Browsing by Subject "OVARIAN"

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  • Saavalainen, Liisu; Lassus, Heini; But, Anna; Tiitinen, Aila; Harkki, Paivi; Gissier, Mika; Pukkala, Eero; Heikinheimo, Oskari (2019)
    Introduction The association between endometriosis and breast cancer is unclear. We assessed the risk of breast cancer in women with surgically verified endometriosis, with special focus on the age at cancer diagnosis, time from endometriosis diagnosis and breast cancer histology. Material and methods All women with first endometriosis-associated diagnoses occurring concomitantly with relevant surgical codes during 1987-2012 were retrieved from the Finnish Hospital Discharge Register in Finland. Breast cancers diagnosed after the endometriosis diagnosis were identified from the Finnish Cancer Registry. The Finnish female population served as the reference. The endometriosis cohort consisted of 49 933 women (23 210 cases of ovarian, 20 187 peritoneal and 2372 deep infiltrating endometriosis). The outcome measure was the standardized incidence ratio (SIR) with 95% confidence interval (95% CI) of breast cancer calculated for the whole cohort and for the subtypes of endometriosis, stratified by the age at breast cancer diagnosis, histology and time from endometriosis diagnosis. Results The overall risk of breast cancer (1555 cases) was similar to the reference population (SIR 0.99; 95% CI 0.94-1.03), did not differ in types of endometriosis, and was similar for ductal and lobular breast cancer. However, the SIR of breast cancer was increased in the age group of 20-29 years (SIR 4.44; 95% CI 2.22-7.94) and in the age group of 30-39 years (SIR 1.28; 95% CI 1.03-1.57). The risk of in situ breast cancer (170 cases) was increased in the entire endometriosis cohort (SIR 1.25; 95% CI 1.07-1.44). Conclusions The overall risk of breast cancer in women with surgically verified endometriosis was similar to that of general population. However, the risk of breast cancer at young age was increased. Young women with surgically verified endometriosis represent highly symptomatic patients with more frequent surgeries and additional therapies that might also contribute to the risk of breast cancer.
  • Blein, Sophie; Bardel, Claire; Danjean, Vincent; McGuffog, Lesley; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Dennis, Joe; Kuchenbaecker, Karoline B.; Soucy, Penny; Terry, Mary Beth; Chung, Wendy K.; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Neuhausen, Susan L.; Ding, Yuan Chun; Gerdes, Anne-Marie; Ejlertsen, Bent; Nielsen, Finn C.; Hansen, Thomas V. O.; Osorio, Ana; Benitez, Javier; Andres Conejero, Raquel; Segota, Ena; Weitzel, Jeffrey N.; Thelander, Margo; Peterlongo, Paolo; Radice, Paolo; Pensotti, Valeria; Dolcetti, Riccardo; Bonanni, Bernardo; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Manoukian, Siranoush; Varesco, Liliana; Capone, Gabriele L.; Papi, Laura; Ottini, Laura; Yannoukakos, Drakoulis; Konstantopoulou, Irene; Garber, Judy; Hamann, Ute; Donaldson, Alan; Brady, Angela; Brewer, Carole; Foo, Claire; Evans, D. Gareth; Frost, Debra; Eccles, Diana; Douglas, Fiona; Cook, Jackie; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E.; Kennedy, M. John; Tischkowitz, Marc; Rogers, Mark