Browsing by Subject "BRCA2"

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  • 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
  • Alhopuro, Pia; Vainionpää, Reetta; Anttonen, Anna-Kaisa; Aittomäki, Kristiina; Nevanlinna, Heli; Pöyhönen, Minna (2020)
    Germline mutations in theBRCA1andBRCA2genes cause hereditary breast and ovarian cancer syndrome (HBOC). Mutations in these genes are usually inherited, and reports ofde novo BRCA1/2mutations are rare. To date, only one patient with low-levelBRCA1mutation mosaicism has been published. We report on a breast cancer patient with constitutional somatic mosaicism of aBRCA2mutation.BRCA2mutation c.9294C>G, p.(Tyr3098Ter) was detected in 20% of reads in DNA extracted from peripheral blood using next-generation sequencing (NGS). TheBRCA2mutation was subsequently observed at similar levels in normal breast tissue, adipose tissue, normal right fallopian tube tissue and ovaries of the patient, suggesting that this mutation occurred early in embryonic development. This is the first case to report constitutional mosaicism for aBRCA2mutation and shows thatBRCA2mosaicism can underlie early-onset breast cancer. NGS forBRCA1/2should be considered for patients whose tumors harbor aBRCA1/2mutation and for individuals suggestive of genetic predisposition but without a family history of HBO.
  • Zheng, Guoqiao; Yu, Hongyao; Hemminki, Akseli; Forsti, Asta; Sundquist, Kristina; Hemminki, Kari (2017)
    Male breast cancer is associated with female breast cancer in families but whether male breast cancer clusters with other discordant cancers has not been studied. As concordant male breast cancers are utterly rare, discordant associations of male breast cancer with other cancers may reveal genetic and possible environmental risk factors contributing to male breast cancer susceptibility. We calculated relative risks (RRs) for male breast cancer in families with discordant cancers, and conversely, for discordant cancers in families of male breast cancer patients, based on 15.7 million individuals in the Swedish Family-Cancer Database. Among 1428 male breast cancer patients, 16.2% had a female relative diagnosed with breast cancer. Ovarian and female anal cancers showed the strongest associations with male breast cancer (p value <0.0005). The other significant associations included colorectal, small intestinal, and thyroid cancers, cancer of unknown primary and non-Hodgkin lymphoma but these were each based on a single positive association with male breast cancer. The RRs for male breast cancer were increased in families in which multiple patients were diagnosed with diverse cancers, reaching an RR of 2.58 when three or more family members were affected. The results suggest that male breast cancer shares susceptibility with a number of other cancers but confirmation is needed in other datasets.
  • Muranen, Taru A.; Greco, Dario; Blomqvist, Carl; Aittomäki, Kristiina; Khan, Sofia; Hogervorst, Frans; Verhoef, Senno; Pharoah, Paul D. P.; Dunning, Alison M.; Shah, Mitul; Luben, Robert; Bojesen, Stig E.; Nordestgaard, Borge G.; Schoemaker, Minouk; Swerdlow, Anthony; Garcia-Closas, Montserrat; Figueroa, Jonine; Doerk, Thilo; Bogdanova, Natalia V.; Hall, Per; Li, Jingmei; Khusnutdinova, Elza; Bermisheva, Marina; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Peto, Julian; Silva, Isabel dos Santos; Couch, Fergus J.; Olson, Janet E.; Hillemans, Peter; Park-Simon, Tjoung-Won; Brauch, Hiltrud; Hamann, Ute; Burwinkel, Barbara; Marme, Frederik; Meindl, Alfons; Schmutzler, Rita K.; Cox, Angela; Cross, Simon S.; Sawyer, Elinor J.; Tomlinson, Ian; Lambrechts, Diether; Moisse, Matthieu; Lindblom, Annika; Margolin, Sara; Hollestelle, Antoinette; Martens, John W. M.; Fasching, Peter A.; Beckmann, Matthias W.; Nevanlinna, Heli; NBCS Investigators; kConFab-AOCS Investigators; Breast Canc Assoc Consortium (2017)
    Purpose: CHEK2*1100delC is a founder variant in European populations that confers a two-to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). Methods: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. Results: The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.212.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average. Conclusion: Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.
  • Donner, Iikki; Katainen, Riku; Sipilä, Lauri J.; Aavikko, Mervi; Pukkala, Eero; Aaltonen, Lauri A. (2018)
    Objectives: Although the primary cause of lung cancer is smoking, a considerable proportion of all lung cancers occur in never smokers. Gender influences the risk and characteristics of lung cancer and women are over-represented among never smokers with the disease. Young age at onset and lack of established environmental risk factors suggest genetic predisposition. In this study, we used population-based sampling of young patients to discover candidate predisposition variants for lung adenocarcinoma in never-smoking women. Materials and methods: We employed archival normal tissue material from 21 never-smoker women who had been diagnosed with lung adenocarcinoma before the age of 45, and exome sequenced their germline DNA. Results and conclusion: Potentially pathogenic variants were found in eight Cancer Gene Census germline genes: BRCAI, BRCA2, ERCC4, EXT1, HNF1 A, PTCH1, SMARCB1 and TP53. The variants in TP53, BRCAI, and BRCA2 are likely to have contributed to the early onset lung cancer in the respective patients (3/21 or 14%). This supports the notion that lung adenocarcinoma can be a component of certain cancer predisposition syndromes. Fifteen genes displayed potentially pathogenic mutations in at least two patients: ABCC10, ATP7B, CACNA1S, CFTR, CLIP4, COL6A1, COL6A6, GCN1, GJB6, RYR1, SCN7A, SEC24A, SP100, TEN and USH2A. Four patients showed a mutation in COL6A1, three in CLIP4 and two in the rest of the genes. Some of these candidate genes may explain a subset of female lung adenocarcinoma.
