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1. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Author: Barnes, DR, Silvestri, V, Leslie, G, McGuffog, L, Dennis, J, Yang, X, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Belotti, M, Benitez, J, Berthet, P, Boonen, SE, Borg, A, Bozsik, A, Brady, AF, Brennan, P, Brewer, C, Brunet, J, Bucalo, A, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cassingham, H, Christensen, LL, Cini, G, Claes, KBM, Cook, J, Coppa, A, Cortesi, L, Damante, G, Darder, E, Davidson, R, de la Hoya, M, De Leeneer, K, de Putter, R, Del Valle, J, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Fostira, F, Frone, M, Frost, D, Gallagher, D, Gehrig, A, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gregory, H, Gross, E, Hahnen, E, Hamann, U, Hansen, TVO, Hanson, H, Hentschel, J, Horvath, J, Izatt, L, Izquierdo, A, James, PA, Janavicius, R, Jensen, UB, Johannsson, OT, John, EM, Kramer, G, Kroeldrup, L, Kruse, TA, Lautrup, C, Lazaro, C, Lesueur, F, Lopez-Fernandez, A, Mai, PL, Manoukian, S, Matrai, Z, Matricardi, L, Maxwell, KN, Mebirouk, N, Meindl, A, Montagna, M, Monteiro, AN, Morrison, PJ, Muranen, TA, Murray, A, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Tu, N-D, Niederacher, D, Olah, E, Olopade, O, Palli, D, Parsons, MT, Pedersen, IS, Peissel, B, Perez-Segura, P, Peterlongo, P, Petersen, AH, Pinto, P, Porteous, ME, Pottinger, C, Pujana, MA, Radice, P, Ramser, J, Rantala, J, Robson, M, Rogers, MT, Ronlund, K, Rump, A, Sanchez de Abajo, AM, Shah, PD, Sharif, S, Side, LE, Singer, CF, Stadler, Z, Steele, L, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Tommasi, S, Toss, A, Trainer, AH, Tripathi, V, Valentini, V, van Asperen, CJ, Venturelli, M, Viel, A, Vijai, J, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Whaite, A, Zanna, I, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Ottini, L, Barnes, DR, Silvestri, V, Leslie, G, McGuffog, L, Dennis, J, Yang, X, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Belotti, M, Benitez, J, Berthet, P, Boonen, SE, Borg, A, Bozsik, A, Brady, AF, Brennan, P, Brewer, C, Brunet, J, Bucalo, A, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cassingham, H, Christensen, LL, Cini, G, Claes, KBM, Cook, J, Coppa, A, Cortesi, L, Damante, G, Darder, E, Davidson, R, de la Hoya, M, De Leeneer, K, de Putter, R, Del Valle, J, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Fostira, F, Frone, M, Frost, D, Gallagher, D, Gehrig, A, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gregory, H, Gross, E, Hahnen, E, Hamann, U, Hansen, TVO, Hanson, H, Hentschel, J, Horvath, J, Izatt, L, Izquierdo, A, James, PA, Janavicius, R, Jensen, UB, Johannsson, OT, John, EM, Kramer, G, Kroeldrup, L, Kruse, TA, Lautrup, C, Lazaro, C, Lesueur, F, Lopez-Fernandez, A, Mai, PL, Manoukian, S, Matrai, Z, Matricardi, L, Maxwell, KN, Mebirouk, N, Meindl, A, Montagna, M, Monteiro, AN, Morrison, PJ, Muranen, TA, Murray, A, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Tu, N-D, Niederacher, D, Olah, E, Olopade, O, Palli, D, Parsons, MT, Pedersen, IS, Peissel, B, Perez-Segura, P, Peterlongo, P, Petersen, AH, Pinto, P, Porteous, ME, Pottinger, C, Pujana, MA, Radice, P, Ramser, J, Rantala, J, Robson, M, Rogers, MT, Ronlund, K, Rump, A, Sanchez de Abajo, AM, Shah, PD, Sharif, S, Side, LE, Singer, CF, Stadler, Z, Steele, L, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Tommasi, S, Toss, A, Trainer, AH, Tripathi, V, Valentini, V, van Asperen, CJ, Venturelli, M, Viel, A, Vijai, J, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Whaite, A, Zanna, I, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Ottini, L
Abstract: BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
Published: 2022

2. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Author: Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, Chu, ATW, Chung, WK, Claes, KBM, Cook, J, Cortesi, L, Couch, FJ, Daly, MB, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Della Puppa, L, Dennis, J, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Donaldson, A, Dworniczak, B, Easton, DF, Eccles, DM, Eeles, RA, Ehrencrona, H, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Faust, U, Feliubadalo, L, Foretova, L, Fostira, F, Fountzilas, G, Frost, D, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Geczi, L, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gutierrez-Barrera, AM, Hahnen, E, Hamann, U, Hauke, J, Herold, N, Hogervorst, FBL, Honisch, E, Hopper, JL, Hulick, PJ, Izatt, L, Jager, A, James, P, Janavicius, R, Jensen, UB, Jensen, TD, Johannsson, OT, John, EM, Joseph, V, Kang, E, Kast, K, Kiiski, J, Kim, S-W, Kim, Z, Ko, K-P, Konstantopoulou, I, Kramer, G, Krogh, L, Kruse, TA, Kwong, A, Larsen, M, Lasset, C, Lautrup, C, Lazaro, C, Lee, J, Lee, JW, Lee, MH, Lemke, J, Lesueur, F, Liljegren, A, Lindblom, A, Llovet, P, Lopez-Fernandez, A, Lopez-Perolio, I, Lorca, V, Loud, JT, Ma, ESK, Mai, PL, Manoukian, S, Mari, V, Martin, L, Matricardi, L, Mebirouk, N, Medici, V, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, C, Gomes, DM, Montagna, M, Mooij, TM, Moserle, L, Mouret-Fourme, E, Mulligan, AM, Nathanson, KL, Navratilova, M, Nevanlinna, H, Niederacher, D, Nielsen, FCC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Ong, K-R, Osorio, A, Ott, C-E, Palli, D, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Perez-Segura, P, Peterlongo, P, Petersen, AH, Porteous, ME, Angel Pujana, M, Radice, P, Ramser, J, Rantala, J, Rashid, MU, Rhiem, K, Rizzolo, P, Robson, ME, Rookus, MA, Rossing, CM, Ruddy, KJ, Santos, C, Saule, C, Scarpitta, R, Schmutzler, RK, Schuster, H, Senter, L, Seynaeve, CM, Shah, PD, Sharma, P, Shin, VY, Silvestri, V, Simard, J, Singer, CF, Skytte, A-B, Snape, K, Solano, AR, Soucy, P, Southey, MC, Spurdle, AB, Steele, L, Steinemann, D, Stoppa-Lyonnet, D, Stradella, A, Sunde, L, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tommasi, S, Torres, D, Toss, A, Trainer, AH, Tung, N, van Asperen, CJ, van der Baan, FH, van der Kolk, LE, van der Luijt, RB, van Hest, LP, Varesco, L, Varon-Mateeva, R, Viel, A, Vierstraete, J, Villa, R, von Wachenfeldt, A, Wagner, P, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Wieme, G, Yadav, S, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zorn, KK, D'Amico, A, Freedman, ML, Pomerantz, MM, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ottini, L, Nielsen, HR, Rebbeck, TR, Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, Chu, ATW, Chung, WK, Claes, KBM, Cook, J, Cortesi, L, Couch, FJ, Daly, MB, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Della Puppa, L, Dennis, J, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Donaldson, A, Dworniczak, B, Easton, DF, Eccles, DM, Eeles, RA, Ehrencrona, H, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Faust, U, Feliubadalo, L, Foretova, L, Fostira, F, Fountzilas, G, Frost, D, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Geczi, L, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gutierrez-Barrera, AM, Hahnen, E, Hamann, U, Hauke, J, Herold, N, Hogervorst, FBL, Honisch, E, Hopper, JL, Hulick, PJ, Izatt, L, Jager, A, James, P, Janavicius, R, Jensen, UB, Jensen, TD, Johannsson, OT, John, EM, Joseph, V, Kang, E, Kast, K, Kiiski, J, Kim, S-W, Kim, Z, Ko, K-P, Konstantopoulou, I, Kramer, G, Krogh, L, Kruse, TA, Kwong, A, Larsen, M, Lasset, C, Lautrup, C, Lazaro, C, Lee, J, Lee, JW, Lee, MH, Lemke, J, Lesueur, F, Liljegren, A, Lindblom, A, Llovet, P, Lopez-Fernandez, A, Lopez-Perolio, I, Lorca, V, Loud, JT, Ma, ESK, Mai, PL, Manoukian, S, Mari, V, Martin, L, Matricardi, L, Mebirouk, N, Medici, V, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, C, Gomes, DM, Montagna, M, Mooij, TM, Moserle, L, Mouret-Fourme, E, Mulligan, AM, Nathanson, KL, Navratilova, M, Nevanlinna, H, Niederacher, D, Nielsen, FCC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Ong, K-R, Osorio, A, Ott, C-E, Palli, D, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Perez-Segura, P, Peterlongo, P, Petersen, AH, Porteous, ME, Angel Pujana, M, Radice, P, Ramser, J, Rantala, J, Rashid, MU, Rhiem, K, Rizzolo, P, Robson, ME, Rookus, MA, Rossing, CM, Ruddy, KJ, Santos, C, Saule, C, Scarpitta, R, Schmutzler, RK, Schuster, H, Senter, L, Seynaeve, CM, Shah, PD, Sharma, P, Shin, VY, Silvestri, V, Simard, J, Singer, CF, Skytte, A-B, Snape, K, Solano, AR, Soucy, P, Southey, MC, Spurdle, AB, Steele, L, Steinemann, D, Stoppa-Lyonnet, D, Stradella, A, Sunde, L, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tommasi, S, Torres, D, Toss, A, Trainer, AH, Tung, N, van Asperen, CJ, van der Baan, FH, van der Kolk, LE, van der Luijt, RB, van Hest, LP, Varesco, L, Varon-Mateeva, R, Viel, A, Vierstraete, J, Villa, R, von Wachenfeldt, A, Wagner, P, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Wieme, G, Yadav, S, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zorn, KK, D'Amico, A, Freedman, ML, Pomerantz, MM, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ottini, L, Nielsen, HR, and Rebbeck, TR
Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
Published: 2020

3. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Author: Figlioli, G, Bogliolo, M, Catucci, I, Caleca, L, Lasheras, SV, Pujol, R, Kiiski, JI, Muranen, TA, Barnes, DR, Dennis, J, Michailidou, K, Bolla, MK, Leslie, G, Aalfs, CM, 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, Adank, MA, Adlard, J, Agata, S, Cadoo, K, Agnarsson, BA, Ahearn, T, Aittomäki, 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, Balmaña, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Beane Freeman, LE, Beauparlant, CJ, Beckmann, MW, Behrens, S, Benitez, J, Berger, R, Bermisheva, M, Blanco, AM, Blomqvist, C, Bogdanova, NV, Bojesen, A, Bojesen, SE, Bonanni, B, Borg, A, Brady, AF, Brauch, H, Brenner, H, Brüning, T, Burwinkel, B, Buys, SS, Caldés, 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, and Durda, K
Subjects: nutritional and metabolic diseases, skin and connective tissue diseases
Abstract: © 2019, The Author(s). 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.
Published: 2019

4. Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Author: Qian, F, Rookus, MA, Leslie, G, Risch, HA, Greene, MH, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arnold, N, Arun, BK, Ausems, MGEM, Azzollini, J, Barrowdale, D, Barwell, J, Benitez, J, Bialkowska, K, Bonadona, V, Borde, J, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Carter, J, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Collonge-Rame, M-A, Couch, FJ, Daly, MB, Delnatte, C, Diez, O, Domchek, SM, Dorfling, CM, Eason, J, Easton, DF, Eeles, R, Engel, C, Evans, DG, Faivre, L, Feliubado, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Garcia-Barberan, V, Gehrig, A, Glendon, G, Godwin, AK, Garcia, EBG, Hamann, U, Hauke, J, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, Janavicius, R, John, EM, Karlan, BY, Kets, CM, Laitman, Y, Lazaro, C, Leroux, D, Lester, J, Lesueur, F, Loud, JT, Lubinski, J, Lukomska, A, McGuffog, L, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mooij, TM, Mouret-Fourme, E, Nathanson, KL, Nehoray, B, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, Offit, K, Olah, E, Ong, K-R, Oosterwijk, JC, Ottini, L, Parsons, MT, Peterlongo, P, Pfeiler, G, Pradhan, N, Radice, P, Ramus, SJ, Rantala, J, Rennert, G, Robson, M, Rodriguez, GC, Salani, R, Scheuner, MT, Schmutzler, RK, Shah, PD, Side, LE, Simard, J, Singer, CF, Steinemann, D, Stoppa-Lyonnet, D, Tan, YY, Teixeira, MR, Terry, MB, Thomassen, M, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van Asperen, CJ, van Engelen, K, van Rensburg, EJ, Venat-Bouvet, L, Vierstraete, J, Wagner, G, Walker, L, Weitze, JN, Yannoukakos, D, Antoniou, AC, Goldgar, DE, Olopade, O, Chenevix-Trench, G, Rebbeck, TR, Huo, D, Qian, F, Rookus, MA, Leslie, G, Risch, HA, Greene, MH, Aalfs, CM, Adank, MA, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arnold, N, Arun, BK, Ausems, MGEM, Azzollini, J, Barrowdale, D, Barwell, J, Benitez, J, Bialkowska, K, Bonadona, V, Borde, J, Borg, A, Bradbury, AR, Brunet, J, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Carter, J, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Collonge-Rame, M-A, Couch, FJ, Daly, MB, Delnatte, C, Diez, O, Domchek, SM, Dorfling, CM, Eason, J, Easton, DF, Eeles, R, Engel, C, Evans, DG, Faivre, L, Feliubado, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Garcia-Barberan, V, Gehrig, A, Glendon, G, Godwin, AK, Garcia, EBG, Hamann, U, Hauke, J, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, Janavicius, R, John, EM, Karlan, BY, Kets, CM, Laitman, Y, Lazaro, C, Leroux, D, Lester, J, Lesueur, F, Loud, JT, Lubinski, J, Lukomska, A, McGuffog, L, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mooij, TM, Mouret-Fourme, E, Nathanson, KL, Nehoray, B, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, Offit, K, Olah, E, Ong, K-R, Oosterwijk, JC, Ottini, L, Parsons, MT, Peterlongo, P, Pfeiler, G, Pradhan, N, Radice, P, Ramus, SJ, Rantala, J, Rennert, G, Robson, M, Rodriguez, GC, Salani, R, Scheuner, MT, Schmutzler, RK, Shah, PD, Side, LE, Simard, J, Singer, CF, Steinemann, D, Stoppa-Lyonnet, D, Tan, YY, Teixeira, MR, Terry, MB, Thomassen, M, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van Asperen, CJ, van Engelen, K, van Rensburg, EJ, Venat-Bouvet, L, Vierstraete, J, Wagner, G, Walker, L, Weitze, JN, Yannoukakos, D, Antoniou, AC, Goldgar, DE, Olopade, O, Chenevix-Trench, G, Rebbeck, TR, and Huo, D
Abstract: BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.
Published: 2019

5. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Author: Lecarpentier, J, Silvestri, V, Kuchenbaecker, KB, Barrowdale, D, Dennis, J, McGuffog, L, Soucy, P, Leslie, G, Rizzolo, P, Navazio, AS, Valentini, V, Zelli, V, Lee, A, Al Olama, AA, Tyrer, JP, Southey, M, John, EM, Conner, TA, Goldgar, DE, Buys, SS, Janavicius, R, Steele, L, Ding, YC, Neuhausen, SL, Hansen, TVO, Osorio, A, Weitzel, JN, Toss, A, Medici, V, Cortesi, L, Zanna, I, Palli, D, Radice, P, Manoukian, S, Peissel, B, Azzollini, J, Viel, A, Cini, G, Damante, G, Tommasi, S, Peterlongo, P, Fostira, F, Hamann, U, Evans, DG, Henderson, A, Brewer, C, Eccles, D, Cook, J, Ong, K-R, Walker, L, Side, LE, Porteous, ME, Davidson, R, Hodgson, S, Frost, D, Adlard, J, Izatt, L, Eeles, R, Ellis, S, Tischkowitz, M, Godwin, AK, Meindl, A, Gehrig, A, Dworniczak, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Hahnen, E, Hauke, J, Rhiem, K, Kast, K, Arnold, N, Ditsch, N, Wang-Gohrke, S, Wappenschmidt, B, Wand, D, Lasset, C, Stoppa-Lyonnet, D, Belotti, M, Damiola, F, Barjhoux, L, Mazoyer, S, Van Heetvelde, M, Poppe, B, De Leeneer, K, Claes, KBM, de la Hoya, M, Garcia-Barberan, V, Caldes, T, Perez Segura, P, Kiiski, JI, Aittomaeki, K, Khan, S, Nevanlinna, H, van Asperen, CJ, Vaszko, T, Kasler, M, Olah, E, Balmana, J, Gutierrez-Enriquez, S, Diez, O, Teule, A, Izquierdo, A, Darder, E, Brunet, J, Del Valle, J, Feliubadalo, L, Pujana, MA, Lazaro, C, Arason, A, Agnarsson, BA, Johannsson, OT, Barkardottir, RB, Alducci, E, Tognazzo, S, Montagna, M, Teixeira, MR, Pinto, P, Spurdle, AB, Holland, H, Lee, JW, Lee, MH, Lee, J, Kim, S-W, Kang, E, Kim, Z, Sharma, P, Rebbeck, TR, Vijai, J, Robson, M, Lincoln, A, Musinsky, J, Gaddam, P, Tan, YY, Berger, A, Singer, CF, Loud, JT, Greene, MH, Mulligan, AM, Glendon, G, Andrulis, IL, Toland, AE, Senter, L, Bojesen, A, Nielsen, HR, Skytte, A-B, Sunde, L, Jensen, UB, Pedersen, IS, Krogh, L, Kruse, TA, Caligo, MA, Yoon, S-Y, Teo, S-H, von Wachenfeldt, A, Huo, D, Nielsen, SM, Olopade, OI, Nathanson, KL, Domchek, SM, Lorenchick, C, Jankowitz, RC, Campbell, I, James, P, Mitchell, G, Orr, N, Park, SK, Thomassen, M, Offit, K, Couch, FJ, Simard, J, Easton, DF, Chenevix-Trench, G, Schmutzler, RK, Antoniou, AC, Ottini, L, Lecarpentier, J, Silvestri, V, Kuchenbaecker, KB, Barrowdale, D, Dennis, J, McGuffog, L, Soucy, P, Leslie, G, Rizzolo, P, Navazio, AS, Valentini, V, Zelli, V, Lee, A, Al Olama, AA, Tyrer, JP, Southey, M, John, EM, Conner, TA, Goldgar, DE, Buys, SS, Janavicius, R, Steele, L, Ding, YC, Neuhausen, SL, Hansen, TVO, Osorio, A, Weitzel, JN, Toss, A, Medici, V, Cortesi, L, Zanna, I, Palli, D, Radice, P, Manoukian, S, Peissel, B, Azzollini, J, Viel, A, Cini, G, Damante, G, Tommasi, S, Peterlongo, P, Fostira, F, Hamann, U, Evans, DG, Henderson, A, Brewer, C, Eccles, D, Cook, J, Ong, K-R, Walker, L, Side, LE, Porteous, ME, Davidson, R, Hodgson, S, Frost, D, Adlard, J, Izatt, L, Eeles, R, Ellis, S, Tischkowitz, M, Godwin, AK, Meindl, A, Gehrig, A, Dworniczak, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Hahnen, E, Hauke, J, Rhiem, K, Kast, K, Arnold, N, Ditsch, N, Wang-Gohrke, S, Wappenschmidt, B, Wand, D, Lasset, C, Stoppa-Lyonnet, D, Belotti, M, Damiola, F, Barjhoux, L, Mazoyer, S, Van Heetvelde, M, Poppe, B, De Leeneer, K, Claes, KBM, de la Hoya, M, Garcia-Barberan, V, Caldes, T, Perez Segura, P, Kiiski, JI, Aittomaeki, K, Khan, S, Nevanlinna, H, van Asperen, CJ, Vaszko, T, Kasler, M, Olah, E, Balmana, J, Gutierrez-Enriquez, S, Diez, O, Teule, A, Izquierdo, A, Darder, E, Brunet, J, Del Valle, J, Feliubadalo, L, Pujana, MA, Lazaro, C, Arason, A, Agnarsson, BA, Johannsson, OT, Barkardottir, RB, Alducci, E, Tognazzo, S, Montagna, M, Teixeira, MR, Pinto, P, Spurdle, AB, Holland, H, Lee, JW, Lee, MH, Lee, J, Kim, S-W, Kang, E, Kim, Z, Sharma, P, Rebbeck, TR, Vijai, J, Robson, M, Lincoln, A, Musinsky, J, Gaddam, P, Tan, YY, Berger, A, Singer, CF, Loud, JT, Greene, MH, Mulligan, AM, Glendon, G, Andrulis, IL, Toland, AE, Senter, L, Bojesen, A, Nielsen, HR, Skytte, A-B, Sunde, L, Jensen, UB, Pedersen, IS, Krogh, L, Kruse, TA, Caligo, MA, Yoon, S-Y, Teo, S-H, von Wachenfeldt, A, Huo, D, Nielsen, SM, Olopade, OI, Nathanson, KL, Domchek, SM, Lorenchick, C, Jankowitz, RC, Campbell, I, James, P, Mitchell, G, Orr, N, Park, SK, Thomassen, M, Offit, K, Couch, FJ, Simard, J, Easton, DF, Chenevix-Trench, G, Schmutzler, RK, Antoniou, AC, and Ottini, L
Abstract: Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
Published: 2017

6. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author: Hollestelle, A, Van Der Baan, FH, Berchuck, A, Johnatty, SE, Aben, KK, Agnarsson, BA, Aittomäki, K, Alducci, E, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Antoniou, AC, Apicella, C, Arndt, V, Arnold, N, Arun, BK, Arver, B, Ashworth, A, Baglietto, L, Balleine, R, Bandera, EV, Barrowdale, D, Bean, YT, Beckmann, L, Beckmann, MW, Benitez, J, Berger, A, Berger, R, Beuselinck, B, Bisogna, M, Bjorge, L, Blomqvist, C, Bogdanova, NV, Bojesen, A, Bojesen, SE, Bolla, MK, Bonanni, B, Brand, JS, Brauch, H, Brenner, H, Brinton, L, Brooks-Wilson, A, Bruinsma, F, Brunet, J, Brüning, T, Budzilowska, A, Bunker, CH, Burwinkel, B, Butzow, R, Buys, SS, Caligo, MA, Campbell, I, Carter, J, Chang-Claude, J, Chanock, SJ, Claes, KBM, Collée, JM, Cook, LS, Couch, FJ, Cox, A, Cramer, D, Cross, SS, Cunningham, JM, Cybulski, C, Czene, K, Damiola, F, Dansonka-Mieszkowska, A, Darabi, H, De La Hoya, M, Defazio, A, Dennis, J, Devilee, P, and Dicks, EM
Abstract: © 2015 Elsevier Inc. All rights reserved. Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
Published: 2016

7. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Pfeiler, G, Vigorito, E, Kuchenbaecker, KB, Beesley, J, Adlard, J, Agnarsson, BA, Andrulis, IL, Arun, BK, Barjhoux, L, Belotti, M, Benitez, J, Berger, A, Phelan, CM, Piedmonte, M, Poppe, B, Pujana, MA, Radice, P, Rennert, G, Rodriguez, GC, Rookus, MA, Ross, EA, Bojesen, A, Schmutzler, RK, Simard, J, Singer, CF, Slavin, TP, Soucy, P, Southey, M, Steinemann, D, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Bonanni, B, Szabo, CI, Tea, MK, Teixeira, MR, Teo, SH, Terry, MB, Thomassen, M, Tibiletti, MG, Tihomirova, L, Tognazzo, S, van Rensburg, EJ, Brewer, C, Varesco, L, Varon-Mateeva, R, Vratimos, A, Weitzel, JN, McGuffog, L, Kirk, J, Toland, AE, Hamann, U, Lindor, N, Ramus, SJ, Caldes, T, Greene, MH, Couch, FJ, Offit, K, Pharoah, PDP, Chenevix-Trench, G, Antoniou, AC, Prokunina-Olsson, L, Caligo, MA, Campbell, I, Chan, SB, Claes, KBM, Cohn, DE, Cook, J, Daly, MB, Damiola, F, Davidson, R, Pauw, AD, Delnatte, C, Diez, O, Domchek, SM, Dumont, M, Durda, K, Dworniczak, B, Easton, DF, Eccles, D, Edwinsdotter Ardnor, C, Eeles, R, Ejlertsen, B, Ellis, S, Evans, G, Feliubadalo, L, Fostira, F, Foulkes, WD, Friedman, E, Frost, D, Gaddam, P, Ganz, PA, Garber, J, Garcia-Barberan, V, Gauthier-Villars, M, Gehrig, A, Gerdes, AM, Giraud, S, Godwin, AK, Goldgar, DE, Hake, CR, Hansen, TVO, Healey, S, Hodgson, S, Hogervorst, FBL, Houdayer, C, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jacobs, L, Jakubowska, A, Janavicius, R, Jaworska-Bieniek, K, Jensen, UB, John, EM, Vijai, J, Karlan, BY, Kast, K, Investigators, K, Khan, S, Kwong, A, Laitman, Y, Lester, J, Lesueur, F, Liljegren, A, Lubinski, J, Mai, PL, Manoukian, S, Mazoyer, S, Meindl, A, Mensenkamp, AR, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Olah, E, Olopade, OI, Ong, KR, Osorio, A, Park, SK, Paulsson-Karlsson, Y, Pedersen, IS, Peissel, B, and Peterlongo, P
Subjects: endocrine system diseases, skin and connective tissue diseases
Abstract: Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA 1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population
Published: 2016

8. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Author: Blein, S, Bardel, C, Danjean, V, McGuffog, L, Healey, S, Barrowdale, D, Lee, A, Dennis, J, Kuchenbaecker, KB, Soucy, P, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Gerdes, A-M, Ejlertsen, B, Nielsen, FC, Hansen, TVO, Osorio, A, Benitez, J, Andres Conejero, R, Segota, E, Weitzel, JN, Thelander, M, Peterlongo, P, Radice, P, Pensotti, V, Dolcetti, R, Bonanni, B, Peissel, B, Zaffaroni, D, Scuvera, G, Manoukian, S, Varesco, L, Capone, GL, Papi, L, Ottini, L, Yannoukakos, D, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brady, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Cook, J, Adlard, J, Barwell, J, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Tischkowitz, M, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Cole, T, Godwin, AK, Isaacs, C, Claes, K, De Leeneer, K, Meindl, A, Gehrig, A, Wappenschmidt, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Plendl, H, Kast, K, Rhiem, K, Ditsch, N, Arnold, N, Varon-Mateeva, R, Schmutzler, RK, Preisler-Adams, S, Markov, NB, Wang-Gohrke, S, de Pauw, A, Lefol, C, Lasset, C, Leroux, D, Rouleau, E, Damiola, F, Dreyfus, H, Barjhoux, L, Golmard, L, Uhrhammer, N, Bonadona, V, Sornin, V, Bignon, Y-J, Carter, J, Van Le, L, Piedmonte, M, DiSilvestro, PA, de la Hoya, M, Caldes, T, Nevanlinna, H, Aittomaki, K, Jager, A, van den Ouweland, AMW, Kets, CM, Aalfs, CM, van Leeuwen, FE, Hogervorst, FBL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Roozendaal, KEP, Rookus, MA, Devilee, P, van der Luijt, RB, Olah, E, Diez, O, Teule, A, Lazaro, C, Blanco, I, Del Valle, J, Jakubowska, A, Sukiennicki, G, Gronwald, J, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Agnarsson, BA, Maugard, C, Amadori, A, Montagna, M, Teixeira, MR, Spurdle, AB, Foulkes, W, Olswold, C, Lindor, NM, Pankratz, VS, Szabo, CI, Lincoln, A, Jacobs, L, Corines, M, Robson, M, Vijai, J, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Kaulich, DG, Pfeiler, G, Tea, M-K, Greene, MH, Mai, PL, Rennert, G, Imyanitov, EN, Mulligan, AM, Glendon, G, Andrulis, IL, Tchatchou, S, Toland, AE, Pedersen, IS, Thomassen, M, Kruse, TA, Jensen, UB, Caligo, MA, Friedman, E, Zidan, J, Laitman, Y, Lindblom, A, Melin, B, Arver, B, Loman, N, Rosenquist, R, Olopade, OI, Nussbaum, RL, Ramus, SJ, Nathanson, KL, Domchek, SM, Rebbeck, TR, Arun, BK, Mitchell, G, Karlan, BY, Lester, J, Orsulic, S, Stoppa-Lyonnet, D, Thomas, G, Simard, J, Couch, FJ, Offit, K, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Mazoyer, S, Phelan, CM, Sinilnikova, OM, Cox, DG, Blein, S, Bardel, C, Danjean, V, McGuffog, L, Healey, S, Barrowdale, D, Lee, A, Dennis, J, Kuchenbaecker, KB, Soucy, P, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Gerdes, A-M, Ejlertsen, B, Nielsen, FC, Hansen, TVO, Osorio, A, Benitez, J, Andres Conejero, R, Segota, E, Weitzel, JN, Thelander, M, Peterlongo, P, Radice, P, Pensotti, V, Dolcetti, R, Bonanni, B, Peissel, B, Zaffaroni, D, Scuvera, G, Manoukian, S, Varesco, L, Capone, GL, Papi, L, Ottini, L, Yannoukakos, D, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brady, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Cook, J, Adlard, J, Barwell, J, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Tischkowitz, M, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Cole, T, Godwin, AK, Isaacs, C, Claes, K, De Leeneer, K, Meindl, A, Gehrig, A, Wappenschmidt, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Plendl, H, Kast, K, Rhiem, K, Ditsch, N, Arnold, N, Varon-Mateeva, R, Schmutzler, RK, Preisler-Adams, S, Markov, NB, Wang-Gohrke, S, de Pauw, A, Lefol, C, Lasset, C, Leroux, D, Rouleau, E, Damiola, F, Dreyfus, H, Barjhoux, L, Golmard, L, Uhrhammer, N, Bonadona, V, Sornin, V, Bignon, Y-J, Carter, J, Van Le, L, Piedmonte, M, DiSilvestro, PA, de la Hoya, M, Caldes, T, Nevanlinna, H, Aittomaki, K, Jager, A, van den Ouweland, AMW, Kets, CM, Aalfs, CM, van Leeuwen, FE, Hogervorst, FBL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Roozendaal, KEP, Rookus, MA, Devilee, P, van der Luijt, RB, Olah, E, Diez, O, Teule, A, Lazaro, C, Blanco, I, Del Valle, J, Jakubowska, A, Sukiennicki, G, Gronwald, J, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Agnarsson, BA, Maugard, C, Amadori, A, Montagna, M, Teixeira, MR, Spurdle, AB, Foulkes, W, Olswold, C, Lindor, NM, Pankratz, VS, Szabo, CI, Lincoln, A, Jacobs, L, Corines, M, Robson, M, Vijai, J, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Kaulich, DG, Pfeiler, G, Tea, M-K, Greene, MH, Mai, PL, Rennert, G, Imyanitov, EN, Mulligan, AM, Glendon, G, Andrulis, IL, Tchatchou, S, Toland, AE, Pedersen, IS, Thomassen, M, Kruse, TA, Jensen, UB, Caligo, MA, Friedman, E, Zidan, J, Laitman, Y, Lindblom, A, Melin, B, Arver, B, Loman, N, Rosenquist, R, Olopade, OI, Nussbaum, RL, Ramus, SJ, Nathanson, KL, Domchek, SM, Rebbeck, TR, Arun, BK, Mitchell, G, Karlan, BY, Lester, J, Orsulic, S, Stoppa-Lyonnet, D, Thomas, G, Simard, J, Couch, FJ, Offit, K, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Mazoyer, S, Phelan, CM, Sinilnikova, OM, and Cox, DG
Abstract: INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effe
Published: 2015

9. A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

Author: Gudmundsson, J, Sulem, P, Gudbjartsson, DF, Masson, G, Agnarsson, BA, Benediktsdottir, KR, Sigurdsson, A, Magnusson, OT, Gudjonsson, SA, Magnusdottir, DN, Johannsdottir, H, Helgadottir, HT, Stacey, SN, Jonasdottir, A, Olafsdottir, SB, Thorleifsson, G, Jonasson, JG, Tryggvadottir, L, Navarrete, S, Fuertes, F, Helfand, BT, Hu, Q, Csiki, IE, Mates, IN, Jinga, V, Aben, KKH, Van Oort, IM, Vermeulen, SH, Donovan, JL, Hamdy, FC, Ng, CF, Chiu, PKF, Lau, KM, Ng, MCY, Gulcher, JR, Kong, A, Catalona, WJ, Mayordomo, JI, Einarsson, GV, Barkardottir, RB, Jonsson, E, Mates, D, Neal, DE, Kiemeney, LA, Thorsteinsdottir, U, Rafnar, T, and Stefansson, K
Subjects: Male, Risk, Molecular Sequence Data, Iceland, Aetiology, screening and detection [ONCOL 5], Adenocarcinoma, Biology, Polymorphism, Single Nucleotide, Article, White People, Cell Line, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Gene Frequency, Translational research [ONCOL 3], Genetics, medicine, Humans, Genetic Predisposition to Disease, Aged, 030304 developmental biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Aged, 80 and over, Homeodomain Proteins, Whole genome sequencing, Prostate cancer risk, 0303 health sciences, Base Sequence, Genome, Human, Prostatic Neoplasms, Sequence Analysis, DNA, Middle Aged, medicine.disease, 3. Good health, Risk variant, 030220 oncology & carcinogenesis, Mutation, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract: Contains fulltext : 108025.pdf (Publisher’s version ) (Closed access) In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 x 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2)
Published: 2012

10. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Author: Hunter, KW, Couch, FJ, Wang, X, McGuffog, L, Lee, A, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, M, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmana, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, S-H, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, CHM, Seynaeve, C, Garcia, EBG, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Leone, M, Pujol, P, Mazoyer, S, Bignon, Y-J, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, M-K, Lindor, NM, Kaufman, B, Paluch, SS, Laitman, Y, Skytte, A-B, Gerdes, A-M, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jonson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teule, A, Lazaro, C, Brunet, J, Angel Pujana, M, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomaki, K, Muranen, TA, Duran, M, Chung, WK, Lasa, A, Dorfling, CM, Miron, A, Benitez, J, Senter, L, Huo, D, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Hunter, KW, Couch, FJ, Wang, X, McGuffog, L, Lee, A, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, M, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmana, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, S-H, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, CHM, Seynaeve, C, Garcia, EBG, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Leone, M, Pujol, P, Mazoyer, S, Bignon, Y-J, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, M-K, Lindor, NM, Kaufman, B, Paluch, SS, Laitman, Y, Skytte, A-B, Gerdes, A-M, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jonson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teule, A, Lazaro, C, Brunet, J, Angel Pujana, M, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomaki, K, Muranen, TA, Duran, M, Chung, WK, Lasa, A, Dorfling, CM, Miron, A, Benitez, J, Senter, L, Huo, D, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, and Antoniou, AC
Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Published: 2013

11. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Author: Couch, FJ, Wang, XS, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, van der Lee, A, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, Marga, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmana, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, SH, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, Carolien, Seynaeve, Caroline, Garcia, EBG, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Leone, M, Pujol, P, Mazoyer, S, Bignon, YJ, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, MK, Lindor, NM, Kaufman, B, Paluch, SS, Laitman, Y, Skytte, AB, Gerdes, AM, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jonson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teule, A, Lazaro, C (Conxi), Brunet, J, Pujana, MA, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomaki, K, Muranen, TA, Duran, M (Mercedes), Chung, WK, Lasa, A, Dorfling, CM, Miron, A, Benitez, J, Senter, L, Huo, DZ, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Couch, FJ, Wang, XS, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, van der Lee, A, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, Marga, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmana, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, SH, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, Carolien, Seynaeve, Caroline, Garcia, EBG, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Leone, M, Pujol, P, Mazoyer, S, Bignon, YJ, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, MK, Lindor, NM, Kaufman, B, Paluch, SS, Laitman, Y, Skytte, AB, Gerdes, AM, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jonson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teule, A, Lazaro, C (Conxi), Brunet, J, Pujana, MA, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomaki, K, Muranen, TA, Duran, M (Mercedes), Chung, WK, Lasa, A, Dorfling, CM, Miron, A, Benitez, J, Senter, L, Huo, DZ, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, and Antoniou, AC
Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Published: 2013

12. Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2

Author: Prokunina-Olsson, L, Kirchhoff, T, Gaudet, MM, Antoniou, AC, McGuffog, L, Humphreys, MK, Dunning, AM, Bojesen, SE, Nordestgaard, BG, Flyger, H, Kang, D, Yoo, K-Y, Noh, D-Y, Ahn, S-H, Dork, T, Schuermann, P, Karstens, JH, Hillemanns, P, Couch, FJ, Olson, J, Vachon, C, Wang, X, Cox, A, Brock, I, Elliott, G, Reed, MWR, Burwinkel, B, Meindl, A, Brauch, H, Hamann, U, Ko, Y-D, Broeks, A, Schmidt, MK, Van 't Veer, LJ, Braaf, LM, Johnson, N, Fletcher, O, Gibson, L, Peto, J, Turnbull, C, Seal, S, Renwick, A, Rahman, N, Wu, P-E, Yu, J-C, Hsiung, C-N, Shen, C-Y, Southey, MC, Hopper, JL, Hammet, F, Van Dorpe, T, Dieudonne, A-S, Hatse, S, Lambrechts, D, Andrulis, IL, Bogdanova, N, Antonenkova, N, Rogov, JI, Prokofieva, D, Bermisheva, M, Khusnutdinova, E, van Asperen, CJ, Tollenaar, RAEM, Hooning, MJ, Devilee, P, Margolin, S, Lindblom, A, Milne, RL, Ignacio Arias, J, Pilar Zamora, M, Benitez, J, Severi, G, Baglietto, L, Giles, GG, Spurdle, AB, Beesley, J, Chen, X, Holland, H, Healey, S, Wang-Gohrke, S, Chang-Claude, J, Mannermaa, A, Kosma, V-M, Kauppinen, J, Kataja, V, Agnarsson, BA, Caligo, MA, Godwin, AK, Nevanlinna, H, Heikkinen, T, Fredericksen, Z, Lindor, N, Nathanson, KL, Domchek, SM, Loman, N, Karlsson, P, Askmalm, MS, Melin, B, von Wachenfeldt, A, Hogervorst, FBL, Verheus, M, Rookus, MA, Seynaeve, C, Oldenburg, RA, Ligtenberg, MJ, Ausems, MGEM, Aalfs, CM, Gille, HJP, Wijnen, JT, Garcia, EBG, Peock, S, Cook, M, Oliver, CT, Frost, D, Luccarini, C, Pichert, G, Davidson, R, Chu, C, Eccles, D, Ong, K-R, Cook, J, Douglas, F, Hodgson, S, Evans, DG, Eeles, R, Gold, B, Pharoah, PDP, Offit, K, Chenevix-Trench, G, Easton, DF, Prokunina-Olsson, L, Kirchhoff, T, Gaudet, MM, Antoniou, AC, McGuffog, L, Humphreys, MK, Dunning, AM, Bojesen, SE, Nordestgaard, BG, Flyger, H, Kang, D, Yoo, K-Y, Noh, D-Y, Ahn, S-H, Dork, T, Schuermann, P, Karstens, JH, Hillemanns, P, Couch, FJ, Olson, J, Vachon, C, Wang, X, Cox, A, Brock, I, Elliott, G, Reed, MWR, Burwinkel, B, Meindl, A, Brauch, H, Hamann, U, Ko, Y-D, Broeks, A, Schmidt, MK, Van 't Veer, LJ, Braaf, LM, Johnson, N, Fletcher, O, Gibson, L, Peto, J, Turnbull, C, Seal, S, Renwick, A, Rahman, N, Wu, P-E, Yu, J-C, Hsiung, C-N, Shen, C-Y, Southey, MC, Hopper, JL, Hammet, F, Van Dorpe, T, Dieudonne, A-S, Hatse, S, Lambrechts, D, Andrulis, IL, Bogdanova, N, Antonenkova, N, Rogov, JI, Prokofieva, D, Bermisheva, M, Khusnutdinova, E, van Asperen, CJ, Tollenaar, RAEM, Hooning, MJ, Devilee, P, Margolin, S, Lindblom, A, Milne, RL, Ignacio Arias, J, Pilar Zamora, M, Benitez, J, Severi, G, Baglietto, L, Giles, GG, Spurdle, AB, Beesley, J, Chen, X, Holland, H, Healey, S, Wang-Gohrke, S, Chang-Claude, J, Mannermaa, A, Kosma, V-M, Kauppinen, J, Kataja, V, Agnarsson, BA, Caligo, MA, Godwin, AK, Nevanlinna, H, Heikkinen, T, Fredericksen, Z, Lindor, N, Nathanson, KL, Domchek, SM, Loman, N, Karlsson, P, Askmalm, MS, Melin, B, von Wachenfeldt, A, Hogervorst, FBL, Verheus, M, Rookus, MA, Seynaeve, C, Oldenburg, RA, Ligtenberg, MJ, Ausems, MGEM, Aalfs, CM, Gille, HJP, Wijnen, JT, Garcia, EBG, Peock, S, Cook, M, Oliver, CT, Frost, D, Luccarini, C, Pichert, G, Davidson, R, Chu, C, Eccles, D, Ong, K-R, Cook, J, Douglas, F, Hodgson, S, Evans, DG, Eeles, R, Gold, B, Pharoah, PDP, Offit, K, Chenevix-Trench, G, and Easton, DF
Abstract: Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
Published: 2012

13. Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2

Author: Kirchhoff, T, Gaudet, MM, Antoniou, AC, McGuffog, L, Humphreys, MK, Dunning, AM, Bojesen, SE, Nordestgaard, BG, Flyger, H, Kang, D, Yoo, KY, Noh, DY, Ahn, SH, Dork, T, Schurmann, P, Karstens, JH, Hillemanns, P, Couch, FJ, Olson, J, Vachon, C, Wang, XS, Cox, A, Brock, I, Elliott, G, Reed, MWR, Burwinkel, B, Meindl, A, Brauch, H, Hamann, U, Ko, YD, Broeks, A, Schmidt, Marjanka K, van 't Veer, LJ (Laura), Braaf, LM, Johnson, N, Fletcher, O, Gibson, L, Peto, J, Turnbull, C, Seal, S, Renwick, A, Rahman, N, Wu, PE, Yu, JC, Hsiung, CN, Shen, CY, Southey, MC, Hopper, JL, Hammet, F, Van Dorpe, T, Dieudonne, AS, Hatse, S, Lambrechts, D, Andrulis, IL, Bogdanova, N, Antonenkova, N, Rogov, JI, Prokofieva, D, Bermisheva, M, Khusnutdinova, E, van Asperen, CJ, Tollenaar, RAEM, Hooning, Maartje, Devilee, P, Margolin, S, Lindblom, A, Milne, RL, Arias, JI, Zamora, MP, Benitez, J, Severi, G, Baglietto, L, Giles, GG, Spurdle, AB, Beesley, J, Chen, XQ, Holland, H, Healey, S, Wang-Gohrke, S, Chang-Claude, J, Mannermaa, A, Kosma, VM, Kauppinen, J, Kataja, V, Agnarsson, BA, Caligo, MA, Godwin, AK, Nevanlinna, H, Heikkinen, T, Fredericksen, Z, Lindor, N, Nathanson, KL, Domchek, SM, Loman, N, Karlsson, P, Askmalm, MS, Melin, B, von Wachenfeldt, A, Hogervorst, FBL, Verheus, M, Rookus, MA, Seynaeve, Caroline, Oldenburg, Rogier, Ligtenberg, MJ, Ausems, MGEM, Aalfs, CM, Gille, HJP, Wijnen, JT, Garcia, EBG, Peock, S, Cook, M, Oliver, CT, Frost, D, Luccarini, C, Pichert, G, Davidson, R, Chu, C, Eccles, D, Ong, KR, Cook, J, Douglas, F, Hodgson, S, Evans, DG, Eeles, R, Gold, B, Pharoah, PDP, Offit, K, Chenevix-Trench, G, Easton, DF, Kirchhoff, T, Gaudet, MM, Antoniou, AC, McGuffog, L, Humphreys, MK, Dunning, AM, Bojesen, SE, Nordestgaard, BG, Flyger, H, Kang, D, Yoo, KY, Noh, DY, Ahn, SH, Dork, T, Schurmann, P, Karstens, JH, Hillemanns, P, Couch, FJ, Olson, J, Vachon, C, Wang, XS, Cox, A, Brock, I, Elliott, G, Reed, MWR, Burwinkel, B, Meindl, A, Brauch, H, Hamann, U, Ko, YD, Broeks, A, Schmidt, Marjanka K, van 't Veer, LJ (Laura), Braaf, LM, Johnson, N, Fletcher, O, Gibson, L, Peto, J, Turnbull, C, Seal, S, Renwick, A, Rahman, N, Wu, PE, Yu, JC, Hsiung, CN, Shen, CY, Southey, MC, Hopper, JL, Hammet, F, Van Dorpe, T, Dieudonne, AS, Hatse, S, Lambrechts, D, Andrulis, IL, Bogdanova, N, Antonenkova, N, Rogov, JI, Prokofieva, D, Bermisheva, M, Khusnutdinova, E, van Asperen, CJ, Tollenaar, RAEM, Hooning, Maartje, Devilee, P, Margolin, S, Lindblom, A, Milne, RL, Arias, JI, Zamora, MP, Benitez, J, Severi, G, Baglietto, L, Giles, GG, Spurdle, AB, Beesley, J, Chen, XQ, Holland, H, Healey, S, Wang-Gohrke, S, Chang-Claude, J, Mannermaa, A, Kosma, VM, Kauppinen, J, Kataja, V, Agnarsson, BA, Caligo, MA, Godwin, AK, Nevanlinna, H, Heikkinen, T, Fredericksen, Z, Lindor, N, Nathanson, KL, Domchek, SM, Loman, N, Karlsson, P, Askmalm, MS, Melin, B, von Wachenfeldt, A, Hogervorst, FBL, Verheus, M, Rookus, MA, Seynaeve, Caroline, Oldenburg, Rogier, Ligtenberg, MJ, Ausems, MGEM, Aalfs, CM, Gille, HJP, Wijnen, JT, Garcia, EBG, Peock, S, Cook, M, Oliver, CT, Frost, D, Luccarini, C, Pichert, G, Davidson, R, Chu, C, Eccles, D, Ong, KR, Cook, J, Douglas, F, Hodgson, S, Evans, DG, Eeles, R, Gold, B, Pharoah, PDP, Offit, K, Chenevix-Trench, G, and Easton, DF
Abstract: Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I-2 = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95% CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
Published: 2012

14. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

Author: Ramus, S, Kartsonaki, C, Gayther, S, Pharoah, P, Sinilnikova, O, Beesley, J, Chen, X, Mcguffog, L, Healey, S, Couch, F, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, M, Mai, P, Andrulis, I, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A, Kruse, T, Cruger, D, Jensen, U, Caligo, M, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, S, Ding, Y, Nathanson, K, Domchek, S, Jakubowska, A, Lubiński, J, Huzarski, T, Byrski, T, Gronwald, J, Górski, B, Cybulski, C, Dębniak, T, Osorio, A, Durán, M, Tejada, M, Benítez, J, Hamann, U, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Bodmer, D, Ausems, M, van Os, T, Asperen, C, Blok, M, Meijers Heijboer, H, Peock, S, Cook, M, Oliver, C, Frost, D, Dunning, A, Evans, D, Eeles, R, Pichert, G, Cole, T, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Kennedy, M, Rogers, M, Side, L, Donaldson, A, Gregory, H, Godwin, A, Stoppa Lyonnet, D, Moncoutier, V, Castera, L, Mazoyer, S, Barjhoux, L, Bonadona, V, Leroux, D, Faivre, L, Lidereau, R, Nogues, C, Bignon, Y, Prieur, F, Collonge Rame, M, Venat Bouvet, L, Fert Ferrer, S, Miron, A, Buys, S, Hopper, J, Daly, M, John, E, Terry, M, Goldgar, D, Hansen, T, Jønson, L, Ejlertsen, B, Agnarsson, B, Offit, K, Kirchhoff, T, Vijai, J, Dutra Clarke, A, Przybylo, J, Montagna, M, Casella, C, Imyanitov, E, Janavicius, R, Blanco, I, Lázaro, C, Moysich, K, Karlan, B, Gross, J, Beattie, M, Schmutzler, R, Wappenschmidt, B, Meindl, A, Ruehl, I, Fiebig, B, Sutter, C, Arnold, N, Deissler, H, Varon Mateeva, R, Kast, K, Niederacher, D, Gadzicki, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Simard, J, Soucy, P, Spurdle, A, Holland, H, Chenevix Trench, G, Easton, D, Antoniou, A, Ramus, SJ, Gayther, SA, Pharoah, PDP, Sinilnikova, OM, McGuffog, L, Couch, FJ, Greene, MH, Mai, PL, Andrulis, IL, Kruse, TA, Jensen, UB, Caligo, MA, Neuhausen, SL, Ding, YC, Nathanson, KL, Domchek, SM, Rookus, MA, Tilanus Linthorst, MA, Vreeswijk, MP, Ausems, MGEM, van Os, TA, Asperen, CJ, Blok, MJ, Meijers Heijboer, HEJ, Dunning, AM, Evans, DG, Morrison, PJ, Kennedy, MJ, Rogers, MT, Side, LE, Buys, SS, Hopper, JL, Daly, MB, John, EM, Terry, MB, Hansen, TvO, Agnarsson, BA, Dutra Clarke, AVC, Przybylo, JA, Imyanitov, EN, Moysich, KB, Karlan, BY, Beattie, MS, Spurdle, AB, Easton, DF, Antoniou, AC, ROVERSI, GAIA, Ramus, S, Kartsonaki, C, Gayther, S, Pharoah, P, Sinilnikova, O, Beesley, J, Chen, X, Mcguffog, L, Healey, S, Couch, F, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, M, Mai, P, Andrulis, I, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A, Kruse, T, Cruger, D, Jensen, U, Caligo, M, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, S, Ding, Y, Nathanson, K, Domchek, S, Jakubowska, A, Lubiński, J, Huzarski, T, Byrski, T, Gronwald, J, Górski, B, Cybulski, C, Dębniak, T, Osorio, A, Durán, M, Tejada, M, Benítez, J, Hamann, U, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Bodmer, D, Ausems, M, van Os, T, Asperen, C, Blok, M, Meijers Heijboer, H, Peock, S, Cook, M, Oliver, C, Frost, D, Dunning, A, Evans, D, Eeles, R, Pichert, G, Cole, T, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Kennedy, M, Rogers, M, Side, L, Donaldson, A, Gregory, H, Godwin, A, Stoppa Lyonnet, D, Moncoutier, V, Castera, L, Mazoyer, S, Barjhoux, L, Bonadona, V, Leroux, D, Faivre, L, Lidereau, R, Nogues, C, Bignon, Y, Prieur, F, Collonge Rame, M, Venat Bouvet, L, Fert Ferrer, S, Miron, A, Buys, S, Hopper, J, Daly, M, John, E, Terry, M, Goldgar, D, Hansen, T, Jønson, L, Ejlertsen, B, Agnarsson, B, Offit, K, Kirchhoff, T, Vijai, J, Dutra Clarke, A, Przybylo, J, Montagna, M, Casella, C, Imyanitov, E, Janavicius, R, Blanco, I, Lázaro, C, Moysich, K, Karlan, B, Gross, J, Beattie, M, Schmutzler, R, Wappenschmidt, B, Meindl, A, Ruehl, I, Fiebig, B, Sutter, C, Arnold, N, Deissler, H, Varon Mateeva, R, Kast, K, Niederacher, D, Gadzicki, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Simard, J, Soucy, P, Spurdle, A, Holland, H, Chenevix Trench, G, Easton, D, Antoniou, A, Ramus, SJ, Gayther, SA, Pharoah, PDP, Sinilnikova, OM, McGuffog, L, Couch, FJ, Greene, MH, Mai, PL, Andrulis, IL, Kruse, TA, Jensen, UB, Caligo, MA, Neuhausen, SL, Ding, YC, Nathanson, KL, Domchek, SM, Rookus, MA, Tilanus Linthorst, MA, Vreeswijk, MP, Ausems, MGEM, van Os, TA, Asperen, CJ, Blok, MJ, Meijers Heijboer, HEJ, Dunning, AM, Evans, DG, Morrison, PJ, Kennedy, MJ, Rogers, MT, Side, LE, Buys, SS, Hopper, JL, Daly, MB, John, EM, Terry, MB, Hansen, TvO, Agnarsson, BA, Dutra Clarke, AVC, Przybylo, JA, Imyanitov, EN, Moysich, KB, Karlan, BY, Beattie, MS, Spurdle, AB, Easton, DF, Antoniou, AC, and ROVERSI, GAIA
Abstract: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.
Published: 2011

15. Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers

Author: Walker, LC, Fredericksen, ZS, Wang, XS, Tarrell, R, Pankratz, VS, Lindor, NM, Beesley, J, Healey, S, Chen, XQ, Fab, KC, Stoppa-Lyonnet, D, Tirapo, C, Giraud, S, Mazoyer, S, Muller, D, Fricker, JP, Delnatte, C, Schmutzler, RK, Wappenschmidt, B, Engel, C, Schonbuchner, I, Deissler, H, Meindl, A, Hogervorst, FB, Verheus, M, Hooning, Maartje, van den Ouweland, Ans, Nelen, MR, Ausems, MGEM, Aalfs, CM, van Asperen, CJ, Devilee, P, Gerrits, MM, Waisfisz, Q, Szabo, CI, Quad, MS, Easton, DF, Peock, S, Cook, M, Oliver, CT, Frost, D, Harrington, P, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Eccles, D, Ong, KR, Cook, J, Rebbeck, T, Nathanson, KL, Domchek, SM, Singer, CF, Gschwantler-Kaulich, D, Dressler, AC, Pfeiler, G, Godwin, AK, Heikkinen, T, Nevanlinna, H, Agnarsson, BA, Caligo, MA, Olsson, H, Kristoffersson, U, Liljegren, A, Arver, B, Karlsson, P, Melin, B, Sinilnikova, OM, McGuffog, L, Antoniou, AC, Chenevix-Trench, G, Spurdle, AB, Couch, FJ, Walker, LC, Fredericksen, ZS, Wang, XS, Tarrell, R, Pankratz, VS, Lindor, NM, Beesley, J, Healey, S, Chen, XQ, Fab, KC, Stoppa-Lyonnet, D, Tirapo, C, Giraud, S, Mazoyer, S, Muller, D, Fricker, JP, Delnatte, C, Schmutzler, RK, Wappenschmidt, B, Engel, C, Schonbuchner, I, Deissler, H, Meindl, A, Hogervorst, FB, Verheus, M, Hooning, Maartje, van den Ouweland, Ans, Nelen, MR, Ausems, MGEM, Aalfs, CM, van Asperen, CJ, Devilee, P, Gerrits, MM, Waisfisz, Q, Szabo, CI, Quad, MS, Easton, DF, Peock, S, Cook, M, Oliver, CT, Frost, D, Harrington, P, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Eccles, D, Ong, KR, Cook, J, Rebbeck, T, Nathanson, KL, Domchek, SM, Singer, CF, Gschwantler-Kaulich, D, Dressler, AC, Pfeiler, G, Godwin, AK, Heikkinen, T, Nevanlinna, H, Agnarsson, BA, Caligo, MA, Olsson, H, Kristoffersson, U, Liljegren, A, Arver, B, Karlsson, P, Melin, B, Sinilnikova, OM, McGuffog, L, Antoniou, AC, Chenevix-Trench, G, Spurdle, AB, and Couch, FJ
Abstract: Introduction: Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies. Methods: We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Results: SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r(2) = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, P-trend = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P-trend = 0.018). Conclusions: This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.
Published: 2010

16. Analysis of chromosome alterations and the E-cadherin and FHIT genes in lobular breast cancer

Author: Ingvarsson, S, primary, Huiping, C, additional, Jonasson, JG, additional, and Agnarsson, BA, additional
Published: 2000
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17. TP53 mutation analyses on breast carcinomas: a study of paraffin-embedded archival material

Author: Gretarsdottir, S, primary, Tryggvadottir, L, additional, Jonasson, JG, additional, Sigurdsson, H, additional, Olafsdottir, K, additional, Agnarsson, BA, additional, Ogmundsdottir, H, additional, and Eyfjörd, JE, additional
Published: 1996
Full Text: View/download PDF

18. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

Author: Rafnar, T., Tj&#248, nneland, A., Grasa, P., Mates, D., Jinga, V., Hansen, T., Sigurgeirsson, B., Nagore, E., Hemminki, K., Badescu, D., Panadero, A., Steinthorsdottir, V., J&#248, rgensen, T., Rudnai, P., Mayordomo, Ji, Stacey, Sn, Helfand, Bt, Peters, Wh, Garci&#769, a-prats, Md, Lachance, Dh, Jenkins, Rb, Agnarsson, Ba, Gurzau, E., Sulem, P., Banasik, K., Masson, G., Thorisdottir, K., Constantinescu, V., Corredera, C., Rossum, Mm, Overvad, K., Requena, C., Ragnarsson, R., Kristjansdottir, S., Jonsson, T., Planelles, D., Fuertes, F., Badea, P., Mates, In, Johannsson, Ot, Jinga, M., Rice, T., Constantin, A., Wrensch, M., Sigurdsson, H., Spronsen, Dj, Hamdy, Fc, Kumar, R., Oort, Im, Johannsdottir, H., Tryggvadottir, L., Rivera, F., Stefansson, T., Dinu, DE, Keku, To, Moller, Ph, Kosel, Ml, Csiki, Ie, Gudjonsson, Sa, Benediktsdottir, Kr, Decker, Pa, Sandler, Rs, Aben, Kk, Pedersen, O., Wiencke, J., Soriano, V., Sanambrosio, E., Navarrete, S., Garcia, A., Jonsson, E., Barkardottir, Rb, Stefansson, K., Neal, DE, Gudbjartsson, Df, Juan, A., Donovan, Jl, Codreanu, O., Lindblom, A., Fuentelsaz, V., Gudmundsson, J., Witte, Dr, Kiemeney, La, Xiao, Y., Kong, A., Jonasdottir, A., Olafsson, Jh, Cremers, Rg, Nex&#248, Einarsson, Gv, Hansen, Hm, Helgadottir, Ht, Catalona, Wj, Magnusson, Ot, O Neill, Bp, Thorleifsson, G., Sigurdsson, F., Thorsteinsdottir, U., Valdimarsson, T., Vogel, U., Jonasson, Jg, Schalken, Ja, Sigurdsson, A., and Koppova, K.

19. BRCA2 Polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Author: Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Meeks, Huong D., Song, Honglin, Michailidou, Kyriaki, Bolla, Manjeet K., Dennis, Joe G., Wang, Qin, Barrowdale, Daniel, Frost, Debra, McGuffog, Lesley, Ellis, Steve, Feng, Bingjian, Buys, Saundra S., Hopper, John Llewelyn, Southey, Melissa C., Tesoriero, Andrea A., Investigators, Kconfab Con Fab, James, Paul Andrew, Bruinsma, Fiona J., Campbell, Ian G., Broeks, Annegien, Schmidt, Marjanka K., Hogervorst, Frans B.L., Beckman, Matthias W., Fasching, Peter Andreas, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J., Riboli, Elio, Banerjee, Susana N., Menon, Usha, Tomlinson, Ian, Burwinkel, Barbara, Hamann, Ute, Marmé, Frederik, Rudolph, Anja, Janavičius, Ramūnas, Tihomirova, Laima P., Tung, Nadine M., Garber, Judy Ellen, Cramer, Daniel W., Terry, Kathryn L., Poole, Elizabeth M., Tworoger, Shelley S., Dorfling, Cecilia M., van Rensburg, Elizabeth J., Godwin, Andrew K., Guénel, Pascal, Truong, Thérèse, Stoppa-Lyonnet, Dominique, Damiola, Francesca, Mazoyer, Sylvie, Sinilnikova, Olga M., Isaacs, Claudine J.D., Maugard, Christine M., Bojesen, Stig Egil, Flyger, Henrik Lavlund, Gerdes, Anne Marie, Hansen, Thomas Van Overeem, Jensen, Allan, Kjaer, Susan K., Høgdall, Claus K., Høgdall, Estrid, Pedersen, Inge Søkilde, Thomassen, Mads, Benit́ez, Javier J., González-Neira, Anna, Osorio, Ana, de la Hoya, Miguel, Peréz-Segura, Pedro, Díez-Gibert, Orland, Lázaro, Conxi, Brunet, Joan Maria, Anton-Culver, Hoda, Eunjung, Lee, John, Esther M., Neuhausen, Susan L., Ding, YC, Castillo, Sandra D., Weitzel, JN, Ganz, PA, Nussbaum, RL, Chan, SB, Karlan, BY, Lester, J, Wu, A, Gayther, S, Ramus, SJ, Sieh, W, Whittermore, AS, Monteiro, AN, Phelan, CM, Terry, MB, Piedmonte, M, Offit, K, Robson, M, Levine, D, Moysich, KB, Cannioto, R, Olson, SH, Daly, MB, Nathanson, KL, Domchek, SM, Lu, KH, Liang, D, Hildebrant, MA, Ness, R, Modugno, F, Pearce, L, Goodman, MT, Thompson, PJ, Brenner, H, Butterbach, K, Meindl, A, Hahnen, E, Wappenschmidt, B, Brauch, H, Brüning, T, Blomqvist, C, Khan, S, Nevanlinna, H, Pelttari, LM, Aittomäki, K, Butzow, R, Bogdanova, NV, Dörk, T, Lindblom, A, Margolin, S, Rantala, J, Kosma, VM, Mannermaa, A, Lambrechts, D, Neven, P, Claes, KB, Maerken, TV, Chang-Claude, J, Flesch-Janys, D, Heitz, F, Varon-Mateeva, R, Peterlongo, P, Radice, P, Viel, A, Barile, M, Peissel, B, Manoukian, S, Montagna, M, Oliani, C, Peixoto, A, Teixeira, MR, Collavoli, A, Hallberg, E, Olson, JE, Goode, EL, Hart, SN, Shimelis, H, Cunningham, JM, Giles, GG, Milne, RL, Healey, S, Tucker, K, Haiman, CA, Henderson, BE, Goldberg, MS, Tischkowitz, M, Simard, J, Soucy, P, Eccles, DM, Le, N, Borresen-Dale, AL, Kristensen, V, Salvesen, HB, Bjorge, L, Bandera, EV, Risch, H, Zheng, W, Beeghly-Fadiel, A, Cai, H, Pylkäs, K, Tollenaar, RA, Ouweland, AM, Andrulis, IL, Knight, JA, OCGN, Narod, S, Devilee, P, Winqvist, R, Figueroa, J, Greene, MH, Mai, PL, Loud, JT, García-Closas, M, Schoemaker, MJ, Czene, K, Darabi, H, McNeish, I, Siddiquil, N, Glasspool, R, Kwong, A, Park, SK, Teo, SH, Yoon, SY, Matsuo, K, Hosono, S, Woo, YL, Gao, YT, Foretova, L, Singer, CF, Rappaport-Feurhauser, C, Friedman, E, Laitman, Y, Rennert, G, Imyanitov, EN, Hulick, PJ, Olopade, OI, Senter, L, Olah, E, Doherty, JA, Schildkraut, J, Koppert, LB, Kiemeney, LA, Massuger, LF, Cook, LS, Pejovic, T, Li, J, Borg, A, Öfverholm, A, Rossing, MA, Wentzensen, N, Henriksson, K, Cox, A, Cross, SS, Pasini, BJ, Shah, M, Kabisch, M, Torres, D, Jakubowska, A, Lubinski, J, Gronwald, J, Agnarsson, BA, Kupryjanczyk, J, Moes-Sosnowska, J, Fostira, F, Konstantopoulou, I, Slager, S, Jones, M, PRostate cancer AssoCiation group To Investigate Cancer Associated aLterations in the genome, Antoniou, AC, Berchuck, A, Swerdlow, A, Chenevix-Trench, G, Dunning, AM, Pharoah, PD, Hall, P, Easton, DF, Couch, FJ, Spurdle, AB, Goldgar, DE., Australia Ovarian Cancer Study Group, HEBON, EMBRACE, Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Meeks, Huong D., Song, Honglin, Michailidou, Kyriaki, Bolla, Manjeet K., Dennis, Joe G., Wang, Qin, Barrowdale, Daniel, Frost, Debra, McGuffog, Lesley, Ellis, Steve, Feng, Bingjian, Buys, Saundra S., Hopper, John Llewelyn, Southey, Melissa C., Tesoriero, Andrea A., Investigators, Kconfab Con Fab, James, Paul Andrew, Bruinsma, Fiona J., Campbell, Ian G., Broeks, Annegien, Schmidt, Marjanka K., Hogervorst, Frans B.L., Beckman, Matthias W., Fasching, Peter Andreas, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J., Riboli, Elio, Banerjee, Susana N., Menon, Usha, Tomlinson, Ian, Burwinkel, Barbara, Hamann, Ute, Marmé, Frederik, Rudolph, Anja, Janavičius, Ramūnas, Tihomirova, Laima P., Tung, Nadine M., Garber, Judy Ellen, Cramer, Daniel W., Terry, Kathryn L., Poole, Elizabeth M., Tworoger, Shelley S., Dorfling, Cecilia M., van Rensburg, Elizabeth J., Godwin, Andrew K., Guénel, Pascal, Truong, Thérèse, Stoppa-Lyonnet, Dominique, Damiola, Francesca, Mazoyer, Sylvie, Sinilnikova, Olga M., Isaacs, Claudine J.D., Maugard, Christine M., Bojesen, Stig Egil, Flyger, Henrik Lavlund, Gerdes, Anne Marie, Hansen, Thomas Van Overeem, Jensen, Allan, Kjaer, Susan K., Høgdall, Claus K., Høgdall, Estrid, Pedersen, Inge Søkilde, Thomassen, Mads, Benit́ez, Javier J., González-Neira, Anna, Osorio, Ana, de la Hoya, Miguel, Peréz-Segura, Pedro, Díez-Gibert, Orland, Lázaro, Conxi, Brunet, Joan Maria, Anton-Culver, Hoda, Eunjung, Lee, John, Esther M., Neuhausen, Susan L., Ding, YC, Castillo, Sandra D., Weitzel, JN, Ganz, PA, Nussbaum, RL, Chan, SB, Karlan, BY, Lester, J, Wu, A, Gayther, S, Ramus, SJ, Sieh, W, Whittermore, AS, Monteiro, AN, Phelan, CM, Terry, MB, Piedmonte, M, Offit, K, Robson, M, Levine, D, Moysich, KB, Cannioto, R, Olson, SH, Daly, MB, Nathanson, KL, Domchek, SM, Lu, KH, Liang, D, Hildebrant, MA, Ness, R, Modugno, F, Pearce, L, Goodman, MT, Thompson, PJ, Brenner, H, Butterbach, K, Meindl, A, Hahnen, E, Wappenschmidt, B, Brauch, H, Brüning, T, Blomqvist, C, Khan, S, Nevanlinna, H, Pelttari, LM, Aittomäki, K, Butzow, R, Bogdanova, NV, Dörk, T, Lindblom, A, Margolin, S, Rantala, J, Kosma, VM, Mannermaa, A, Lambrechts, D, Neven, P, Claes, KB, Maerken, TV, Chang-Claude, J, Flesch-Janys, D, Heitz, F, Varon-Mateeva, R, Peterlongo, P, Radice, P, Viel, A, Barile, M, Peissel, B, Manoukian, S, Montagna, M, Oliani, C, Peixoto, A, Teixeira, MR, Collavoli, A, Hallberg, E, Olson, JE, Goode, EL, Hart, SN, Shimelis, H, Cunningham, JM, Giles, GG, Milne, RL, Healey, S, Tucker, K, Haiman, CA, Henderson, BE, Goldberg, MS, Tischkowitz, M, Simard, J, Soucy, P, Eccles, DM, Le, N, Borresen-Dale, AL, Kristensen, V, Salvesen, HB, Bjorge, L, Bandera, EV, Risch, H, Zheng, W, Beeghly-Fadiel, A, Cai, H, Pylkäs, K, Tollenaar, RA, Ouweland, AM, Andrulis, IL, Knight, JA, OCGN, Narod, S, Devilee, P, Winqvist, R, Figueroa, J, Greene, MH, Mai, PL, Loud, JT, García-Closas, M, Schoemaker, MJ, Czene, K, Darabi, H, McNeish, I, Siddiquil, N, Glasspool, R, Kwong, A, Park, SK, Teo, SH, Yoon, SY, Matsuo, K, Hosono, S, Woo, YL, Gao, YT, Foretova, L, Singer, CF, Rappaport-Feurhauser, C, Friedman, E, Laitman, Y, Rennert, G, Imyanitov, EN, Hulick, PJ, Olopade, OI, Senter, L, Olah, E, Doherty, JA, Schildkraut, J, Koppert, LB, Kiemeney, LA, Massuger, LF, Cook, LS, Pejovic, T, Li, J, Borg, A, Öfverholm, A, Rossing, MA, Wentzensen, N, Henriksson, K, Cox, A, Cross, SS, Pasini, BJ, Shah, M, Kabisch, M, Torres, D, Jakubowska, A, Lubinski, J, Gronwald, J, Agnarsson, BA, Kupryjanczyk, J, Moes-Sosnowska, J, Fostira, F, Konstantopoulou, I, Slager, S, Jones, M, PRostate cancer AssoCiation group To Investigate Cancer Associated aLterations in the genome, Antoniou, AC, Berchuck, A, Swerdlow, A, Chenevix-Trench, G, Dunning, AM, Pharoah, PD, Hall, P, Easton, DF, Couch, FJ, Spurdle, AB, Goldgar, DE., Australia Ovarian Cancer Study Group, HEBON, and EMBRACE