T.; Porteous, Mary E.; Morrison, Patrick J.; Platte, Radka; Eeles, Ros; Davidson, Rosemarie; Hodgson, Shirley; Cole, Trevor; Godwin, Andrew K.; Isaacs, Claudine; Claes, Kathleen; De Leeneer, Kim; Meindl, Alfons; Gehrig, Andrea; Wappenschmidt, Barbara; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Schmutzler, Rita K.; Preisler-Adams, Sabine; Markov, Nadja Bogdanova; Wang-Gohrke, Shan; de Pauw, Antoine; Lefol, Cedrick; Lasset, Christine; Leroux, Dominique; Rouleau, Etienne; Damiola, Francesca; Dreyfus, Helene; Barjhoux, Laure; Golmard, Lisa; Uhrhammer, Nancy; Bonadona, Valerie; Sornin, Valerie; Bignon, Yves-Jean; Carter, Jonathan; Van Le, Linda; Piedmonte, Marion; DiSilvestro, Paul A.; de la Hoya, Miguel; Caldes, Trinidad; Nevanlinna, Heli; Aittomaki, Kristiina; Jager, Agnes; van den Ouweland, Ans M. W.; Kets, Carolien M.; Aalfs, Cora M.; van Leeuwen, Flora E.; Hogervorst, Frans B. L.; Meijers-Heijboer, Hanne E. J.; Oosterwijk, Jan C.; van Roozendaal, Kees E. P.; Rookus, Matti A.; Devilee, Peter; van der Luijt, Rob B.; Olah, Edith; Diez, Orland; Teule, Alex; Lazaro, Conxi; Blanco, Ignacio; Del Valle, Jesus; Jakubowska, Anna; Sukiennicki, Grzegorz; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Agnarsson, Bjarni A.; Maugard, Christine; Amadori, Alberto; Montagna, Marco; Teixeira, Manuel R.; Spurdle, Amanda B.; Foulkes, William; Olswold, Curtis; Lindor, Noralane M.; Pankratz, Vernon S.; Szabo, Csilla I.; Lincoln, Anne; Jacobs, Lauren; Corines, Marina; Robson, Mark; Vijai, Joseph; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Imyanitov, Evgeny N.; Mulligan, Anna Marie; Glendon, Gord; Andrulis, Irene L.; Tchatchou, Sandrine; Toland, Amanda Ewart; Pedersen, Inge Sokilde; Thomassen, Mads; Kruse, Torben A.; Jensen, Uffe Birk; Caligo, Maria A.; Friedman, Eitan; Zidan, Jamal; Laitman, Yael; Lindblom, Annika; Melin, Beatrice; Arver, Brita; Loman, Niklas; Rosenquist, Richard; Olopade, Olufunmilayo I.; Nussbaum, Robert L.; Ramus, Susan J.; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Arun, Banu K.; Mitchell, Gillian; Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra; Stoppa-Lyonnet, Dominique; Thomas, Gilles; Simard, Jacques; Couch, Fergus J.; Offit, Kenneth; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Mazoyer, Sylvie; Phelan, Catherine M.; Sinilnikova, Olga M.; Cox, David G.; Breast Canc Family Registry; EMBRACE; GEMO Study Collaborators; HEBON (2015)
    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 effects.
  • Patel, V.L.; Busch, E.L.; Friebel, T.M.; Cronin, A.; Leslie, G.; McGuffog, L.; Adlard, J.; Agata, S.; Agnarsson, B.A.; Ahmed, M.; Aittomäki, K.; Alducci, E.; Andrulis, I.L.; Arason, A.; Arnold, N.; Artioli, G.; Arver, B.; Auber, B.; Azzollini, J.; Balmaña, J.; Barkardottir, R.B.; Barnes, D.R.; Barroso, A.; Barrowdale, D.; Belotti, M.; Benitez, J.; Bertelsen, B.; Blok, M.J.; Bodrogi, I.; Bonadona, V.; Bonanni, B.; Bondavalli, D.; Boonen, S.E.; Borde, J.; Borg, A.; Bradbury, A.R.; Brady, A.; Brewer, C.; Brunet, J.; Buecher, B.; Buys, S.S.; Cabezas-Camarero, S.; Caldes, T.; Caliebe, A.; Caligo, M.A.; Calvello, M.; Campbell, I.G.; Carnevali, I.; Carrasco, E.; Chan, T.L.; Chu, A.T.W.; Chung, W.K.; Claes, K.B.M.; Cook, J.; Cortesi, L.; Couch, F.J.; Daly, M.B.; Damante, G.; Darder, E.; Davidson, R.; De