Browsing by Subject "BRCA1"

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  • Laury, Anna Ray; Blom, Sami; Ropponen, Tuomas; Virtanen, Anni; Carpen, Olli Mikael (2021)
    High-grade extrauterine serous carcinoma (HGSC) is an aggressive tumor with high rates of recurrence, frequent chemotherapy resistance, and overall 5-year survival of less than 50%. Beyond determining and confirming the diagnosis itself, pathologist review of histologic slides provides no prognostic or predictive information, which is in sharp contrast to almost all other carcinoma types. Deep-learning based image analysis has recently been able to predict outcome and/or identify morphology-based representations of underlying molecular alterations in other tumor types, such as colorectal carcinoma, lung carcinoma, breast carcinoma, and melanoma. Using a carefully stratified HGSC patient cohort consisting of women (n = 30) with similar presentations who experienced very different treatment responses (platinum free intervals of either = 18 months), we used whole slide images (WSI, n = 205) to train a convolutional neural network. The neural network was trained, in three steps, to identify morphologic regions (digital biomarkers) that are highly associating with one or the other treatment response group. We tested the classifier using a separate 22 slide test set, and 18/22 slides were correctly classified. We show that a neural network based approach can discriminate extremes in patient response to primary platinum-based chemotherapy with high sensitivity (73%) and specificity (91%). These proof-of-concept results are novel, because for the first time, prospective prognostic information is identified specifically within HGSC tumor morphology.
  • Gu, Yuexi; Helenius, Mikko; Vaananen, Kristiina; Bulanova, Daria; Saarela, Jani; Sokolenko, Anna; Martens, John; Imyanitov, Evgeny; Kuznetsov, Sergey (2016)
    Germ-line or somatic inactivation of BRCA1 is a defining feature for a portion of human breast cancers. Here we evaluated the anti-proliferative activity of 198 FDA-approved and experimental drugs against four BRCA1-mutant (HCC1937, MDA-MB-436, SUM1315MO2, and SUM149PT) and four BRCA1-wild-type (MDA-MB-231, SUM229PE, MCF10A, and MCF7) breast cancer cell lines. We found that all BRCA1-mutant cell lines were insensitive to inhibitors of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) Selumetinib and Pimasertib in contrast to BRCA1-wildtype control cell lines. However, unexpectedly, only two BRCA1-mutant cell lines, HCC1937 and MDA-MB-436, were hypersensitive to a nucleotide analogue 6-thioguanine (6-TG). SUM149PT cells readily formed radiation-induced RAD51-positive nuclear foci indicating a functional homologous recombination, which may explain their resistance to 6-TG. However, the reason underlying 6-TG resistance of SUM1315MO2 cells remains unclear. Our data reveal a remarkable heterogeneity among BRCA1-mutant cell lines and provide a reference for future studies.
  • NBCS Collaborators; kConFab Investigators; SGBCC Investigators; Dorling, Leila; Carvalho, Sara; Allen, Jamie; Nevanlinna, Heli; Suvanto, Maija (2022)
    Background Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
  • Mantere, Tuomo; Tervasmäki, Anna; Nurmi, Anna; Rapakko, Katrin; Kauppila, Saila; Tang, Jiangbo; Schleutker, Johanna; Kallioniemi, Anne; Hartikainen, Jaana M.; Mannermaa, Arto; Nieminen, Pentti; Hanhisalo, Riitta; Lehto, Sini; Suvanto, Maija; Grip, Mervi; Jukkola-Vuorinen, Arja; Tengström, Maria; Auvinen, Päivi; Kvist, Anders; Borg, Åke; Blomqvist, Carl; Aittomäki, Kristiina; Greenberg, Roger A.; Winqvist, Robert; Nevanlinna, Heli; Pylkäs, Katri (2017)
    Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578-1565) and controls (n = 337-1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts.c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.