20. Analysis of chromosome alterations and the E-cadherinand FHITgenes in lobular breast cancer

Author: Ingvarsson, S, Huiping, C, Jonasson, JG, and Agnarsson, BA
Published: 2000
Full Text: View/download PDF

21. Monoclonal gammopathy of undetermined significance with multiple paraproteins: A population-based screening study.

Author: Rögnvaldsson S, Óskarsson JÞ, Thorsteinsdóttir S, Hultcrantz M, Palmason R, Sverrisdottir IS, Eythorsson E, Long TE, Olafsson I, Thorsteinsdottir I, Vidarsson B, Onundarson PT, Agnarsson BA, Sigurdardottir M, Jonsson A, Durie BGM, Harding S, Landgren O, Love TJ, and Kristinsson SY
Abstract: Monoclonal gammopathy of undetermined significance (MGUS) is the precursor of multiple myeloma (MM) and related disorders. MGUS is characterized by asymptomatic paraproteinemia. In some cases, multiple paraproteins can be identified but the clinical implications of this phenomenon are poorly understood. In this study, we aim to inform the approach to this challenging MGUS subgroup by utilizing data from iStopMM, a population-based screening study and randomized trial of follow-up strategies. In total, 75,422 Icelanders over the age of 40 were screened for MGUS with 3389 (4.4%) having at least one paraprotein of whom 303 (9%) had multiple paraproteins. IgM paraproteins were more common in those with multiple paraproteins (49% vs. 27% of paraproteins, p < 0.001), and IgM and non-IgM paraproteins frequently co-occurred (60% of cases). Two-thirds of these participants were randomized to active follow-up where only 31% of multiple paraproteins were persistent. Paraprotein concentrations were mostly independent, and although progression events were few, the progression rate was similar between those with multiple paraproteins and a single paraprotein. In a next-generation flow cytometry (NGF) sub-study, two phenotypically distinct aberrant plasma cell populations could be identified in some with multiple paraproteins. The findings suggest that multiple paraproteins often reflect independent ongoing disease processes that should be monitored independently but otherwise treated similarly to other MGUS cases. Specifically, the findings highlight the need for independent monitoring of IgM and non-IgM paraproteins in these individuals. The study provides novel insights into the management of this understudied MGUS subset., Competing Interests: Sæmundur Rögnvaldsson: Honoraria for scientific talks: Siemens Healthineers and Johnson & Johnson. Malin Hultcrantz: Amgen, GlaxoSmithKline, Daiichi Sankyo Company–Research grant; Bristol‐Meyers Squibb, Curio Science, GlaxoSmithKline, Intellisphere–consultant/advisor. Stephen Harding: Current employment at The BindingsSite Ltd. Ola Landgren: Research funding from NCI/NIH, FDA, LLS, Rising Tide Foundation, MMRF, IMF, Paula and Rodger Riney Foundation, Tow Foundation, Myeloma Solutions Fund, Perelman Family Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, Karyopharm; Honoraria for scientific talks/participated in advisory boards for: Adaptive, Amgen, Binding Site, BMS, Celgene, Cellectis, Glenmark, Janssen, Juno, Pfizer; Independent Data Monitoring Committees for: Takeda, Merck, Janssen. Sigurdur Y. Kristinsson: Research funding from Amgen and Celgene; Independent Data Monitoring Committee for Jansen., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)
Published: 2024
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22. Gene-based burden tests of rare germline variants identify six cancer susceptibility genes.

Author: Ivarsdottir EV, Gudmundsson J, Tragante V, Sveinbjornsson G, Kristmundsdottir S, Stacey SN, Halldorsson GH, Magnusson MI, Oddsson A, Walters GB, Sigurdsson A, Saevarsdottir S, Beyter D, Thorleifsson G, Halldorsson BV, Melsted P, Stefansson H, Jonsdottir I, Sørensen E, Pedersen OB, Erikstrup C, Bøgsted M, Pøhl M, Røder A, Stroomberg HV, Gögenur I, Hillingsø J, Bojesen SE, Lassen U, Høgdall E, Ullum H, Brunak S, Ostrowski SR, Sonderby IE, Frei O, Djurovic S, Havdahl A, Moller P, Dominguez-Valentin M, Haavik J, Andreassen OA, Hovig E, Agnarsson BA, Hilmarsson R, Johannsson OT, Valdimarsson T, Jonsson S, Moller PH, Olafsson JH, Sigurgeirsson B, Jonasson JG, Tryggvason G, Holm H, Sulem P, Rafnar T, Gudbjartsson DF, and Stefansson K
Subjects: Humans, Female, Male, United Kingdom epidemiology, Iceland, Norway, Case-Control Studies, Autophagy genetics, Genetic Predisposition to Disease, Germ-Line Mutation, Neoplasms genetics
Abstract: Discovery of cancer risk variants in the sequence of the germline genome can shed light on carcinogenesis. Here we describe gene burden association analyses, aggregating rare missense and loss of function variants, at 22 cancer sites, including 130,991 cancer cases and 733,486 controls from Iceland, Norway and the United Kingdom. We identified four genes associated with increased cancer risk; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer and CMTR2 for both lung cancer and cutaneous melanoma. Further, we found genes with rare variants that associate with decreased risk of cancer; AURKB for any cancer, irrespective of site, and PPP1R15A for breast cancer, suggesting that inhibition of PPP1R15A may be a preventive strategy for breast cancer. Our findings pinpoint several new cancer risk genes and emphasize autophagy, apoptosis and cell stress response as a focus point for developing new therapeutics., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2024
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23. Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden.

Author: Rögnvaldsson S, Thorsteinsdóttir S, Syriopoulou E, Sverrisdottir I, Turesson I, Eythorsson E, Oskarsson JT, Long TE, Vidarsson B, Onundarson PT, Agnarsson BA, Sigurdardottir M, Olafsson I, Thorsteinsdottir I, Aspelund T, Gislason GK, Olafsson A, Sigurdsson JK, Hultcrantz M, Durie BGM, Harding S, Bjorkholm M, Landgren O, Love TJ, and Kristinsson SY
Subjects: Humans, Iceland epidemiology, Sweden epidemiology, Male, Female, Middle Aged, Aged, Risk Factors, Multiple Myeloma epidemiology, Multiple Myeloma diagnosis, Multiple Myeloma etiology, Neoplasms epidemiology, Neoplasms etiology, Neoplasms diagnosis, Disease Progression, Adult, Population Surveillance, Monoclonal Gammopathy of Undetermined Significance epidemiology, Monoclonal Gammopathy of Undetermined Significance diagnosis
Abstract: There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with a higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore constitute a target population for MGUS screening. This two-part study is the first study to evaluate a relationship between MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio=1.10; 95% confidence interval: 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer was associated with progression of MGUS, except for myeloid malignancies which were associated with a lower risk of progression (hazard ratio=0.37; 95% confidence interval: 0.16-0.89; P=0.028). Our findings indicate that a prior cancer is not a significant etiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.
Published: 2024
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24. Association Between Autoimmune Diseases and Monoclonal Gammopathy of Undetermined Significance : An Analysis From a Population-Based Screening Study.

Author: Sverrisdottir I, Thorsteinsdottir S, Rognvaldsson S, Aspelund T, Vidarsson B, Onundarson PT, Agnarsson BA, Sigurdardottir M, Thorsteinsdóttir I, Sveinsdottir SV, Palmason R, Olafsson I, Sigurdsson F, Thordardóttir AR, Eythorsson E, Jonsson A, Palsson R, Indridason OS, Gislason GK, Olafsson A, Sigurdsson J, Steingrímsdóttir H, Einarsson Long T, Hultcrantz M, Durie BGM, Harding S, Landgren O, Kristinsson SY, and Love TJ
Subjects: Humans, Male, Female, Iceland epidemiology, Middle Aged, Cross-Sectional Studies, Aged, Adult, Prevalence, Prospective Studies, Autoimmune Diseases epidemiology, Autoimmune Diseases complications, Autoimmune Diseases diagnosis, Monoclonal Gammopathy of Undetermined Significance epidemiology, Monoclonal Gammopathy of Undetermined Significance diagnosis, Monoclonal Gammopathy of Undetermined Significance complications, Mass Screening methods
Abstract: Background: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. In previous registry-based, retrospective studies, autoimmune diseases have been associated with MGUS. However, these studies were not based on a screened population and are therefore prone to ascertainment bias., Objective: To examine whether MGUS is associated with autoimmune diseases., Design: A cross-sectional study within iStopMM (Iceland Screens, Treats, or Prevents MM), a prospective, population-based screening study of MGUS., Setting: Icelandic population of adults aged 40 years or older., Patients: 75 422 persons screened for MGUS., Measurements: Poisson regression for prevalence ratios (PRs) of MGUS among persons with or without an autoimmune disease, adjusted for age and sex., Results: A total of 10 818 participants had an autoimmune disorder, of whom 599 had MGUS (61 with a prior clinical diagnosis and 538 diagnosed at study screening or evaluation). A diagnosis of an autoimmune disease was not associated with MGUS (PR, 1.05 [95% CI, 0.97 to 1.15]). However, autoimmune disease diagnoses were associated with a prior clinical diagnosis of MGUS (PR, 2.11 [CI, 1.64 to 2.70])., Limitation: Registry data were used to gather information on autoimmune diseases, and the homogeneity of the Icelandic population may limit the generalizability of these results., Conclusion: The study did not find an association between autoimmune disease and MGUS in a systematically screened population. Previous studies not done in systematically screened populations have likely been subject to ascertainment bias. The findings indicate that recommendations to routinely screen patients with autoimmune disease for MGUS may not be warranted., Primary Funding Source: The International Myeloma Foundation and the European Research Council., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2867.
Published: 2024
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25. Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

Author: Eythorsson E, Rognvaldsson S, Thorsteinsdottir S, Einarsson Long T, Reed ER, Sigurdardottir GA, Vidarsson B, Onundarson PT, Agnarsson BA, Sigurdardottir M, Olafsson I, Thorsteinsdottir I, Sveinsdottir SV, Sigurdsson F, Thordardottir AR, Palsson R, Indridason OS, Jonsson A, Gislason GK, Olafsson A, Sigurdsson J, Steingrimsdottir H, Hultcrantz M, Durie BGM, Harding S, Landgren O, Aspelund T, Love TJ, and Kristinsson SY
Subjects: Adult, Humans, Bone Marrow, Cohort Studies, Prospective Studies, Immunoglobulin A, Immunoglobulin G, Disease Progression, Monoclonal Gammopathy of Undetermined Significance diagnosis, Monoclonal Gammopathy of Undetermined Significance epidemiology, Multiple Myeloma diagnosis, Multiple Myeloma epidemiology, Multiple Myeloma therapy, Smoldering Multiple Myeloma, Paraproteinemias
Abstract: Background: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management., Objective: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model., Design: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597)., Setting: Icelandic population of adults aged 40 years or older., Patients: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample., Measurements: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater., Results: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds., Limitation: The prediction model will require external validation., Conclusion: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology., Primary Funding Source: International Myeloma Foundation and the European Research Council., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2540.
Published: 2024
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26. A Breast Cancer Candidate Locus at 6q Narrowed to 6q15-q21.

Author: Csuka D, Freysteinsdottir ES, Johannesdottir G, Agnarsson BA, Johannsson OT, Barkardottir RB, and Arason A
Subjects: Humans, Middle Aged, Female, Genes, BRCA2, Haplotypes, Breast, Breast Neoplasms genetics
Abstract: Although a number of high-risk breast cancer genes have been identified, including BRCA1 and BRCA2 , the risk profile of many high-risk families cannot be explained using known breast cancer genes. Previously, we have shown strong indications of new breast cancer risk loci at chromosomes 2p, 6q, and 14q in a family of six generations including 10 breast cancer cases. In this study, we identified and traced four new family branches descending from siblings of the parents in the top generation of the studied family. One distantly related branch included four breast cancer cases, two of whom were diagnosed at age < 45 years. DNA samples from the cases were typed at selected polymorphic markers from all three chromosome loci, to test identical origin of the haplotypes. All four cases were shown to segregate a common 6q haplotype with a region identical to the previously identified 6q haplotype. The data strongly support a new breast cancer locus at 6q, and narrow it down to a 17 MB interval at 6q15-q21.
Published: 2024
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27. Disease associations with monoclonal gammopathy of undetermined significance can only be evaluated using screened cohorts: results from the population-based iStopMM study.

Author: Sigurbergsdóttir AÝ, Rögnvaldsson S, Thorsteinsdóttir S, Sverrisdóttir I, Sigurðardóttir GÁ, Viðarsson B, Önundarson PT, Agnarsson BA, Sigurðardóttir M, Þorsteinsdóttir I, Ólafsson Í, Þórðardóttir ÁR, Gíslason GK, Ólafsson A, Hultcrantz M, Durie BGM, Harding S, Landgren O, Löve TJ, and Kristinsson SY
Subjects: Humans, Iceland, Comorbidity, Disease Progression, Multiple Myeloma diagnosis, Multiple Myeloma epidemiology, Multiple Myeloma complications, Monoclonal Gammopathy of Undetermined Significance diagnosis, Monoclonal Gammopathy of Undetermined Significance epidemiology, Paraproteinemias diagnosis, Paraproteinemias epidemiology
Abstract: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been associated with other medical conditions. Since systematic screening is not recommended, MGUS is typically diagnosed due to underlying diseases and most cases are not diagnosed. Most previous studies on MGUS disease associations have been based on clinical cohorts, possibly resulting in selection bias. Here we estimate this selection bias by comparing clinically diagnosed and screened individuals with MGUS with regards to demographics, laboratory features, and comorbidities. A total of 75,422 participants in the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study were screened for MGUS by serum protein electrophoresis, immunofixation and free light chain assay (clinicaltrials gov. Identifier: NCT03327597). We identified 3,352 individuals with MGUS, whereof 240 had previously been clinically diagnosed (clinical MGUS), and crosslinked our data with large, nationwide registries for information on comorbidities. Those with clinical MGUS were more likely to have at least one comorbidity (odds ratio=2.24; 95% confidence interval: 1.30-4.19), and on average had more comorbidities than the screened MGUS group (3.23 vs. 2.36, mean difference 0.68; 95% confidence interval: 0.46-0.90). They were also more likely to have rheumatological disease, neurological disease, chronic kidney disease, liver disease, heart failure, or endocrine disorders. These findings indicate that individuals with clinical MGUS have more comorbidities than the general MGUS population and that previous studies have been affected by significant selection bias. Our findings highlight the importance of screening data when studying biological and epidemiological implications of MGUS.
Published: 2023
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28. Author Correction: Prevalence of smoldering multiple myeloma based on nationwide screening.