La Hoya, M.; Della Puppa, L.; Dennis, J.; Díez, O.; Ding, Y.C.; Ditsch, N.; Domchek, S.M.; Donaldson, A.; Dworniczak, B.; Easton, D.F.; Eccles, D.M.; Eeles, R.A.; Ehrencrona, H.; Ejlertsen, B.; Engel, C.; Evans, D.G.; Faivre, L.; Faust, U.; Feliubadalo, L.; Foretova, L.; Fostira, F.; Fountzilas, G.; Frost, D.; García-Barberan, V.; Garre, P.; Gauthier-Villars, M.; Geczi, L.; Gehrig, A.; Gerdes, A.-M.; Gesta, P.; Giannini, G.; Glendon, G.; Godwin, A.K.; Goldgar, D.E.; Greene, M.H.; Gutierrez-Barrera, A.M.; Hahnen, E.; Hamann, U.; Hauke, J.; Herold, N.; Hogervorst, F.B.L.; Honisch, E.; Hopper, J.L.; Hulick, P.J.; Izatt, L.; Jager, A.; James, P.; Janavicius, R.; Jensen, U.B.; Jensen, T.D.; Johannsson, O.Th.; John, E.M.; Joseph, V.; Kang, E.; Kast, K.; Kiiski, J.I.; Kim, S.-W.; Kim, Z.; Ko, K.-P.; Konstantopoulou, I.; Kramer, G.; Krogh, L.; Kruse, T.A.; Kwong, A.; Larsen, M.; Lasset, C.; Lautrup, C.; Lazaro, C.; Lee, J.; Lee, J.W.; Lee, M.H.; Lemke, J.; Lesueur, F.; Liljegren, A.; Lindblom, A.; Llovet, P.; Lopez-Fernandez, A.; Lopez-Perolio, I.; Lorca, V.; Loud, J.T.; Ma, E.S.K.; Mai, P.L.; Manoukian, S.; Mari, V.; Martin, L.; Matricardi, L.; Mebirouk, N.; Medici, V.; Meijers-Heijboer, H.E.J.; Meindl, A.; Mensenkamp, A.R.; Miller, C.; Gomes, D.M.; Montagna, M.; Mooij, T.M.; Moserle, L.; Mouret-Fourme, E.; Mulligan, A.M.; Nathanson, K.L.; Navratilova, M.; Nevanlinna, H.; Niederacher, D.; Cilius Nielsen, F.C.; Nikitina-Zake, L.; Offit, K.; Olah, E.; Olopade, O.I.; Ong, K.-R.; Osorio, A.; Ott, C.-E.; Palli, D.; Park, S.K.; Parsons, M.T.; Pedersen, I.S.; Peissel, B.; Peixoto, A.; Perez-Segura, P.; Peterlongo, P.; Petersen, A.H.; Porteous, M.E.; Pujana, M.A.; Radice, P.; Ramser, J.; Rantala, J.; Rashid, M.U.; Rhiem, K.; Rizzolo, P.; Robson, M.E.; Rookus, M.A.; Rossing, C.M.; Ruddy, K.J.; Santos, C.; Saule, C.; Scarpitta, R.; Schmutzler, R.K.; Schuster, H.; Senter, L.; Seynaeve, C.M.; Shah, P.D.; Sharma, P.; Shin, V.Y.; Silvestri, V.; Simard, J.; Singer, C.F.; Skytte, A.-B.; Snape, K.; Solano, A.R.; Soucy, P.; Southey, M.C.; Spurdle, A.B.; Steele, L.; Steinemann, D.; Stoppa-Lyonnet, D.; Stradella, A.; Sunde, L.; Sutter, C.; Tan, Y.Y.; Teixeira, M.R.; Teo, S.H.; Thomassen, M.; Tibiletti, M.G.; Tischkowitz, M.; Tognazzo, S.; Toland, A.E.; Tommasi, S.; Torres, D.; Toss, A.; Trainer, A.H.; Tung, N.; Van Asperen, C.J.; Van Der Baan, F.H.; Van Der Kolk, L.E.; Van Der Luijt, R.B.; Van Hest, L.P.; Varesco, L.; Varon-Mateeva, R.; Viel, A.; Vierstrate, J.; Villa, R.; Von Wachenfeldt, A.; Wagner, P.; Wang-Gohrke, S.; Wappenschmidt, B.; Weitzel, J.N.; Wieme, G.; Yadav, S.; Yannoukakos, D.; Yoon, S.-Y.; Zanzottera, C.; Zorn, K.K.; D’Amico, A.V.; Freedman, M.L.; Pomerantz, M.M.; Chenevix-Trench, G.; Antoniou, A.C.; Neuhausen, S.L.; Ottini, L.; Nielsen, H.R.; Rebbeck, T.R. (2020)
    Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 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 30 region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.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.