  • Laine, Anni; Nagelli, Srikar G.; Farrington, Caroline; Butt, Umar; Cvrljevic, Anna N.; Vainonen, Julia P.; Feringa, Femke M.; Gronroos, Tove J.; Gautam, Prson; Khan, Sofia; Sihto, Harri; Qiao, Xi; Pavic, Karolina; Connolly, Denise C.; Kronqvist, Pauliina; Elo, Laura L.; Maurer, Jochen; Wennerberg, Krister; Medema, Rene H.; Joensuu, Heikki; Peuhu, Emilia; de Visser, Karin; Narla, Goutham; Westermarck, Jukka (2021)
    Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage-induced initiation of mouse BLBC-like mammary tumors and for survival of HR-defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNAdamage-induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. Significance: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage-induced G2-M checkpoint and proliferative signaling.
  • 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; Kanerva, Anna; Försti, Asta; Sundquist, Kristina; Hemminki, Kari (2018)
    Ovarian cancer is a heterogeneous disease. Data regarding familial risks for specific proband, age at diagnosis and histology are limited. Such data can assist genetic counseling and help elucidate etiologic differences among various histologic types of ovarian malignancies. By using the Swedish Family-Cancer Database, we calculated relative risks (RRs) for detailed family histories using a two-way comparison, which implied e.g. estimation of RRs for overall ovarian cancer when family history was histology-specific ovarian cancer, and conversely, RRs for histology-specific ovarian cancer when family history was overall ovarian cancer. In families of only mother, only sisters or both mother and sisters diagnosed with ovarian cancer, cancer risks for ovary were 2.40, 2.59 and 10.40, respectively; and were higher for cases diagnosed before the age of 50 years. All histological types showed a familial risk in two-way analyses, except mucinous and sex cord-stromal tumors. RRs for concordant histology were found for serous (2.47), endometrioid (3.59) and mucinous ovarian cancers (6.91). Concordant familial risks were highest for mucinous cancer; for others, some discordant associations, such as endometrioid-undifferentiated (9.27) and serous-undifferentiated (4.80), showed the highest RRs. Familial risks are high for early-onset patients and for those with multiple affected relatives. Sharing of different histological types of ovarian cancer is likely an indication of the complexity of the underlying mechanisms.
  • Pelttari, L. M.; Shimelis, H.; Toiminen, H.; Kvist, A.; Törngren, T.; Borg, Å.; Blomqvist, C.; Bützow, R.; Couch, F.; Aittomäki, K.; Nevanlinna, H. (2018)
    Gene-panel sequencing allows comprehensive analysis of multiple genes simultaneously and is now routinely used in clinical mutation testing of high-risk breast and ovarian cancer patients. However, only BRCA1 and BRCA2 are often analyzed also for large genomic changes. Here, we have analyzed 10 clinically relevant susceptibility genes in 95 breast or ovarian cancer patients with gene-panel sequencing including also copy number variants (CNV) analysis for genomic changes. We identified 12 different pathogenic BRCA1, BRCA2, TP53, PTEN, CHEK2, or RAD51C mutations in 18 of 95 patients (19%). BRCA1/2 mutations were observed in 8 patients (8.4%) and CHEK2 protein-truncating mutations in 7 patients (7.4%). In addition, we identified a novel duplication encompassing most of the RAD51C gene. We further genotyped the duplication in breast or ovarian cancer families (n=1149), in unselected breast (n=1729) and ovarian cancer cohorts (n=553), and in population controls (n=1273). Seven additional duplication carries were observed among cases but none among controls. The duplication associated with ovarian cancer risk (3/590 of all ovarian cancer patients, 0.5%, P=.032 compared with controls) and was found to represent a large fraction of all identified RAD51C mutations in the Finnish population. Our data emphasizes the importance of comprehensive mutation analysis including CNV detection in all the relevant genes.