Author: Thorsteinsdóttir S, Gíslason GK, Aspelund T, Rögnvaldsson S, Óskarsson JÞ, Sigurðardóttir GÁ, Þórðardóttir ÁR, Viðarsson B, Önundarson PT, Agnarsson BA, Sigurðardóttir M, Þorsteinsdóttir I, Ólafsson Í, Eyþórsson E, Jónsson Á, Berlanga O, Hultcrantz M, Durie BGM, Löve TJ, Harding S, Landgren O, and Kristinsson SY
Published: 2023
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29. Determining hemodilution in diagnostic bone marrow aspirated samples in plasma cell disorders by next-generation flow cytometry: Proposal for a bone marrow quality index.

Author: Óskarsson JÞ, Rögnvaldsson S, Thorsteinsdottir S, Aspelund T, Gunnarsson SB, Hákonardóttir GK, Sigurðardóttir GÁ, Þórðardóttir ÁR, Gíslason GK, Ólafsson A, Sigurðsson JK, Eyþórsson E, Jónsson Á, Viðarsson B, Önundarson PT, Agnarsson BA, Pálmason R, Sigurðardóttir M, Þorsteinsdóttir I, Ólafsson Í, Harding S, Flores-Montero J, Orfao A, Durie BGM, Love TJ, and Kristinsson SY
Subjects: Humans, Flow Cytometry methods, Plasma Cells, Hemodilution, Bone Marrow Cells, Bone Marrow, Paraproteinemias
Abstract: Hemodilution of bone marrow (BM) aspirates is a limitation of multiparameter flow cytometry (MFC) in plasma cell disorders. There is a need for a validated approach for assessing sample quality and the distribution of non-plasma cell BM populations by MFC could provide a solution. We evaluated BM-associated cell populations, assessed by next-generation flow cytometry (NGF) and white blood cell (WBC) count in 351 BM aspirated samples from 219 participants with plasma cell disorders in the Iceland Screens, Treats, or Prevents MM study (iStopMM), as markers of hemodilution by their discriminatory ability between first and (generally more hemodiluted) second pull BM aspirated samples. The most discriminating markers were used to derive a novel BM quality index (BMQI). Nucleated red blood cells and myeloid precursors provided the greatest discriminatory ability between first vs second pull samples (area under the curve (AUC): 0.87 and 0.85, respectively), significantly better than B cell precursors (AUC = 0.64; p < 0.001), mast cells (AUC = 0.65; p < 0.001), and the BM WBC count (AUC = 0.77; p < 0.05). We generated a novel BMQI that is intrinsic to current NGF protocols, for evaluating quality of diagnostic BM samples and suggest the use of a BMQI scoring system for interpreting results and guiding appropriate actions., (© 2023. The Author(s).)
Published: 2023
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30. Immunohistochemical staining seems mandatory for individualizing and shortening follow-up in unilateral primary aldosteronism.

Author: Gunnarsdottir H, Agnarsson BA, Jonasdottir S, Gudmundsson J, Birgisson G, and Sigurjonsdottir HA
Abstract: Objective: The clinical significance of immunohistochemistry (IHC) for unilateral primary aldosteronism (PA) has been unclear. Individualized follow-up of PA patients could be in sight. Long-term outcomes of patients, classified based on IHC, need further investigation. We aimed to assess long-term clinical outcomes for unilateral PA, classifying patients based on IHC., Design: A nationwide observational study, with up to 16 years follow-up, executed in 2007-2016 at Landspitali University Hospital, tertiary referral center. Patients were diagnosed and treated in line with the current guidelines. Haematoxylin and eosin (H&E) tissue slides were stained using CYP11B1 and -B2 antibodies. All cases were re-evaluated and classified according to the HISTALDO consensus. Outcomes were assessed using the PASO criteria., Patients: All unilateral PA patients diagnosed in 2007-2016 in Iceland, 26 patients aged 28-73 years, who underwent adrenalectomy, were included., Measurements: Aldosterone, renin, and cortisol values, use and dosage of antihypertensives, potassium supplementation, blood pressure and serum potassium pre-intervention and throughout follow-up, and histopathology results post-adrenalectomy., Results: Following IHC, an aldosterone-producing nodule was seen in 12 adrenals, an aldosterone-producing adenoma in 10 and multiple aldosterone-producing micronodules in four. IHC altered histopathology from previous H&E diagnosis in 23% (6/26) of the patients. In total, 81% (21/26) of the patients had partial clinical success. Eight percent (2/26) of the patients needed potassium supplementation during follow-up. In the classical group, the AVS results were more determinative with significantly higher lateralization index (median 10.1 vs. 5.3, p = .04) and more contralateral suppression (median nondominant ratio 0.4 vs. 1.0, p = .03). One out of five patients with complete clinical success at 12 months post-op had severe relapse later, the other four were normotensive without antihypertensives for up to 10 years., Conclusions: We found IHC mandatory for accurate histopathologic diagnosis of PA. Our results support the importance of contralateral suppression when interpreting AVS results. Also, the study highlights the complicated assessment of clinical outcome and importance of aldosterone and renin measurements during follow-up., (© 2023 John Wiley & Sons Ltd.)
Published: 2023
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31. Histopathology and levels of proteins in plasma associate with survival after colorectal cancer diagnosis.

Author: Magnusson MI, Agnarsson BA, Jonasson JG, Tryggvason T, Aeffner F, le Roux L, Magnusdottir DN, Gunnarsdottir HS, Alexíusdóttir KK, Gunnarsdottir K, Söebech E, Runarsdottir H, Jonsdottir EM, Kristinsdottir BS, Olafsson S, Knutsdottir H, Thorsteinsdottir U, Ulfarsson MO, Gudbjartsson DF, Saemundsdottir J, Magnusson OT, Norddahl GL, Watson JEV, Rafnar T, Lund SH, and Stefansson K
Subjects: Humans, Prognosis, Proportional Hazards Models, Microsatellite Instability, Proto-Oncogene Proteins B-raf genetics, Mutation, Colorectal Neoplasms diagnosis, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism
Abstract: Background: The TNM system is used to assess prognosis after colorectal cancer (CRC) diagnosis. Other prognostic factors reported include histopathological assessments of the tumour, tumour mutations and proteins in the blood. As some of these factors are strongly correlated, it is important to evaluate the independent effects they may have on survival., Methods: Tumour samples from 2162 CRC patients were visually assessed for amount of tumour stroma, severity of lymphocytic infiltrate at the tumour margins and the presence of lymphoid follicles. Somatic mutations in the tumour were assessed for 2134 individuals. Pre-surgical levels of 4963 plasma proteins were measured in 128 individuals. The associations between these features and prognosis were inspected by a Cox Proportional Hazards Model (CPH)., Results: Levels of stroma, lymphocytic infiltration and presence of lymphoid follicles all associate with prognosis, along with high tumour mutation burden, high microsatellite instability and TP53 and BRAF mutations. The somatic mutations are correlated with the histopathology and none of the somatic mutations associate with survival in a multivariate analysis. Amount of stroma and lymphocytic infiltration associate with local invasion of tumours. Elevated levels of two plasma proteins, CA-125 and PPP1R1A, associate with a worse prognosis., Conclusions: Tumour stroma and lymphocytic infiltration variables are strongly associated with prognosis of CRC and capture the prognostic effects of tumour mutation status. CA-125 and PPP1R1A may be useful prognostic biomarkers in CRC., (© 2023. The Author(s).)
Published: 2023
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32. High Atlastin 2-2 (ATL2-2) Expression Associates with Worse Prognosis in Estrogen-Receptor-Positive Breast Cancer.

Author: Reynisdottir I, Arason A, Freysteinsdottir ES, Kristjansdottir SB, Hilmarsdottir B, Traustadottir GA, Johannsson OT, Agnarsson BA, and Barkardottir RB
Subjects: Humans, Animals, Mice, Female, Breast, Prognosis, RNA, Messenger, Estrogens, Breast Neoplasms genetics
Abstract: The disruption of endoplasmic reticulum (ER) homeostasis occurs in many human diseases. Atlastins (ATLs) maintain the branched network of the ER. The dysregulation of ATL2, located at ER network junctions, has been associated with cancer. ATL2 is necessary for lipid droplet formation in murine breast tissue. Thus, we analyzed whether ATL2 has a role in human breast cancer (BC) pathology. The expression of ATL2 variant ATL2-2 was analyzed in breast tumors from the BC cohorts of the TCGA, METABRIC, and two independent Icelandic cohorts, Cohort 1 and 2; its association with clinical, pathological, survival, and cellular pathways was explored. ATL2-2 mRNA and protein expression were higher in breast tumors than in normal tissue. ATL2-2 mRNA associated with tumor characteristics that indicate a worse prognosis. In METABRIC, high ATL2-2 mRNA levels were associated with shorter BC-specific survival (BCSS) in patients with estrogen-receptor-positive luminal breast tumors, which remained significant after correction for grade and tumor size (HR 1.334, CI 1.063-1.673). Tumors with high ATL2 mRNA showed an upregulation of hallmark pathways MYC targets v1, E2F targets, and G2M checkpoint genes. Taken together, the results suggest that high levels of ATL2-2 may support BC progression through key cancer driver pathways.
Published: 2023
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33. Correction: Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies.

Author: Rögnvaldsson S, Love TJ, Thorsteinsdottir S, Reed ER, Óskarsson JÞ, Pétursdóttir Í, Sigurðardóttir GÁ, Viðarsson B, Önundarson PT, Agnarsson BA, Sigurðardóttir M, Þorsteinsdóttir I, Ólafsson Í, Þórðardóttir ÁR, Eyþórsson E, Jónsson Á, Björnsson AS, Gunnarsson GÞ, Pálsson R, Indriðason ÓS, Gíslason GK, Ólafsson A, Hákonardóttir GK, Brinkhuis M, Halldórsdóttir SL, Ásgeirsdóttir TL, Steingrímsdóttir H, Danielsen R, Dröfn Wessman I, Kampanis P, Hultcrantz M, Durie BGM, Harding S, Landgren O, and Kristinsson SY
Published: 2023
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34. Prevalence of smoldering multiple myeloma based on nationwide screening.

Author: Thorsteinsdóttir S, Gíslason GK, Aspelund T, Rögnvaldsson S, Óskarsson JÞ, Sigurðardóttir GÁ, Þórðardóttir ÁR, Viðarsson B, Önundarson PT, Agnarsson BA, Sigurðardóttir M, Þorsteinsdóttir I, Ólafsson Í, Eyþórsson E, Jónsson Á, Berlanga O, Hultcrantz M, Durie BGM, Löve TJ, Harding S, Landgren O, and Kristinsson SY
Subjects: Humans, Female, Adult, Middle Aged, Aged, Aged, 80 and over, Prevalence, Risk Factors, Disease Progression, Smoldering Multiple Myeloma, Multiple Myeloma therapy
Abstract: Smoldering multiple myeloma (SMM) is an asymptomatic precursor to multiple myeloma. Here we define the epidemiological characteristics of SMM in the general population in Iceland. The iStopMM study (ClinicalTrials.gov ID: NCT03327597 ) is a nationwide screening study for multiple myeloma precursors where all residents in Iceland 40 years or older were invited to participate. SMM was defined as 10-60% bone marrow plasma cells and/or monoclonal (M) protein concentration ≥3 g dl -1 , in the absence of myeloma-defining events. Of the 80,759 who gave informed consent to participate, 75,422 (93%) were screened. The prevalence of SMM in the total population was 0.53% (95% confidence interval (CI) = 0.49-0.57%) in individuals 40 years or older. In men and women, the prevalence of SMM was 0.67% (95% CI = 0.62-0.73%) and 0.39% (95% CI = 0.35-0.43%), respectively; it increased with age in both sexes. For the 193 individuals with SMM, median age was 70 years (range 44-92 years) and 60% were males. The mean M protein concentration of individuals with SMM was 0.62 g dl -1 (range 0.01-3.5 g dl -1 ) and 73% had 11-20% bone marrow plasma cell infiltration. The high prevalence of SMM has implications for future treatment policies in multiple myeloma as the evidence supporting treatment initiation at the SMM stage is emerging., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2023
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35. Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study.

Author: Long TE, Indridason OS, Palsson R, Rognvaldsson S, Love TJ, Thorsteinsdottir S, Sverrisdottir IS, Vidarsson B, Onundarson PT, Agnarsson BA, Sigurdardottir M, Thorsteinsdottir I, Olafsson I, Thordardottir AR, Eythorsson E, Jonsson A, Gislason G, Olafsson A, Steingrimsdottir H, Hultcrantz M, Durie BGM, Harding S, Landgren O, and Kristinsson SY
Subjects: Humans, Immunoglobulin lambda-Chains, Prospective Studies, Reference Values, Immunoglobulin Light Chains, Renal Insufficiency, Chronic diagnosis
Abstract: Serum free light chain (FLC) concentration is greatly affected by kidney function. Using a large prospective population-based cohort, we aimed to establish a reference interval for FLCs in persons with chronic kidney disease (CKD). A total of 75422 participants of the iStopMM study were screened with serum FLC, serum protein electrophoresis and immunofixation. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. Central 99% reference intervals were determined, and 95% confidence intervals calculated. Included were 6461 (12%) participants with measured FLCs, eGFR < 60 mL/min/1.73 m 2 , not receiving renal replacement therapy, and without evidence of monoclonality. Using current reference intervals, 60% and 21% had kappa and lambda FLC values outside the normal range. The FLC ratio was outside standard reference interval (0.26-1.65) in 9% of participants and outside current kidney reference interval (0.37-3.10) in 0.7%. New reference intervals for FLC and FLC ratio were established. New reference intervals for the FLC ratio were 0.46-2.62, 0.48-3.38, and 0.54-3.30 for eGFR 45-59, 30-44, and < 30 mL/min/1.73 m 2 groups, respectively. The crude prevalence of LC-MGUS in CKD patients was 0.5%. We conclude that current reference intervals for FLC and FLC ratio are inaccurate in CKD patients and propose new eGFR based reference intervals to be implemented., (© 2022. The Author(s).)
Published: 2022
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36. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

Author: Barnes DR, Silvestri V, Leslie G, McGuffog L, Dennis J, Yang X, Adlard J, Agnarsson BA, Ahmed M, Aittomäki K, Andrulis IL, Arason A, Arnold N, Auber B, Azzollini J, Balmaña J, Barkardottir RB, Barrowdale D, Barwell J, Belotti M, Benitez J, Berthet P, Boonen SE, Borg Å, Bozsik A, Brady AF, Brennan P, Brewer C, Brunet J, Bucalo A, Buys SS, Caldés T, Caligo MA, Campbell I, Cassingham H, Christensen LL, Cini G, Claes KBM, Cook J, Coppa A, Cortesi L, Damante G, Darder E, Davidson R, de la Hoya M, De Leeneer K, de Putter R, Del Valle J, Diez O, Ding YC, Domchek SM, Donaldson A, Eason J, Eeles R, Engel C, Evans DG, Feliubadaló L, Fostira F, Frone M, Frost D, Gallagher D, Gehrig A, Giraud S, Glendon G, Godwin AK, Goldgar DE, Greene MH, Gregory H, Gross E, Hahnen E, Hamann U, Hansen TVO, Hanson H, Hentschel J, Horvath J, Izatt L, Izquierdo A, James PA, Janavicius R, Jensen UB, Johannsson OT, John EM, Kramer G, Kroeldrup L, Kruse TA, Lautrup C, Lazaro C, Lesueur F, Lopez-Fernández A, Mai PL, Manoukian S, Matrai Z, Matricardi L, Maxwell KN, Mebirouk N, Meindl A, Montagna M, Monteiro AN, Morrison PJ, Muranen TA, Murray A, Nathanson KL, Neuhausen SL, Nevanlinna H, Nguyen-Dumont T, Niederacher D, Olah E, Olopade OI, Palli D, Parsons MT, Pedersen IS, Peissel B, Perez-Segura P, Peterlongo P, Petersen AH, Pinto P, Porteous ME, Pottinger C, Pujana MA, Radice P, Ramser J, Rantala J, Robson M, Rogers MT, Rønlund K, Rump A, Sánchez de Abajo AM, Shah PD, Sharif S, Side LE, Singer CF, Stadler Z, Steele L, Stoppa-Lyonnet D, Sutter C, Tan YY, Teixeira MR, Teulé A, Thull DL, Tischkowitz M, Toland AE, Tommasi S, Toss A, Trainer AH, Tripathi V, Valentini V, van Asperen CJ, Venturelli M, Viel A, Vijai J, Walker L, Wang-Gohrke S, Wappenschmidt B, Whaite A, Zanna I, Offit K, Thomassen M, Couch FJ, Schmutzler RK, Simard J, Easton DF, Chenevix-Trench G, Antoniou AC, and Ottini L
Subjects: Aged, 80 and over, BRCA1 Protein genetics, BRCA2 Protein genetics, Genetic Predisposition to Disease, Heterozygote, Humans, Male, Mutation, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Prostatic Neoplasms epidemiology, Prostatic Neoplasms genetics
Abstract: Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers., Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk., Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions., Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management., (© The Author(s) 2021. Published by Oxford University Press.)
Published: 2022
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37. Keratinocytes secrete multiple inflammatory and immune biomarkers, which are regulated by LL-37, in a psoriasis mimicking microenvironment.