  • kConFab Investigators; HEBON Investigators; SWE BRCA Investigators; Muranen, Taru A.; Khan, Sofia; Fagerholm, Rainer; Aittomäki, Kristiina; Cunningham, Julie M.; Blomqvist, Carl; Nevanlinna, Heli (2020)
    Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P=3.1x10(-9)). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.
  • Yang, Xin; Leslie, Goska; Doroszuk, Alicja; Aittomäki, Kristiina; Blomqvist, Carl; Heikkinen, Tuomas; Nevanlinna, Heli; Tischkowitz, Marc (2020)
    PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 x 10(-76)), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 x 10(-3)), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 x 10(-3)), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 x 10(-2)). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 x 10(-3)). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers. (C) 2019 by American Society of Clinical Oncology
  • Maguire, Sarah; Perraki, Eleni; Tomczyk, Katarzyna; KConFab Consortium; Trainer, Alison; James, Paul; Bojesen, Stig; Flyger, Henrik; Nevanlinna, Heli; Mattson, Johanna; Friedman, Eital; Laitman, Yael; Palli, Domenico; Masala, Giovanna; Zanna, Ines; Ottini, Laura; Silvestri, Valentina; Hollestelle, Antoinette; Hooning, Maartje J.; Novakovic, Srdjan; Krajc, Mateja; Gago-Dominguez, Manuela; Castelao, Jose Esteban; Olsson, Hakan; Hedenfalk, Ingrid; Saloustros, Emmanouil; Georgoulias, Vasilios; Easton, Douglas F.; Pharoah, Paul; Dunning, Alison M.; Bishop, D. Timothy; Neuhausen, Susan L.; Steele, Linda; Ashworth, Alan; Garcia Closas, Montserrat; Houlston, Richard; Swerdlow, Anthony; Orr, Nick (2021)
    Background: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC. Methods: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 x 10(-06). Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided. Results: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 x 10(-08)). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 x 10(-30)). Conclusions: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.
  • Holopainen, Elina; Vakkilainen, Svetlana; Mäkitie, Outi (2018)
    BackgroundPatients with cartilage-hair hypoplasia (CHH), a rare metaphyseal chondrodysplasia, manifest severe growth failure, variable immunodeficiency and increased risk of malignancies. The impact of CHH on gynecologic and reproductive health is unknown. Vulnerability to genital infections may predispose CHH patients to prolonged human papillomavirus (HPV) infections potentially leading to cervical, vaginal and vulvar cancer.MethodsWe carried out gynecologic evaluation, pelvic ultrasound and laboratory assessment in 19 women with genetically confirmed CHH. All patients were clinically examined and retrospective data were collected from hospital records.ResultsThe women ranged in age from 19.2 to 70.8years (median 40.8years) and in height from 103 to 150cm (median 123cm). All women had undergone normal pubertal development as assessed by breast development according to Tanner scale and by age of menarche (mean 12.5yrs., range 11-14yrs). Despite significant short stature and potentially small pelvic diameters, a well-developed uterus with fairly normal size and shape was found by pelvic ultrasound in mostof the patients. Ovarian follicle reserve, assessed by ultrasound was normal in relation to age in all premenopausal women it could be assessed (12 cases). Anti-Mullerian hormone was normal in relation to age in 17 women (89%). HPV was detected in 44% (8/18) and three women carried more than one HPV serotype; findings did not associate with immunological parameters. Three patients had a concurrent cell atypia in Pap smear.ConclusionsPubertal development, reproductive hormones and ovarian structure and function were usually normal in women with CHH suggesting fairly normal reproductive health. However, the immunodeficiency characteristic to CHH may predispose the patients to HPV infections. High prevalence of HPV infections detected in this series highlights the importance of careful gynecologic follow up of these patients.