  • Färkkilä, Anniina; Rodriguez, Alfredo; Oikkonen, Jaana; Gulhan, Doga C.; Huy Nguyen; Dominguez, Julieta; Ramos, Sandra; Mills, Caitlin E.; Perez-Villatoro, Fernando; Lazaro, Jean-Bernard; Zhou, Jia; Clairmont, Connor S.; Moreau, Lisa A.; Park, Peter J.; Sorger, Peter K.; Hautaniemi, Sampsa; Frias, Sara; D'Andrea, Alan D. (2021)
    Homologous recombination (HR)-deficient cancers are sensitive to poly- ADP ribose polymerase inhibitors (PARPi), which have shown clinical efficacy in the treatment of high-grade serous cancers (HGSC). However, the majority of patients will relapse, and acquired PARPi resistance is emerging as a pressing clinical problem. Here we generated seven single-cell clones with acquired PARPi resistance derived from a PARPi-sensitive TP53(-/-) and BRCA1(-/-) epithelial cell line generated using CRISPR/Cas9. These clones showed diverse resistance mechanisms, and some clones presented with multiple mechanisms of resistance at the same time. Genomic analysis of the clones revealed unique transcriptional and mutational profiles and increased genomic instability in comparison with a PARPi-sensitive cell line. Clonal evolutionary analyses suggested that acquired PARPi resistance arose via clonal selection from an intrinsically unstable and heterogenous cell population in the sensitive cell line, which contained preexisting drug-tolerant cells. Similarly, clonal and spatial heterogeneity in tumor biopsies from a clinical patient with BRCA1-mutant HGSC with acquired PARPi resistance was observed. In an imaging-based drug screening, the clones showed heterogenous responses to targeted therapeutic agents, indicating that not all PARPi-resistant clones can be targeted with just one therapy. Furthermore, PARPi-resistant clones showed mechanism-dependent vulnerabilities to the selected agents, demonstrating that a deeper understanding on the mechanisms of resistance could lead to improved targeting and biomarkers for HGSC with acquired PARPi resistance. Significance: This study shows that BRCA1-deficient cells can give rise to multiple genomically and functionally heterogenous PARPi-resistant clones, which are associated with various vulnerabilities that can be targeted in a mechanism-specific manner.
  • Toufakis, V; Katuwal, S; Pukkala, E; Tapanainen, JS (2021)
    Background Parity is known to have a protective effect as regards ovarian cancer, but its effect on the different histological subtypes of ovarian cancer is not well known. The impact of parity on the incidence of ovarian cancer subtypes was studied. Material and methods All Finnish women diagnosed 1994-2013 with ovarian cancer for the first time were included. Altogether, 5412 cases of ovarian cancer were identified in the Finnish Cancer Registry and stratified according to morphology into serous, mucinous, endometrioid, clear cell and others. Five age-matched controls were randomly selected for each case from the Finnish National Population Registry. Data on postmenopausal hormonal therapy were derived from the Registry of Prescribed drugs and used as cofactors. Multivariate conditional logistic regression for matched case-control data was used to examine the associations between parity parameters and ovarian cancer risk. Results Parous women had lower risk than nulliparous women in getting ovarian cancer of any type under age of 55 years. The odds ratio (OR) for serous cancer was 0.65 (95% confidence interval 0.56-0.77), for mucinous cancer 0.66 (0.52-0.83), for endometrioid cancer 0.52 (0.40-0.68), for clear-cell cancer 0.30 (0.19-0.46) and for other types 0.59 (0.43-0.80). In women aged 55 or older, the respective ORs were 0.86 (0.75-0.99), 0.78 (0.57-1.07), 0.61 (0.47-0.79), 0.44 (0.29-0.66) and 0.74 (0.57-0.95), adjusted for hormone therapy. Number of childbirths was associated with a trend toward reduction of risk, especially in serous and clear-cell cancers. Higher age at first birth was associated with higher risk of clear-cell cancer but otherwise age at first or last birth did not have an impact on the incidence of cancer subtypes. Conclusions Childbirths decrease the risk of all histologic subtypes of epithelial ovarian cancer in women in premenopausal and postmenopausal age.
  • 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.
