Sir Peter MacCallum Department of Oncology - Research Publications

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    Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations
    Rebbeck, TR ; Friebel, TM ; Friedman, E ; Hamann, U ; Huo, D ; Kwong, A ; Olah, E ; Olopade, OI ; Solano, AR ; Teo, S-H ; Thomassen, M ; Weitzel, JN ; Chan, TL ; Couch, FJ ; Goldgar, DE ; Kruse, TA ; Palmero, EI ; Park, SK ; Torres, D ; van Rensburg, EJ ; McGuffog, L ; Parsons, MT ; Leslie, G ; Aalfs, CM ; Abugattas, J ; Adlard, J ; Agata, S ; Aittomaki, K ; Andrews, L ; Andrulis, IL ; Arason, A ; Arnold, N ; Arun, BK ; Asseryanis, E ; Auerbach, L ; Azzollini, J ; Balmana, J ; Barile, M ; Barkardottir, RB ; Barrowdale, D ; Benitez, J ; Berger, A ; Berger, R ; Blanco, AM ; Blazer, KR ; Blok, MJ ; Bonadona, V ; Bonanni, B ; Bradbury, AR ; Brewer, C ; Buecher, B ; Buys, SS ; Caldes, T ; Caliebe, A ; Caligo, MA ; Campbell, I ; Caputo, SM ; Chiquette, J ; Chung, WK ; Claes, KBM ; Collee, JM ; Cook, J ; Davidson, R ; de la Hoya, M ; De Leeneer, K ; de Pauw, A ; Delnatte, C ; Diez, O ; Ding, YC ; Ditsch, N ; Domchek, S ; Dorfling, CM ; Velazquez, C ; Dworniczak, B ; Eason, J ; Easton, DF ; Eeles, R ; Ehrencrona, H ; Ejlertsen, B ; Engel, C ; Engert, S ; Evans, DG ; Faivre, L ; Feliubadalo, L ; Ferrer, SF ; Foretova, L ; Fowler, J ; Frost, D ; Galvao, HCR ; Ganz, PA ; Garber, J ; Gauthier-Villars, M ; Gehrig, A ; Gerdes, A-M ; Gesta, P ; Giannini, G ; Giraud, S ; Glendon, G ; Godwin, AK ; Greene, MH ; Gronwald, J ; Gutierrez-Barrera, A ; Hahnen, E ; Hauke, J ; Henderson, A ; Hentschel, J ; Hogervorst, FBL ; Honisch, E ; Imyanitov, EN ; Isaacs, C ; Izatt, L ; Izquierdo, A ; Jakubowska, A ; James, P ; Janavicius, R ; Jensen, UB ; John, EM ; Vijai, J ; Kaczmarek, K ; Karlan, BY ; Kast, K ; Kim, S-W ; Konstantopoulou, I ; Korach, J ; Laitman, Y ; Lasa, A ; Lasset, C ; Lazaro, C ; Lee, A ; Lee, MH ; Lester, J ; Lesueur, F ; Liljegren, A ; Lindor, NM ; Longy, M ; Loud, JT ; Lu, KH ; Lubinski, J ; Machackova, E ; Manoukian, S ; Mari, V ; Martinez-Bouzas, C ; Matrai, Z ; Mebirouk, N ; Meijers-Heijboer, HEJ ; Meindl, A ; Mensenkamp, AR ; Mickys, U ; Miller, A ; Montagna, M ; Moysich, KB ; Mulligan, AM ; Musinsky, J ; Neuhausen, SL ; Nevanlinna, H ; Ngeow, J ; Nguyen, HP ; Niederacher, D ; Nielsen, HR ; Nielsen, FC ; Nussbaum, RL ; Offit, K ; Ofverholm, A ; Ong, K-R ; Osorio, A ; Papi, L ; Papp, J ; Pasini, B ; Pedersen, IS ; Peixoto, A ; Peruga, N ; Peterlongo, P ; Pohl, E ; Pradhan, N ; Prajzendanc, K ; Prieur, F ; Pujol, P ; Radice, P ; Ramus, SJ ; Rantala, J ; Rashid, MU ; Rhiem, K ; Robson, M ; Rodriguez, GC ; Rogers, MT ; Rudaitis, V ; Schmidt, AY ; Schmutzler, RK ; Senter, L ; Shah, PD ; Sharma, P ; Side, LE ; Simard, J ; Singer, CF ; Skytte, A-B ; Slavin, TP ; Snape, K ; Sobol, H ; Southey, M ; Steele, L ; Steinemann, D ; Sukiennicki, G ; Sutter, C ; Szabo, CI ; Tan, YY ; Teixeira, MR ; Terry, MB ; Teule, A ; Thomas, A ; Thull, DL ; Tischkowitz, M ; Tognazzo, S ; Toland, AE ; Topka, S ; Trainer, AH ; Tung, N ; van Asperen, CJ ; van der Hout, AH ; van der Kolk, LE ; van der Luijt, RB ; Van Heetvelde, M ; Varesco, L ; Varon-Mateeva, R ; Vega, A ; Villarreal-Garza, C ; von Wachenfeldt, A ; Walker, L ; Wang-Gohrke, S ; Wappenschmidt, B ; Weber, BHF ; Yannoukakos, D ; Yoon, S-Y ; Zanzottera, C ; Zidan, J ; Zorn, KK ; Selkirk, CGH ; Hulick, PJ ; Chenevix-Trench, G ; Spurdle, AB ; Antoniou, AC ; Nathanson, KL (WILEY-HINDAWI, 2018-05)
    The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
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    Exome Sequencing Identifies Rare Deleterious Mutations in DNA Repair Genes FANCC and BLM as Potential Breast Cancer Susceptibility Alleles
    Thompson, ER ; Doyle, MA ; Ryland, GL ; Rowley, SM ; Choong, DYH ; Tothill, RW ; Thorne, H ; Barnes, DR ; Li, J ; Ellul, J ; Philip, GK ; Antill, YC ; James, PA ; Trainer, AH ; Mitchell, G ; Campbell, IG ; Horwitz, MS (PUBLIC LIBRARY SCIENCE, 2012-09)
    Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.