Author: Sigurgrimsdottir H, Bjornsdottir EO, Eysteinsdottir JH, Olafsson JH, Sigurgeirsson B, Agnarsson BA, Einarsdottir HK, Freysdottir J, and Ludviksson BR
Subjects: Biomarkers metabolism, Chemokines metabolism, Humans, Keratinocytes metabolism, Skin pathology, Psoriasis, Vascular Endothelial Growth Factor A metabolism
Abstract: Psoriasis is an autoimmune disease driven by a Th17 response linked to the antimicrobial peptide (AMP) LL-37 that has been connected to the induction and chronicity of psoriasis. We show that keratinocytes secrete various immune biomarkers with a direct link to psoriasis immunopathogenesis. Under pro-inflammatory microenvironmental conditions, LL-37 was found to regulate keratinocyte secretion of various immune biomarkers (eg C-X-C motif chemokine ligand (CXCL)8 and interleukin (IL)-1β) and alter extracellular signal-regulated kinase (ERK)1/2 signalling. However, during neutral conditions LL-37 induced a different pattern of keratinocyte immune biomarker secretion (eg vascular endothelial growth factor, CXCL8 and IL-6). Thus, an interesting pattern emerged regarding the immunomodulatory effects of LL-37 on keratinocytes; in general, expression of immune biomarkers that were upregulated in a Th1-like microenvironment was downregulated in the presence of LL-37. In contrast, LL-37 reinforced the Th17 response. In active psoriatic skin lesions, LL-37 expression was found to be significantly upregulated, which was also evident from the unique diffuse epidermic expression pattern not found in healthy skin. Finally, successful phototherapy of psoriasis patients converted this LL-37 inflammatory psoriatic skin pattern into a more localized basal layer expression as found in healthy controls. Thus, these findings demonstrate that LL-37 has a significant role in skin immune homeostasis and that its interplay with keratinocytes may have a more direct role in the immunopathogenesis of psoriasis than previously thought., (© 2021 The Scandinavian Foundation for Immunology.)
Published: 2021
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38. Monoclonal gammopathy of undetermined significance and COVID-19: a population-based cohort study.

Author: Rognvaldsson S, Eythorsson E, Thorsteinsdottir S, Vidarsson B, Onundarson PT, Agnarsson BA, Sigurdardottir M, Thorsteinsdóttir I, Olafsson I, Runolfsdottir HL, Helgason D, Emilsdottir AR, Agustsson AS, Bjornsson AH, Kristjansdottir G, Thordardottir AR, Indridason OS, Jonsson A, Gislason GK, Olafsson A, Steingrimsdottir H, Kampanis P, Hultcrantz M, Durie BGM, Harding S, Landgren O, Palsson R, Love TJ, and Kristinsson SY
Subjects: Adult, Aged, Cohort Studies, Female, Humans, Iceland epidemiology, Male, Middle Aged, Risk Factors, SARS-CoV-2, COVID-19 epidemiology, Monoclonal Gammopathy of Undetermined Significance epidemiology
Abstract: Multiple myeloma (MM) patients have increased risk of severe coronavirus disease 2019 (COVID-19) when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM has been associated with immune dysfunction which may lead to severe COVID-19. No systematic data have been published on COVID-19 in individuals with MGUS. We conducted a large population-based cohort study evaluating the risk of SARS-CoV-2 infection and severe COVID-19 among individuals with MGUS. We included 75,422 Icelanders born before 1976, who had been screened for MGUS in the Iceland Screens Treats or Prevents Multiple Myeloma study (iStopMM). Data on SARS-CoV-2 testing and COVID-19 severity were acquired from the Icelandic COVID-19 Study Group. Using a test-negative study design, we included 32,047 iStopMM participants who had been tested for SARS-CoV-2, of whom 1754 had MGUS. Among these participants, 1100 participants, tested positive, 65 of whom had MGUS. Severe COVID-19 developed in 230 participants, including 16 with MGUS. MGUS was not associated with SARS-CoV-2 infection (Odds ratio (OR): 1.05; 95% confidence interval (CI): 0.81-1.36; p = 0.72) or severe COVID-19 (OR: 0.99; 95%CI: 0.52-1.91; p = 0.99). These findings indicate that MGUS does not affect the susceptibility to SARS-CoV-2 or the severity of COVID-19., (© 2021. The Author(s).)
Published: 2021
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39. Hsa-miR-21-3p associates with breast cancer patient survival and targets genes in tumor suppressive pathways.

Author: Amirfallah A, Knutsdottir H, Arason A, Hilmarsdottir B, Johannsson OT, Agnarsson BA, Barkardottir RB, and Reynisdottir I
Subjects: Biomarkers, Tumor genetics, Breast Neoplasms pathology, Cancer Survivors, Cell Proliferation genetics, Cohort Studies, Down-Regulation genetics, Epithelial-Mesenchymal Transition genetics, Female, GTPase-Activating Proteins genetics, Gene Expression genetics, Humans, Lymph Nodes pathology, Breast Neoplasms genetics, MicroRNAs genetics, Signal Transduction genetics, Tumor Suppressor Proteins genetics
Abstract: Breast cancer is the cancer most often diagnosed in women. MicroRNAs (MIRs) are short RNA molecules that bind mRNA resulting in their downregulation. MIR21 has been shown to be an oncomiR in most cancer types, including breast cancer. Most of the effects of miR-21 have been attributed to hsa-miR-21-5p that is transcribed from the leading strand of MIR21, but hsa-miR-21-3p (miR-21-3p), transcribed from the lagging strand, is much less studied. The aim of the study is to analyze whether expression of miR-21-3p is prognostic for breast cancer. MiR-21-3p association with survival, clinical and pathological characteristics was analyzed in a large breast cancer cohort and validated in three separate cohorts, including TCGA and METABRIC. Analytical tools were also used to infer miR-21-3p function and to identify potential target genes and functional pathways. The results showed that in the exploration cohort, high miR-21-3p levels associated with shorter survival and lymph node positivity. In the three validation cohorts, high miR-21-3p levels associated with pathological characteristics that predict worse prognosis. Specifically, in the largest validation cohort, METABRIC (n = 1174), high miR-21-3p levels associated with large tumors, a high grade, lymph node and HER2 positivity, and shorter breast-cancer-specific survival (HR = 1.38, CI 1.13-1.68). This association remained significant after adjusting for confounding factors. The genes with expression levels that correlated with miR-21-3p were enriched in particular pathways, including the epithelial-to-mesenchymal transition and proliferation. Among the most significantly downregulated targets were MAT2A and the tumor suppressive genes STARD13 and ZNF132. The results from this study emphasize that both 3p- and 5p-arms from a MIR warrant independent study. The data show that miR-21-3p overexpression in breast tumors is a marker of worse breast cancer progression and it affects genes in pathways that drive breast cancer by down-regulating tumor suppressor genes. The results suggest miR-21-3p as a potential biomarker., Competing Interests: The authors have declared that no competing interests exist.
Published: 2021
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40. Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies.

Author: Rögnvaldsson S, Love TJ, Thorsteinsdottir S, Reed ER, Óskarsson JÞ, Pétursdóttir Í, Sigurðardóttir GÁ, Viðarsson B, Önundarson PT, Agnarsson BA, Sigurðardóttir M, Þorsteinsdóttir I, Ólafsson Í, Þórðardóttir ÁR, Eyþórsson E, Jónsson Á, Björnsson AS, Gunnarsson GÞ, Pálsson R, Indriðason ÓS, Gíslason GK, Ólafsson A, Hákonardóttir GK, Brinkhuis M, Halldórsdóttir SL, Ásgeirsdóttir TL, Steingrímsdóttir H, Danielsen R, Dröfn Wessman I, Kampanis P, Hultcrantz M, Durie BGM, Harding S, Landgren O, and Kristinsson SY
Subjects: Adult, Aged, Aged, 80 and over, Disease Progression, Female, Follow-Up Studies, Humans, Iceland epidemiology, Male, Middle Aged, Monoclonal Gammopathy of Undetermined Significance epidemiology, Multiple Myeloma epidemiology, Multiple Myeloma prevention & control, Risk Factors, Monoclonal Gammopathy of Undetermined Significance diagnosis, Multiple Myeloma diagnosis
Abstract: Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.
Published: 2021
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41. In situ breast cancer incidence patterns in Iceland and differences in ductal carcinoma in situ treatment compared to Sweden.

Author: Agustsson AS, Birgisson H, Agnarsson BA, Jonsson T, Stefansdottir H, Wärnberg F, Lambe M, Tryggvadottir L, and Sverrisdottir A
Subjects: Adult, Aged, Breast Neoplasms surgery, Carcinoma, Intraductal, Noninfiltrating surgery, Early Detection of Cancer, Female, Humans, Iceland epidemiology, Incidence, Mass Screening, Middle Aged, Sweden epidemiology, Breast Neoplasms epidemiology, Carcinoma, Intraductal, Noninfiltrating epidemiology, Mastectomy
Abstract: The purpose was to review the incidence of in situ carcinoma in Iceland after initiating population-based mammography screening in 1987 and to compare management of ductal carcinoma in situ (DCIS) between Iceland and the Uppsala-Örebro region (UÖR) in Central Sweden. The Icelandic Cancer Registry provided data on in situ breast carcinomas for women between 1957 and 2017. Clinical data for women with DCIS between 2008 and 2014 was extracted from hospital records and compared to women diagnosed in UÖR. In Iceland, in situ carcinoma incidence increased from 7 to 30 per 100 000 women per year, following the introduction of organised mammography screening. The proportion of in situ carcinoma of all breast carcinomas increased from 4 to 12%. More than one third (35%) of women diagnosed with DCIS in Iceland were older than 70 years versus 18% in UÖR. In Iceland, 49% of all DCIS women underwent mastectomy compared to 40% in UÖR. The incidence of in situ carcinoma in Iceland increased four-fold after the uptake of population-based mammography screening causing considerable risk of overtreatment. Differences in treatment of DCIS were seen between Iceland and UÖR, revealing the importance of quality registration for monitoring patterns of management.
Published: 2020
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42. [Comparison of diagnosis and treatment of invasive breast cancer between Iceland and Sweden].

Author: Gisladottir LD, Birgisson H, Agnarsson BA, Jonsson T, Tryggvadottir L, and Sverrisdottir A
Subjects: Adult, Aged, Breast Neoplasms epidemiology, Breast Neoplasms pathology, Female, Humans, Iceland epidemiology, Lymphatic Metastasis, Mastectomy adverse effects, Middle Aged, Neoplasm Invasiveness, Predictive Value of Tests, Quality Indicators, Health Care trends, Radiotherapy, Adjuvant trends, Registries, Retrospective Studies, Sweden epidemiology, Time Factors, Treatment Outcome, Tumor Burden, Breast Neoplasms diagnosis, Breast Neoplasms surgery, Early Detection of Cancer trends, Healthcare Disparities trends, Mastectomy trends, Practice Patterns, Physicians' trends
Abstract: Purpose: As part of the implementation of quality registration in Iceland we used retrospective data to compare diagnosis and treatment of invasive breast cancer between Iceland and Sweden., Materials and Methods: Information on all patients diagnosed with invasive breast cancer in Iceland 2016-2017 was obtained from the Icelandic Cancer Registry. Hospital records were used to register variables in an electronic form adapted from the Swedish quality registration, and compared with data from Sweden for the same period. A chi-square test was used to compare ratios., Results: A total of 486 cases of breast cancer were diagnosed in Iceland and 15.325 in Sweden. A lower proportion of 40-69 year old women were diagnosed within the screening programme in Iceland (46%) compared to Sweden (60%) (p<0.01). Multidisciplinary tumor board meetings held before and after surgery were less frequent in Iceland (92% vs. 96%) compared to Sweden (98% vs. 99%) in 2016 (p<0,01) but no difference was seen in 2017. A sentinel node surgery was done in 69% of the cases in Iceland compared to 94% in Sweden (p<0,01). For cancers ≤30mm breast conserving surgery was done in 48% cases in Iceland but 80% in Sweden (p<0,01). In Iceland 87% of the cases had radiation therapy after breast conserving surgery but 94% in Sweden (p<0,01). Among mastectomy patients with lymph node metastases, 49% received radiation therapy in Iceland compared to 83% in Sweden (p<0,01)., Conclusion: Differences were seen in several areas of diagnosis and treatment of invasive breast cancer between Iceland and Sweden. With quality registration it will be possible to monitor and set goals for the diagnosis and treatment, with the aim of providing the best treatment to as many patients as possible.
Published: 2020
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43. Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Author: Silvestri V, Leslie G, Barnes DR, Agnarsson BA, Aittomäki K, Alducci E, Andrulis IL, Barkardottir RB, Barroso A, Barrowdale D, Benitez J, Bonanni B, Borg A, Buys SS, Caldés T, Caligo MA, Capalbo C, Campbell I, Chung WK, Claes KBM, Colonna SV, Cortesi L, Couch FJ, de la Hoya M, Diez O, Ding YC, Domchek S, Easton DF, Ejlertsen B, Engel C, Evans DG, Feliubadalò L, Foretova L, Fostira F, Géczi L, Gerdes AM, Glendon G, Godwin AK, Goldgar DE, Hahnen E, Hogervorst FBL, Hopper JL, Hulick PJ, Isaacs C, Izquierdo A, James PA, Janavicius R, Jensen UB, John EM, Joseph V, Konstantopoulou I, Kurian AW, Kwong A, Landucci E, Lesueur F, Loud JT, Machackova E, Mai PL, Majidzadeh-A K, Manoukian S, Montagna M, Moserle L, Mulligan AM, Nathanson KL, Nevanlinna H, Ngeow J, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Osorio A, Papi L, Park SK, Pedersen IS, Perez-Segura P, Petersen AH, Pinto P, Porfirio B, Pujana MA, Radice P, Rantala J, Rashid MU, Rosenzweig B, Rossing M, Santamariña M, Schmutzler RK, Senter L, Simard J, Singer CF, Solano AR, Southey MC, Steele L, Steinsnyder Z, Stoppa-Lyonnet D, Tan YY, Teixeira MR, Teo SH, Terry MB, Thomassen M, Toland AE, Torres-Esquius S, Tung N, van Asperen CJ, Vega A, Viel A, Vierstraete J, Wappenschmidt B, Weitzel JN, Wieme G, Yoon SY, Zorn KK, McGuffog L, Parsons MT, Hamann U, Greene MH, Kirk JA, Neuhausen SL, Rebbeck TR, Tischkowitz M, Chenevix-Trench G, Antoniou AC, Friedman E, and Ottini L
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, Germ-Line Mutation, Humans, Male, Middle Aged, Neoplasms diagnosis, Phenotype, Retrospective Studies, Young Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Neoplasms genetics
Abstract: Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population., Objective: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers., Design, Setting, and Participants: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected., Main Outcomes and Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview., Results: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier., Conclusions and Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.
Published: 2020
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44. ECM1 secreted by HER2-overexpressing breast cancer cells promotes formation of a vascular niche accelerating cancer cell migration and invasion.