  • Southey, Melissa C.; Goldgar, David E.; Winqvist, Robert; Pylkas, Katri; Couch, Fergus; Tischkowitz, Marc; Foulkes, William D.; Dennis, Joe; Michailidou, Kyriaki; van Rensburg, Elizabeth J.; Heikkinen, Tuomas; Nevanlinna, Heli; Hopper, John L.; Doerk, Thilo; Claes, Kathleen B. M.; Reis-Filho, Jorge; Teo, Zhi Ling; Radice, Paolo; Catucci, Irene; Peterlongo, Paolo; Tsimiklis, Helen; Odefrey, Fabrice A.; Dowty, James G.; Schmidt, Marjanka K.; Broeks, Annegien; Hogervorst, Frans B.; Verhoef, Senno; Carpenter, Jane; Clarke, Christine; Scott, Rodney J.; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Bolla, Manjeet K.; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Marme, Federik; Burwinkel, Barbara; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Pelttari, Liisa M.; Butzow, Ralf; kConFab Investigators; Australian Ovarian Canc Study Grp (2016)
    Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1x10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9x10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
  • GEMO Study Collaborators; EMBRACE Collaborators; kConFab Investigators; HEBON Investigators; GENEPSO Investigators; Consortium Investigators Modifiers; Barnes, Daniel R.; Rookus, Matti A.; McGuffog, Lesley; Aittomäki, Kristiina (2020)
    Purpose We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks forBRCA1andBRCA2pathogenic variant carriers. Methods Retrospective cohort data on 18,935BRCA1and 12,339BRCA2female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results The ER-negative PRS showed the strongest association with BC risk forBRCA1carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33],P = 3x10(-72)). ForBRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36],P = 7x10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk forBRCA1(HR = 1.32 [95% CI 1.25-1.40],P = 3x10(-22)) andBRCA2(HR = 1.44 [95% CI 1.30-1.60],P = 4x10(-12)) carriers. The associations in the prospective cohort were similar. Conclusion Population-based PRS are strongly associated with BC and EOC risks forBRCA1/2carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
  • Sokolenko, Anna P.; Savonevich, Elena L.; Ivantsov, Alexandr O.; Raskin, Grigory A.; Kuligina, Ekatherina S.; Gorodnova, Tatiana V.; Preobrazhenskaya, Elena V.; Kleshchov, Maxim A.; Tiurin, Vladislav I.; Mukhina, Marina S.; Kotiv, Khristina B.; Shulga, Andrey V.; Kuznetsov, Sergey G.; Berlev, Igor V.; Imyanitov, Evgeny N. (2017)
    Ovarian carcinomas (OC) often demonstrate rapid tumor shrinkage upon neoadjuvant chemotherapy (NACT). However, complete pathologic responses are very rare and the mechanisms underlying the emergence of residual tumor disease remain elusive. We hypothesized that the change of somatic BRCA1 status may contribute to this process. The loss-of-heterozygosity (LOH) at the BRCA1 locus was determined for 23 paired tumor samples obtained from BRCA1 germ-line mutation carriers before and after NACT. We observed a somatic loss of the wild-type BRCAI allele in 74% (17/23) of OCs before NACT. However, a retention of the wild-type BRCA1 copy resulting in a reversion of LOH status was detected in 65% (11/17) of those patients after NACT. Furthermore, we tested 3 of these reversion samples for LOH at intragenic BRCA1single nucleotide polymorphisms (SNPs) and confirmed a complete restoration of the SNP heterozygosity in all instances. The neoadjuvant chemotherapy for BRCA1-associated OC is accompanied by a rapid expansion of pre-existing BRCA1-proficient tumor clones suggesting that continuation of the same therapy after NACT and surgery may not be justified even in patients initially experiencing a rapid tumor regression. (C) 2017 Elsevier B.V. All rights reserved.