  • Parsons, Michael T.; Tudini, Emma; Li, Hongyan; Hahnen, Eric; Wappenschmidt, Barbara; Feliubadaló, Lidia; Aalfs, Cora M.; Agata, Simona; Aittomäki, Kristiina; Alducci, Elisa; Alonso-Cerezo, María Concepción; Arnold, Norbert; Auber, Bernd; Austin, Rachel; Azzollini, Jacopo; Balmaña, Judith; Barbieri, Elena; Bartram, Claus R.; Blanco, Ana; Blümcke, Britta; Bonache, Sandra; Bonanni, Bernardo; Borg, Åke; Bortesi, Beatrice; Brunet, Joan; Bruzzone, Carla; Bucksch, Karolin; Cagnoli, Giulia; Caldés, Trinidad; Caliebe, Almuth; Caligo, Maria A.; Calvello, Mariarosaria; Capone, Gabriele L.; Caputo, Sandrine M.; Carnevali, Ileana; Carrasco, Estela; Caux-Moncoutier, Virginie; Cavalli, Pietro; Cini, Giulia; Clarke, Edward M.; Concolino, Paola; Cops, Elisa J.; Cortesi, Laura; Couch, Fergus J.; Darder, Esther; de la Hoya, Miguel; Dean, Michael; Debatin, Irmgard; del Valle, Jesús; Delnatte, Capucine; Derive, Nicolas; Diez, Orland; Ditsch, Nina; Domchek, Susan M.; Dutrannoy, Véronique; Eccles, Diana M.; Ehrencrona, Hans; Enders, Ute; Evans, D. Gareth; Faust, Ulrike; Felbor, Ute; Feroce, Irene; Fine, Miriam; Galvao, Henrique C.R.; Gambino, Gaetana; Gehrig, Andrea; Gensini, Francesca; Gerdes, Anne-Marie; Germani, Aldo; Giesecke, Jutta; Gismondi, Viviana; Gómez, Carolina; Gómez Garcia, Encarna B.; González, Sara; Grau, Elia; Grill, Sabine; Gross, Eva; Guerrieri-Gonzaga, Aliana; Guillaud-Bataille, Marine; Gutiérrez-Enríquez, Sara; Haaf, Thomas; Hackmann, Karl; Hansen, Thomas V.O.; Harris, Marion; Hauke, Jan; Heinrich, Tilman; Hellebrand, Heide; Herold, Karen N.; Honisch, Ellen; Horvath, Judit; Houdayer, Claude; Hübbel, Verena; Iglesias, Silvia; Izquierdo, Angel; James, Paul A.; Janssen, Linda A.M.; Jeschke, Udo; Kaulfuß, Silke; Keupp, Katharina; Kiechle, Marion; Kölbl, Alexandra; Krieger, Sophie; Kruse, Torben A.; Kvist, Anders; Lalloo, Fiona; Larsen, Mirjam; Lattimore, Vanessa L.; Lautrup, Charlotte; Ledig, Susanne; Leinert, Elena; Lewis, Alexandra L.; Lim, Joanna; Loeffler, Markus; López-Fernández, Adrià; Lucci-Cordisco, Emanuela; Maass, Nicolai; Manoukian, Siranoush; Marabelli, Monica; Matricardi, Laura; Meindl, Alfons; Michelli, Rodrigo D.; Moghadasi, Setareh; Moles-Fernández, Alejandro; Montagna, Marco; Montalban, Gemma; Monteiro, Alvaro N.; Montes, Eva; Mori, Luigi; Moserle, Lidia; Müller, Clemens R.; Mundhenke, Christoph; Naldi, Nadia; Nathanson, Katherine L.; Navarro, Matilde; Nevanlinna, Heli; Nichols, Cassandra B.; Niederacher, Dieter; Nielsen, Henriette R.; Ong, Kai-ren; Pachter, Nicholas; Palmero, Edenir I.; Papi, Laura; Pedersen, Inge Sokilde; Peissel, Bernard; Pérez-Segura, Pedro; Pfeifer, Katharina; Pineda, Marta; Pohl-Rescigno, Esther; Poplawski, Nicola K.; Porfirio, Berardino; Quante, Anne S.; Ramser, Juliane; Reis, Rui M.; Revillion, Françoise; Rhiem, Kerstin; Riboli, Barbara; Ritter, Julia; Rivera, Daniela; Rofes, Paula; Rump, Andreas; Salinas, Monica; Sánchez