  • Rebbeck, Timothy R.; Friebel, Tara M.; Mitra, Nandita; Wan, Fei; Chen, Stephanie; Andrulis, Irene L.; Apostolou, Paraskevi; Arnold, Norbert; Arun, Banu K.; Barrowdale, Daniel; Benitez, Javier; Berger, Raanan; Berthet, Pascaline; Borg, Ake; Buys, Saundra S.; Caldes, Trinidad; Carter, Jonathan; Chiquette, Jocelyne; Claes, Kathleen B. M.; Couch, Fergus J.; Cybulski, Cezary; Daly, Mary B.; de la Hoya, Miguel; Diez, Orland; Domchek, Susan M.; Nathanson, Katherine L.; Durda, Katarzyna; Ellis, Steve; Evans, D. Gareth; Foretova, Lenka; Friedman, Eitan; Frost, Debra; Ganz, Patricia A.; Garber, Judy; Glendon, Gord; Godwin, Andrew K.; Greene, Mark H.; Gronwald, Jacek; Hahnen, Eric; Hallberg, Emily; Hamann, Ute; Hansen, Thomas V. O.; Imyanitov, Evgeny N.; Isaacs, Claudine; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; John, Esther M.; Karlan, Beth Y.; Nevanlinna, Heli; EMBRACE; HEBON; kConFab Investigators (2016)
    Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p <0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p <0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
  • 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.
  • kConFab Investigators; Yang, Xin; Nevanlinna, Heli; Aittomäki, Kristiina; Pelttari, Liisa M. (2020)
    Background: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 x 10(-40); RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 x 10(-39)) and BC (RAD51C: RR =1.99, 95% CI = 1.39 to 2.85; P = 1.55 x 10(-4); RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.
  • Muranen, Taru A.; Mavaddat, Nasim; Khan, Sofia; Fagerholm, Rainer; Pelttari, Liisa; Lee, Andrew; Aittomäki, Kristiina; Blomqvist, Carl; Easton, Douglas F.; Nevanlinna, Heli (2016)
    The risk of developing breast cancer is increased in women with family history of breast cancer and particularly in families with multiple cases of breast or ovarian cancer. Nevertheless, many women with a positive family history never develop the disease. Polygenic risk scores (PRSs) based on the risk effects of multiple common genetic variants have been proposed for individual risk assessment on a population level. We investigate the applicability of the PRS for risk prediction within breast cancer families. We studied the association between breast cancer risk and a PRS based on 75 common genetic variants in 52 Finnish breast cancer families including 427 genotyped women and pedigree information on similar to 4000 additional individuals by comparing the affected to healthy family members, as well as in a case-control dataset comprising 1272 healthy population controls and 1681 breast cancer cases with information on family history. Family structure was summarized using the BOADICEA risk prediction model. The PRS was associated with increased disease risk in women with family history of breast cancer as well as in women within the breast cancer families. The odds ratio (OR) for breast cancer within the family dataset was 1.55 [95 % CI 1.26-1.91] per unit increase in the PRS, similar to OR in unselected breast cancer cases of the case-control dataset (1.49 [1.38-1.62]). High PRS-values were informative for risk prediction in breast cancer families, whereas for the low PRS-categories the results were inconclusive. The PRS is informative in women with family history of breast cancer and should be incorporated within pedigree-based clinical risk assessment.
  • 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.
  • Mars, Nina; Widen, Elisabeth; Meretoja, Tuomo; Kerminen, Sini; Pirinen, Matti; Della Briotta Parolo, Pietro; Palta, Priit; FinnGen; Palotie, Aarno; Kaprio, Jaakko; Joensuu, Heikki; Daly, Mark; Ripatti, Samuli; Pärn, Kalle; Tienari, Pentti (2020)
    Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their utility in various clinical situations. Here we show that among 122,978 women in the FinnGen study with 8401 breast cancer cases, the PRS modifies the breast cancer risk of two high-impact frameshift risk variants. Similarly, we show that after the breast cancer diagnosis, individuals with elevated PRS have an elevated risk of developing contralateral breast cancer, and that the PRS can considerably improve risk assessment among their female first-degree relatives. In more detail, women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 336 carriers) and an average PRS (10-90(th) percentile) have a lifetime risk of breast cancer at 55% (95% CI 49-61%), which increases to 84% (71-97%) with a high PRS (>90(th) percentile), and decreases to 49% (30-68%) with a low PRS (