Author: Steinhaeuser SS, Morera E, Budkova Z, Schepsky A, Wang Q, Rolfsson O, Riedel A, Krueger A, Hilmarsdottir B, Maelandsmo GM, Valdimarsdottir B, Sigurdardottir AK, Agnarsson BA, Jonasson JG, Ingthorsson S, Traustadottir GA, Oskarsson T, and Gudjonsson T
Subjects: Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Cell Movement genetics, Extracellular Matrix Proteins genetics, Female, Humans, Receptor, ErbB-2 genetics, Breast Neoplasms metabolism, Extracellular Matrix Proteins metabolism, Neoplasm Invasiveness genetics, Receptor, ErbB-2 metabolism, Tumor Microenvironment genetics
Abstract: The tumor microenvironment is increasingly recognized as key player in cancer progression. Investigating heterotypic interactions between cancer cells and their microenvironment is important for understanding how specific cell types support cancer. Forming the vasculature, endothelial cells (ECs) are a prominent cell type in the microenvironment of both normal and neoplastic breast gland. Here, we sought out to analyze epithelial-endothelial cross talk in the breast using isogenic non-tumorigenic vs. tumorigenic breast epithelial cell lines and primary ECs. The cellular model used here consists of D492, a breast epithelial cell line with stem cell properties, and two isogenic D492-derived EMT cell lines, D492M and D492HER2. D492M was generated by endothelial-induced EMT and is non-tumorigenic while D492HER2 is tumorigenic, expressing the ErbB2/HER2 oncogene. To investigate cellular cross talk, we used both conditioned medium (CM) and 2D/3D co-culture systems. Secretome analysis of D492 cell lines was performed using mass spectrometry and candidate knockdown (KD), and overexpression (OE) was done using siRNA and CRISPRi/CRISPRa technology. D492HER2 directly enhances endothelial network formation and activates a molecular axis in ECs promoting D492HER2 migration and invasion, suggesting an endothelial feedback response. Secretome analysis identified extracellular matrix protein 1 (ECM1) as potential angiogenic inducer in D492HER2. Confirming its involvement, KD of ECM1 reduced the ability of D492HER2-CM to increase endothelial network formation and induce the endothelial feedback, while recombinant ECM1 (rECM1) increased both. Interestingly, NOTCH1 and NOTCH3 expression was upregulated in ECs upon treatment with D492HER2-CM or rECM1 but not by CM from D492HER2 with ECM1 KD. Blocking endothelial NOTCH signaling inhibited the increase in network formation and the ability of ECs to promote D492HER2 migration and invasion. In summary, our data demonstrate that cancer-secreted ECM1 induces a NOTCH-mediated endothelial feedback promoting cancer progression by enhancing migration and invasion. Targeting this interaction may provide a novel possibility to improve cancer treatment.
Published: 2020
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45. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness.

Author: Patel VL, Busch EL, Friebel TM, Cronin A, Leslie G, McGuffog L, Adlard J, Agata S, Agnarsson BA, Ahmed M, Aittomäki K, Alducci E, Andrulis IL, Arason A, Arnold N, Artioli G, Arver B, Auber B, Azzollini J, Balmaña J, Barkardottir RB, Barnes DR, Barroso A, Barrowdale D, Belotti M, Benitez J, Bertelsen B, Blok MJ, Bodrogi I, Bonadona V, Bonanni B, Bondavalli D, Boonen SE, Borde J, Borg A, Bradbury AR, Brady A, Brewer C, Brunet J, Buecher B, Buys SS, Cabezas-Camarero S, Caldés T, Caliebe A, Caligo MA, Calvello M, Campbell IG, Carnevali I, Carrasco E, Chan TL, Chu ATW, Chung WK, Claes KBM, Collaborators GS, Collaborators E, Cook J, Cortesi L, Couch FJ, Daly MB, Damante G, Darder E, Davidson R, de la Hoya M, Puppa LD, Dennis J, Díez O, Ding YC, Ditsch N, Domchek SM, Donaldson A, Dworniczak B, Easton DF, Eccles DM, Eeles RA, Ehrencrona H, Ejlertsen B, Engel C, Evans DG, Faivre L, Faust U, Feliubadaló L, Foretova L, Fostira F, Fountzilas G, Frost D, García-Barberán V, Garre P, Gauthier-Villars M, Géczi L, Gehrig A, Gerdes AM, Gesta P, Giannini G, Glendon G, Godwin AK, Goldgar DE, Greene MH, Gutierrez-Barrera AM, Hahnen E, Hamann U, Hauke J, Herold N, Hogervorst FBL, Honisch E, Hopper JL, Hulick PJ, Investigators K, Investigators H, Izatt L, Jager A, James P, Janavicius R, Jensen UB, Jensen TD, Johannsson OT, John EM, Joseph V, Kang E, Kast K, Kiiski JI, Kim SW, Kim Z, Ko KP, Konstantopoulou I, Kramer G, Krogh L, Kruse TA, Kwong A, Larsen M, Lasset C, Lautrup C, Lazaro C, Lee J, Lee JW, Lee MH, Lemke J, Lesueur F, Liljegren A, Lindblom A, Llovet P, Lopez-Fernández A, Lopez-Perolio I, Lorca V, Loud JT, Ma ESK, Mai PL, Manoukian S, Mari V, Martin L, Matricardi L, Mebirouk N, Medici V, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Miller C, Gomes DM, Montagna M, Mooij TM, Moserle L, Mouret-Fourme E, Mulligan AM, Nathanson KL, Navratilova M, Nevanlinna H, Niederacher D, Nielsen FCC, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Ong KR, Osorio A, Ott CE, Palli D, Park SK, Parsons MT, Pedersen IS, Peissel B, Peixoto A, Pérez-Segura P, Peterlongo P, Petersen AH, Porteous ME, Pujana MA, Radice P, Ramser J, Rantala J, Rashid MU, Rhiem K, Rizzolo P, Robson ME, Rookus MA, Rossing CM, Ruddy KJ, Santos C, Saule C, Scarpitta R, Schmutzler RK, Schuster H, Senter L, Seynaeve CM, Shah PD, Sharma P, Shin VY, Silvestri V, Simard J, Singer CF, Skytte AB, Snape K, Solano AR, Soucy P, Southey MC, Spurdle AB, Steele L, Steinemann D, Stoppa-Lyonnet D, Stradella A, Sunde L, Sutter C, Tan YY, Teixeira MR, Teo SH, Thomassen M, Tibiletti MG, Tischkowitz M, Tognazzo S, Toland AE, Tommasi S, Torres D, Toss A, Trainer AH, Tung N, van Asperen CJ, van der Baan FH, van der Kolk LE, van der Luijt RB, van Hest LP, Varesco L, Varon-Mateeva R, Viel A, Vierstraete J, Villa R, von Wachenfeldt A, Wagner P, Wang-Gohrke S, Wappenschmidt B, Weitzel JN, Wieme G, Yadav S, Yannoukakos D, Yoon SY, Zanzottera C, Zorn KK, D'Amico AV, Freedman ML, Pomerantz MM, Chenevix-Trench G, Antoniou AC, Neuhausen SL, Ottini L, Nielsen HR, and Rebbeck TR
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, Genetic Association Studies, Heterozygote, Humans, Male, Middle Aged, Prognosis, Risk Factors, Young Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Genetic Predisposition to Disease, Genomics methods, Mutation, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 ( BRCA1/2 ) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1 . These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual., (©2019 American Association for Cancer Research.)
Published: 2020
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46. Effective treatment with balneophototherapy and narrowband UVB monotherapy reduces skin homing Th17/Tc17 and Th22/Tc22 effector cells in peripheral blood in patients with psoriasis.

Author: Eysteinsdóttir JH, Sigurgrímsdóttir H, Einarsdóttir HK, Freysdottir J, Agnarsson BA, Ólafsson JH, Sigurgeirsson B, and Lúðvíksson BR
Subjects: Adult, Female, Hot Springs, Humans, Iceland, Inflammation, Interleukins metabolism, Leukocytes, Mononuclear metabolism, Male, Middle Aged, Psoriasis blood, Seawater, Severity of Illness Index, Skin radiation effects, T-Lymphocytes, Cytotoxic cytology, T-Lymphocytes, Cytotoxic radiation effects, Th1 Cells cytology, Th1 Cells radiation effects, Th17 Cells cytology, Interleukin-22, Balneology methods, Phototherapy methods, Psoriasis therapy, Skin cytology, Th17 Cells radiation effects, Ultraviolet Rays, Ultraviolet Therapy methods
Published: 2019
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47. The FANCM :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Author: Figlioli G, Bogliolo M, Catucci I, Caleca L, Lasheras SV, Pujol R, Kiiski JI, 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, Aittomäki 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, Balmaña J, Barkardottir RB, Barrowdale D, Barwell J, Beane Freeman LE, Beauparlant CJ, Beckmann MW, Behrens S, Benitez J, Berger R, Bermisheva M, Blanco AM, Blomqvist C, Bogdanova NV, Bojesen A, Bojesen SE, Bonanni B, Borg A, Brady AF, Brauch H, Brenner H, Brüning T, Burwinkel B, Buys SS, Caldés 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, García-Closas M, García-Sáenz JA, Gaudet MM, Gayther SA, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, Guénel P, Gutierrez-Barrera AM, Haeberle L, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hein A, Heyworth J, Hillemanns P, Hollestelle A, Hopper JL, Hosgood HD 3rd, 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 OI, Olshan AF, Olson JE, Olsson H, Osorio A, Ottini L, Peissel B, Peixoto A, Peto J, Plaseska-Karanfilska D, Pocza T, Presneau N, Pujana MA, 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, Santamariña M, Scheuner MT, Schmutzler RK, Schneider M, Scott C, Senter L, Shah M, Sharma P, Shu XO, 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, Dörk T, Schmidt MK, Easton DF, Radice P, Hahnen E, Antoniou AC, Couch FJ, Nevanlinna H, Surrallés J, and Peterlongo P
Abstract: 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., Competing Interests: Competing interestsC.I. reports consulting with AstraZeneca and Pfizer and her institution receives research support for Tesaro, AstraZeneca, and Pfizer. B.Y.K. served on Invitae Corporation’s Advisory Board from 2017 to 2018. K.P. reports receiving fee, paid to his institution, for lectures and/or participation in advisory board of AstraZeneca and Pfizer and travel support from AstraZeneca and Pfizer. Jordi Surrallés’ institution received research support from Rocket Pharmaceuticals. The remaining authors declare no competing interests., (© The Author(s) 2019.)
Published: 2019
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48. The BRCA1 c.4096+3A>G Variant Displays Classical Characteristics of Pathogenic BRCA1 Mutations in Hereditary Breast and Ovarian Cancers, But Still Allows Homozygous Viability.

Author: Arason A, Agnarsson BA, Johannesdottir G, Johannsson OT, Hilmarsdottir B, Reynisdottir I, and Barkardottir RB
Subjects: Adult, Aged, Exons, Female, Hereditary Breast and Ovarian Cancer Syndrome pathology, Heterozygote, Humans, Iceland, Loss of Heterozygosity, Middle Aged, Pedigree, BRCA1 Protein genetics, Hereditary Breast and Ovarian Cancer Syndrome genetics, Homozygote, Point Mutation
Abstract: Mutations in BRCA1 result in predisposal to breast and ovarian cancers, but many variants exist with unknown clinical significance (VUS). One is BRCA1 c.4096+3A>G, which affects production of the full-length BRCA1 transcript, while augmenting transcripts lacking most or all of exon 11. Nonetheless, homozygosity of this variant has been reported in a healthy woman. We saw this variant cosegregate with breast and ovarian cancer in several family branches of four Icelandic pedigrees, with instances of phenocopies and a homozygous woman with lung cancer. We found eight heterozygous carriers (0.44%) in 1820 unselected breast cancer cases, and three (0.15%) in 1968 controls ( p = 0.13). Seeking conclusive evidence, we studied tumors from carriers in the pedigrees for wild-type-loss of heterozygosity (wtLOH) and BRCA1 -characteristic prevalence of estrogen receptor (ER) negativity. Of 15 breast and six ovarian tumors, wtLOH occurred in nine breast and all six ovarian tumours, and six of the nine breast tumors with wtLOH were ER-negative. These data accord with a pathogenic BRCA1 -mutation. Our findings add to the current knowledge of BRCA1 , and the role of its exon 11 in cancer pathogenicity, and will be of use in clinical genetic counselling., Competing Interests: The authors declare no conflict of interest.
Published: 2019
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49. High expression of the vacuole membrane protein 1 (VMP1) is a potential marker of poor prognosis in HER2 positive breast cancer.

Author: Amirfallah A, Arason A, Einarsson H, Gudmundsdottir ET, Freysteinsdottir ES, Olafsdottir KA, Johannsson OT, Agnarsson BA, Barkardottir RB, and Reynisdottir I
Subjects: Adult, Aged, Aged, 80 and over, Breast metabolism, Breast pathology, Breast Neoplasms pathology, Carcinogenesis genetics, Cell Line, Tumor, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic genetics, Humans, Middle Aged, Prognosis, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Membrane Proteins genetics, Receptor, ErbB-2 genetics
Abstract: Background: Fusion genes result from genomic structural changes, which can lead to alterations in gene expression that supports tumor development. The aim of the study was to use fusion genes as a tool to identify new breast cancer (BC) genes with a role in BC progression., Methods: Fusion genes from breast tumors and BC cell lines were collected from publications. RNA-Seq data from tumors and cell lines were retrieved from databanks and analyzed for fusions with SOAPfuse or the analysis was purchased. Fusion genes identified in both tumors (n = 1724) and cell lines (n = 45) were confirmed by qRT-PCR and sequencing. Their individual genes were ranked by selection criteria that included correlation of their mRNA level with copy number. The expression of the top ranked gene was measured by qRT-PCR in normal tissue and in breast tumors from an exploratory cohort (n = 141) and a validation cohort (n = 277). Expression levels were correlated with clinical and pathological factors as well as the patients' survival. The results were followed up in BC cohorts from TCGA (n = 818) and METABRIC (n = 2509)., Results: Vacuole membrane protein 1 (VMP1) was the most promising candidate based on specific selection criteria. Its expression was higher in breast tumor tissue than normal tissue (p = 1x10-4), and its expression was significantly higher in HER2 positive than HER2 negative breast tumors in all four cohorts analyzed. High expression of VMP1 associated with breast cancer specific survival (BCSS) in cohort 1 (hazard ratio (HR) = 2.31, CI 1.27-4.18) and METABRIC (HR = 1.26, CI 1.02-1.57), and also after adjusting for HER2 expression in cohort 1 (HR = 2.03, CI 1.10-3.72). BCSS was not significant in cohort 2 or TCGA cohort, which may be due to differences in treatment regimens., Conclusions: The results suggest that high VMP1 expression is a potential marker of poor prognosis in HER2 positive BC. Further studies are needed to elucidate how VMP1 could affect pathways supportive of tumorigenesis., Competing Interests: The authors have declared that no competing interests exist.
Published: 2019
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50. Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers.

Author: Qian F, Rookus MA, Leslie G, Risch HA, Greene MH, Aalfs CM, Adank MA, Adlard J, Agnarsson BA, Ahmed M, Aittomäki K, Andrulis IL, Arnold N, Arun BK, Ausems MGEM, Azzollini J, Barrowdale D, Barwell J, Benitez J, Białkowska K, Bonadona V, Borde J, Borg A, Bradbury AR, Brunet J, Buys SS, Caldés T, Caligo MA, Campbell I, Carter J, Chiquette J, Chung WK, Claes KBM, Collée JM, Collonge-Rame MA, Couch FJ, Daly MB, Delnatte C, Diez O, Domchek SM, Dorfling CM, Eason J, Easton DF, Eeles R, Engel C, Evans DG, Faivre L, Feliubadaló L, Foretova L, Friedman E, Frost D, Ganz PA, Garber J, Garcia-Barberan V, Gehrig A, Glendon G, Godwin AK, Gómez Garcia EB, Hamann U, Hauke J, Hopper JL, Hulick PJ, Imyanitov EN, Isaacs C, Izatt L, Jakubowska A, Janavicius R, John EM, Karlan BY, Kets CM, Laitman Y, Lázaro C, Leroux D, Lester J, Lesueur F, Loud JT, Lubiński J, Łukomska A, McGuffog L, Mebirouk N, Meijers-Heijboer HEJ, Meindl A, Miller A, Montagna M, Mooij TM, Mouret-Fourme E, Nathanson KL, Nehoray B, Neuhausen SL, Nevanlinna H, Nielsen FC, Offit K, Olah E, Ong KR, Oosterwijk JC, Ottini L, Parsons MT, Peterlongo P, Pfeiler G, Pradhan N, Radice P, Ramus SJ, Rantala J, Rennert G, Robson M, Rodriguez GC, Salani R, Scheuner MT, Schmutzler RK, Shah PD, Side LE, Simard J, Singer CF, Steinemann D, Stoppa-Lyonnet D, Tan YY, Teixeira MR, Terry MB, Thomassen M, Tischkowitz M, Tognazzo S, Toland AE, Tung N, van Asperen CJ, van Engelen K, van Rensburg EJ, Venat-Bouvet L, Vierstraete J, Wagner G, Walker L, Weitzel JN, Yannoukakos D, Antoniou AC, Goldgar DE, Olopade OI, Chenevix-Trench G, Rebbeck TR, and Huo D
Subjects: Adult, Aged, Female, Humans, Menopause, Middle Aged, Ovarian Neoplasms genetics, Proportional Hazards Models, Body Height, Body Mass Index, Genes, BRCA1, Genes, BRCA2, Heterozygote, Mendelian Randomization Analysis, Mutation, Ovarian Neoplasms etiology
Abstract: Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown., Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models., Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m 2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P interaction < 0.05)., Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.
Published: 2019
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