de Abajo, Ana María; Schmidt, Gunnar; Schoenwiese, Ulrike; Seggewiß, Jochen; Solanes, Ares; Steinemann, Doris; Stiller, Mathias; Stoppa-Lyonnet, Dominique; Sullivan, Kelly J.; Susman, Rachel; Sutter, Christian; Tavtigian, Sean V.; Teo, Soo H.; Teulé, Alex; Thomassen, Mads; Tibiletti, Maria Grazia; Tognazzo, Silvia; Toland, Amanda E.; Tornero, Eva; Törngren, Therese; Torres-Esquius, Sara; Toss, Angela; Trainer, Alison H.; van Asperen, Christi J.; van Mackelenbergh, Marion T.; Varesco, Liliana; Vargas-Parra, Gardenia; Varon, Raymonda; Vega, Ana; Velasco, Ángela; Vesper, Anne-Sophie; Viel, Alessandra; Vreeswijk, Maaike P.G.; Wagner, Sebastian A.; Waha, Anke; Walker, Logan C.; Walters, Rhiannon J.; Wang-Gohrke, Shan; Weber, Bernhard H.F.; Weichert, Wilko; Wieland, Kerstin; Wiesmüller, Lisa; Witzel, Isabell; Wöckel, Achim; Woodward, Emma R.; Zachariae, Silke; Zampiga, Valentina; Zeder-Göß, Christine; Investigators, KConFab; Lázaro, Conxi; De Nicolo, Arcangela; Radice, Paolo; Engel, Christoph; Schmutzler, Rita K.; Goldgar, David E.; Spurdle, Amanda B. (2019)
    Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.
  • Jurgens, Hannes; Roht, Laura; Leitsalu, Liis; Noukas, Margit; Palover, Marili; Nikopensius, Tiit; Reigo, Anu; Kals, Mart; Kallak, Kersti; Kuetner, Riina; Budrikas, Kai; Kuusk, Saskia; Valvere, Vahur; Laidre, Piret; Toome, Kadri; Rekker, Kadri; Tooming, Mikk; Kahre, Tiina; Kruuv-Kao, Krista; ounap, Katrin; Padrik, Peeter; Metspalu, Andres; Esko, Tonu; Fischer, Krista; Tonisson, Neeme (2022)
    Although hereditary breast cancer screening and management are well accepted and established in clinical settings, these efforts result in the detection of only a fraction of genetic predisposition at the population level. Here, we describe our experience from a national pilot study (2018-2021) in which 180 female participants of Estonian biobank (of >150,000 participants in total) were re-contacted to discuss personalized clinical prevention measures based on their genetic predisposition defined by 11 breast cancer-related genes. Our results show that genetic risk variants are relatively common in the average-risk Estonian population. Seventy-five percent of breast cancer cases in at-risk subjects occurred before the age of 50 years. Only one-third of subjects would have been eligible for clinical screening according to the current criteria. The participants perceived the receipt of genetic risk information as valuable. Fluent cooperation of project teams supported by state-of-art data management, quality control, and secure transfer can enable the integration of research results to everyday medical practice in a highly efficient, timely, and well-accepted manner. The positive experience in this genotype-first breast cancer study confirms the value of using existing basic genomic data from population biobanks for precise prevention.
