; Kim, J ; Kjaer, SK ; Knight, JA ; Kogevinas, M ; Kote-Jarai, Z ; Koutros, S ; Kristensen, VN ; Kupryjanczyk, J ; Lacko, M ; Lam, S ; Lambrechts, D ; Landi, MT ; Lazarus, P ; Le, ND ; Lee, E ; Lejbkowicz, F ; Lenz, H-J ; Leslie, G ; Lessel, D ; Lester, J ; Levine, DA ; Li, L ; Li, CI ; Lindblom, A ; Lindor, NM ; Liu, G ; Loupakis, F ; Lubinski, J ; Maehle, L ; Maier, C ; Mannermaa, A ; Le Marchand, L ; Margolin, S ; May, T ; McGuffog, L ; Meindl, A ; Middha, P ; Miller, A ; Milne, RL ; MacInnis, RJ ; Modugno, F ; Montagna, M ; Moreno, V ; Moysich, KB ; Mucci, L ; Muir, K ; Mulligan, AM ; Nathanson, KL ; Neal, DE ; Ness, AR ; Neuhausen, SL ; Nevanlinna, H ; Newcomb, PA ; Newcomb, LF ; Nielsen, FC ; Nikitina-Zake, L ; Nordestgaard, BG ; Nussbaum, RL ; Offit, K ; Olah, E ; Al Olama, AA ; Olopade, OI ; Olshan, AF ; Olsson, H ; Osorio, A ; Pandha, H ; Park, JY ; Pashayan, N ; Parsons, MT ; Pejovic, T ; Penney, KL ; Peters, WHM ; Phelan, CM ; Phipps, AI ; Plaseska-Karanfilska, D ; Pring, M ; Prokofyeva, D ; Radice, P ; Stefansson, K ; Ramus, SJ ; Raskin, L ; Rennert, G ; Rennert, HS ; van Rensburg, EJ ; Riggan, MJ ; Risch, HA ; Risch, A ; Roobol, MJ ; Rosenstein, BS ; Rossing, MA ; De Ruyck, K ; Saloustros, E ; Sandler, DP ; Sawyer, EJ ; Schabath, MB ; Schleutker, J ; Schmidt, MK ; Setiawan, VW ; Shen, H ; Siegel, EM ; Sieh, W ; Singer, CF ; Slattery, ML ; Sorensen, KD ; Southey, MC ; Spurdle, AB ; Stanford, JL ; Stevens, VL ; Stintzing, S ; Stone, J ; Sundfeldt, K ; Sutphen, R ; Swerdlow, AJ ; Tajara, EH ; Tangen, CM ; Tardon, A ; Taylor, JA ; Teare, MD ; Teixeira, MR ; Terry, MB ; Terry, KL ; Thibodeau, SN ; Thomassen, M ; Bjorge, L ; Tischkowitz, M ; Toland, AE ; Torres, D ; Townsend, PA ; Travis, RC ; Tung, N ; Tworoger, SS ; Ulrich, CM ; Usmani, N ; Vachon, CM ; Van Nieuwenhuysen, E ; Vega, A ; Aguado-Barrera, ME ; Wang, Q ; Webb, PM ; Weinberg, CR ; Weinstein, S ; Weissler, MC ; Weitzel, JN ; West, CML ; White, E ; Whittemore, AS ; Wichmann, H-E ; Wiklund, F ; Winqvist, R ; Wolk, A ; Woll, P ; Woods, M ; Wu, AH ; Wu, X ; Yannoukakos, D ; Zheng, W ; Zienolddiny, S ; Ziogas, A ; Zorn, KK ; Lane, JM ; Saxena, R ; Thomas, D ; Hung, RJ ; Diergaarde, B ; Mckay, J ; Peters, U ; Hsu, L ; Garcia-Closas, M ; Eeles, RA ; Chenevix-Trench, G ; Brennan, PJ ; Haiman, CA ; Simard, J ; Easton, DF ; Gruber, SB ; Pharoah, PDP ; Price, AL ; Pasaniuc, B ; Amos, CI ; Kraft, P ; Lindstrom, S (NATURE PORTFOLIO, 2019-01-25)
    Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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    No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing
    Easton, DF ; Lesueur, F ; Decker, B ; Michailidou, K ; Li, J ; Allen, J ; Luccarini, C ; Pooley, KA ; Shah, M ; Bolla, MK ; Wang, Q ; Dennis, J ; Ahmad, J ; Thompson, ER ; Damiola, F ; Pertesi, M ; Voegele, C ; Mebirouk, N ; Robinot, N ; Durand, G ; Forey, N ; Luben, RN ; Ahmed, S ; Aittomaki, K ; Anton-Culver, H ; Arndt, V ; Baynes, C ; Beckman, MW ; Benitez, J ; Van Den Berg, D ; Blot, WJ ; Bogdanova, NV ; Bojesen, SE ; Brenner, H ; Chang-Claude, J ; Chia, KS ; Choi, J-Y ; Conroy, DM ; Cox, A ; Cross, SS ; Czene, K ; Darabi, H ; Devilee, P ; Eriksson, M ; Fasching, PA ; Figueroa, J ; Flyger, H ; Fostira, F ; Garcia-Closas, M ; Giles, GG ; Glendon, G ; Gonzalez-Neira, A ; Guenel, P ; Haiman, CA ; Hall, P ; Hart, SN ; Hartman, M ; Hooning, MJ ; Hsiung, C-N ; Ito, H ; Jakubowska, A ; James, PA ; John, EM ; Johnson, N ; Jones, M ; Kabisch, M ; Kang, D ; Kosma, V-M ; Kristensen, V ; Lambrechts, D ; Li, N ; Lindblom, A ; Long, J ; Lophatananon, A ; Lubinski, J ; Mannermaa, A ; Manoukian, S ; Margolin, S ; Matsuo, K ; Meindl, A ; Mitchell, G ; Muir, K ; Nevelsteen, I ; van den Ouweland, A ; Peterlongo, P ; Phuah, SY ; Pylkas, K ; Rowley, SM ; Sangrajrang, S ; Schmutzler, RK ; Shen, C-Y ; Shu, X-O ; Southey, MC ; Surowy, H ; Swerdlow, A ; Teo, SH ; Tollenaar, RAEM ; Tomlinson, I ; Torres, D ; Truong, T ; Vachon, C ; Verhoef, S ; Wong-Brown, M ; Zheng, W ; Zheng, Y ; Nevanlinna, H ; Scott, RJ ; Andrulis, IL ; Wu, AH ; Hopper, JL ; Couch, FJ ; Winqvist, R ; Burwinkel, B ; Sawyer, EJ ; Schmidt, MK ; Rudolph, A ; Doerk, T ; Brauch, H ; Hamann, U ; Neuhausen, SL ; Milne, RL ; Fletcher, O ; Pharoah, PDP ; Campbell, IG ; Dunning, AM ; Le Calvez-Kelm, F ; Goldgar, DE ; Tavtigian, SV ; Chenevix-Trench, G (BMJ PUBLISHING GROUP, 2016-05-01)
    BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.