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    Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls
    Thompson, ER ; Gorringe, KL ; Rowley, SM ; Wong-Brown, MW ; McInerny, S ; Li, N ; Trainer, AH ; Devereux, L ; Doyle, MA ; Li, J ; Lupat, R ; Delatycki, MB ; Mitchell, G ; James, PA ; Scott, RJ ; Campbell, IG (BMC, 2015-08-19)
    INTRODUCTION: PALB2 is emerging as a high-penetrance breast cancer predisposition gene in the order of BRCA1 and BRCA2. However, large studies that have evaluated the full gene rather than just the most common variants in both cases and controls are required before all truncating variants can be included in familial breast cancer variant testing. METHODS: In this study we analyse almost 2000 breast cancer cases sourced from individuals referred to familial cancer clinics, thus representing typical cases presenting in clinical practice. These cases were compared to a similar number of population-based cancer-free controls. RESULTS: We identified a significant excess of truncating variants in cases (1.3 %) versus controls (0.2 %), including six novel variants (p = 0.0001; odds ratio (OR) 6.58, 95 % confidence interval (CI) 2.3-18.9). Three of the four control individuals carrying truncating variants had at least one relative with breast cancer. There was no excess of missense variants in cases overall, but the common c.1676A > G variant (rs152451) was significantly enriched in cases and may represent a low-penetrance polymorphism (p = 0.002; OR 1.24 (95 % CI 1.09-1.47). CONCLUSIONS: Our findings support truncating variants in PALB2 as high-penetrance breast cancer susceptibility alleles, and suggest that a common missense variant may also lead to a low level of increased breast cancer risk.
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    Reevaluation of the BRCA2 truncating allele c.9976A > T (p.Lys3326Ter) in a familial breast cancer context
    Thompson, ER ; Gorringe, KL ; Rowley, SM ; Li, N ; McInerny, S ; Wong-Brown, MW ; Devereux, L ; Li, J ; Trainer, AH ; Mitchell, G ; Scott, RJ ; James, PA ; Campbell, IG (NATURE PORTFOLIO, 2015-10-12)
    The breast cancer predisposition gene, BRCA2, has a large number of genetic variants of unknown effect. The variant rs11571833, an A > T transversion in the final exon of the gene that leads to the creation of a stop codon 93 amino acids early (K3326*), is reported as a neutral polymorphism but there is some evidence to suggest an association with an increased risk of breast cancer. We assessed whether this variant was enriched in a cohort of breast cancer cases ascertained through familial cancer clinics compared to population-based non-cancer controls using a targeted sequencing approach. We identified the variant in 66/2634 (2.5%) cases and 33/1996 (1.65%) controls, indicating an enrichment in the breast cancer cases (p = 0.047, OR 1.53, 95% CI 1.00-2.34). This data is consistent with recent iCOGs data suggesting that this variant is not neutral with respect to breast cancer risk. rs11571833 may need to be included in SNP panels for evaluating breast cancer risk.
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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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    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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    Evaluating the breast cancer predisposition role of rare variants in genes associated with low-penetrance breast cancer risk SNPs
    Li, N ; Rowley, SM ; Thompson, ER ; McInerny, S ; Devereux, L ; Amarasinghe, KC ; Zethoven, M ; Lupat, R ; Goode, D ; Li, J ; Trainer, AH ; Gorringe, KL ; James, PA ; Campbell, IG (BIOMED CENTRAL LTD, 2018-01-09)
    BACKGROUND: Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with small increases in breast cancer risk. Studies to date suggest that some SNPs alter the expression of the associated genes, which potentially mediates risk modification. On this basis, we hypothesised that some of these genes may be enriched for rare coding variants associated with a higher breast cancer risk. METHODS: The coding regions and exon-intron boundaries of 56 genes that have either been proposed by GWASs to be the regulatory targets of the SNPs and/or located < 500 kb from the risk SNPs were sequenced in index cases from 1043 familial breast cancer families that previously had negative test results for BRCA1 and BRCA2 mutations and 944 population-matched cancer-free control participants from an Australian population. Rare (minor allele frequency ≤ 0.001 in the Exome Aggregation Consortium and Exome Variant Server databases) loss-of-function (LoF) and missense variants were studied. RESULTS: LoF variants were rare in both the cases and control participants across all the candidate genes, with only 38 different LoF variants observed in a total of 39 carriers. For the majority of genes (n = 36), no LoF variants were detected in either the case or control cohorts. No individual gene showed a significant excess of LoF or missense variants in the cases compared with control participants. Among all candidate genes as a group, the total number of carriers with LoF variants was higher in the cases than in the control participants (26 cases and 13 control participants), as was the total number of carriers with missense variants (406 versus 353), but neither reached statistical significance (p = 0.077 and p = 0.512, respectively). The genes contributing most of the excess of LoF variants in the cases included TET2, NRIP1, RAD51B and SNX32 (12 cases versus 2 control participants), whereas ZNF283 and CASP8 contributed largely to the excess of missense variants (25 cases versus 8 control participants). CONCLUSIONS: Our data suggest that rare LoF and missense variants in genes associated with low-penetrance breast cancer risk SNPs may contribute some additional risk, but as a group these genes are unlikely to be major contributors to breast cancer heritability.