  • Graf, Alexandra; Enyedi, Marton Zsolt; Pinter, Lajos; Kriston-Pal, Eva; Jaksa, Gabor; Balind, Arpad; Ezer, Eva; Horvath, Peter; Sukosd, Farkas; Kiss, Erno; Haracska, Lajos (2021)
    Simple Summary Germline and somatic BRCA1/2 mutations may define therapeutic targets and refine cancer treatment options. However, routine BRCA diagnostic approaches cannot reveal the exact time and origin of BRCA1/2 mutation formation, and thus, the fine details of their contribution to tumor progression remain less clear. We established a diagnostic pipeline using high-resolution microscopy and laser microcapture microscopy to test for BRCA1/2 mutations in tumors at the single-cell level, followed by deep next-generation sequencing of various tissues from the patient. To demonstrate the power of our approach, here we present a detailed analysis of an ovarian cancer patient, in which we describe constitutional somatic mosaicism of a BRCA2 mutation. Characterization of the mosaic mutation at the single-cell level contributes to a better understanding of BRCA mutation formation and supports the concept that the combination of single-cell and next-generation sequencing methods is advantageous over traditional mutational analysis methods. Germline mutations in the BRCA1 and BRCA2 genes are responsible for hereditary breast and ovarian cancer syndrome. Germline and somatic BRCA1/2 mutations may define therapeutic targets and refine cancer treatment options. However, routine BRCA diagnostic approaches cannot reveal the exact time and origin of BRCA1/2 mutation formation, and thus, the fine details of their contribution to tumor progression remain less clear. Here, we establish a diagnostic pipeline using high-resolution microscopy and laser microcapture microscopy to test for BRCA1/2 mutations in the tumor at the single-cell level, followed by deep next-generation sequencing of various tissues from the patient. To demonstrate the power of our approach, here, we describe a detailed single-cell-level analysis of an ovarian cancer patient we found to exhibit constitutional somatic mosaicism of a pathogenic BRCA2 mutation. Employing next-generation sequencing, BRCA2 c.7795G>T, p.(Glu2599Ter) was detected in 78% of reads in DNA extracted from ovarian cancer tissue and 25% of reads in DNA derived from peripheral blood, which differs significantly from the expected 50% of a hereditary mutation. The BRCA2 mutation was subsequently observed at 17-20% levels in the normal ovarian and buccal tissue of the patient. Together, our findings suggest that this mutation occurred early in embryonic development. Characterization of the mosaic mutation at the single-cell level contributes to a better understanding of BRCA mutation formation and supports the concept that the combination of single-cell and next-generation sequencing methods is advantageous over traditional mutational analysis methods. This study is the first to characterize constitutional mosaicism down to the single-cell level, and it demonstrates that BRCA2 mosaicism occurring early during embryogenesis can drive tumorigenesis in ovarian cancer.
  • GEMO Study Collaborators; EMBRACE Collaborators; OCGN Investigators; HEBON Investigators; kConFab Investigators; Lakeman, Inge M. M.; van den Broek, Alexandra J.; Vos, Julien A. M.; Nevanlinna, Heli (2021)
    Purpose To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
  • Webb, P. M.; Na, R.; Weiderpass, E.; Adami, H. O.; Anderson, K. E.; Bertrand, K. A.; Botteri, E.; Brasky, T. M.; Brinton, L. A.; Chen, C.; Doherty, J. A.; Lu, L.; McCann, S. E.; Moysich, K. B.; Olson, S.; Petruzella, S.; Palmer, J. R.; Prizment, A. E.; Schairer, C.; Setiawan, V. W.; Spurdle, A. B.; Trabert, B.; Wentzensen, N.; Wilkens, L.; Yang, H. P.; Yu, H.; Risch, H. A.; Jordan, S. J. (2019)
    Background: Regular use of aspirin has been associated with a reduced risk of cancer at several sites but the data for endometrial cancer are conflicting. Evidence regarding use of other analgesics is limited. Patients and methods: We pooled individual-level data from seven cohort and five case-control studies participating in the Epidemiology of Endometrial Cancer Consortium including 7120 women with endometrial cancer and 16 069 controls. For overall analyses, study-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression and combined using random-effects meta-analysis; for stratified analyses, we used mixed-effects logistic regression with study as a random effect. Results: At least weekly use of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an approximately 15% reduced risk of endometrial cancer among both overweight and obese women (OR 1/4 0.86 [95% CI 0.760.98] and 0.86 [95% CI 0.76-0.97], respectively, for aspirin; 0.87 [95% CI 0.76-1.00] and 0.84 [0.74-0.96], respectively, for nonaspirin NSAIDs). There was no association among women of normal weight (body mass index<25 kg/ m2, Pheterogeneity 0.04 for aspirin, Pheterogeneity 1/4 0.003 for NSAIDs). Among overweight and obese women, the inverse association with aspirin was stronger for use 2-6 times/ week (OR 1/4 0.81, 95% CI 0.68-0.96) than for daily use (0.91, 0.80-1.03), possibly because a high proportion of daily users use low-dose formulations. There was no clear association with use of acetaminophen. Conclusion: Our pooled analysis provides further evidence that use of standard-dose aspirin or other NSAIDs may reduce risk of endometrial cancer among overweight and obese women.