  • Bolck, Hella A.; Przetocka, Sara; Meier, Roger; von Aesch, Christine; Zurfluh, Christina; Haenggi, Kay; Spegg, Vincent; Altmeyer, Matthias; Stebler, Michael; Norrelykke, Simon F.; Horvath, Peter; Sartori, Alessandro A.; Porro, Antonio (2022)
    Human CtIP is best known for its role in DNA end resection to initiate DNA double-strand break repair by homologous recombination. Recently, CtIP has also been shown to protect reversed replication forks from nucleolytic degradation upon DNA replication stress. However, still little is known about the DNA damage response (DDR) networks that preserve genome integrity and sustain cell survival in the context of CtIP insufficiency. Here, to reveal such potential buffering relationships, we screened a DDR siRNA library in CtIP-deficient cells to identify candidate genes that induce synthetic sickness/lethality (SSL). Our analyses unveil a negative genetic interaction between CtIP and BARD1, the heterodimeric binding partner of BRCA1. We found that simultaneous disruption of CtIP and BARD1 triggers enhanced apoptosis due to persistent replication stress-induced DNA lesions giving rise to chromosomal abnormalities. Moreover, we observed that the genetic interaction between CtIP and BARD1 occurs independently of the BRCA1-BARD1 complex formation and might be, therefore, therapeutical relevant for the treatment of BRCA-defective tumors.
  • Zheng, Guoqiao; Hemminki, Akseli; Försti, Asta; Sundquist, Jan; Sundquist, Kristina; Hemminki, Kari (2019)
    Background With continuous increases in survival rates following breast cancer (BC) diagnosis, the challenge of multiple primary cancers has become an issue. The data on familial risk of SPCs after BC diagnosis and the related mortality in BC patients are scarce. Methods A total of 87 752 female BC patients were followed for SPC diagnoses and records of death. Relative risks (RRs) of SPC in BC patients who had first-degree relatives (parents or siblings) affected by the same cancer were compared to the patients without family history. Causes of death were compared between patients with and without SPC. Results After a median follow-up of 5 years, 14 952 BC patients developed SPCs, among which 10 280 (68.8%) had first-degree relatives diagnosed with cancer. Familial risks were significant for 14 site-specific SPCs, and the highest risk was for second ovarian cancer (RR = 6.28, 95%CI: 4.50-8.75), compared to those without family history (1.49, 1.34-1.65). In patients with SPC, SPC was the main cause of death, including diverse cancers and BC in approximately equal proportions. Conclusions Family history contributed to the excess number of patients with SPCs, and SPC was the leading cause of death in patients with SPC. Taking family history at diagnosis of BC may provide warning signs with regard to possible subsequent SPCs and may offer possibilities for counseling, intervention and management.
  • Siddiqui, Arafat; Tumiati, Manuela; Joko, Alia; Sandholm, Jouko; Roering, Pia; Aakko, Sofia; Vainionpää, Reetta; Kaipio, Katja; Huhtinen, Kaisa; Kauppi, Liisa; Tuomela, Johanna; Hietanen, Sakari (2021)
    Critical DNA repair pathways become deranged during cancer development. This vulnerability may be exploited with DNA-targeting chemotherapy. Topoisomerase II inhibitors induce double-strand breaks which, if not repaired, are detrimental to the cell. This repair process requires high-fidelity functional homologous recombination (HR) or error-prone non-homologous end joining (NHEJ). If either of these pathways is defective, a compensatory pathway may rescue the cells and induce treatment resistance. Consistently, HR proficiency, either inherent or acquired during the course of the disease, enables tumor cells competent to repair the DNA damage, which is a major problem for chemotherapy in general. In this context, c-Abl is a protein tyrosine kinase that is involved in DNA damage-induced stress. We used a low-dose topoisomerase II inhibitor mitoxantrone to induce DNA damage which caused a transient cell cycle delay but allowed eventual passage through this checkpoint in most cells. We show that the percentage of HR and NHEJ efficient HeLa cells decreased more than 50% by combining c-Abl inhibitor imatinib with mitoxantrone. This inhibition of DNA repair caused more than 87% of cells in G2/M arrest and a significant increase in apoptosis. To validate the effect of the combination treatment, we tested it on commercial and patient-derived cell lines in high-grade serous ovarian cancer (HGSOC), where chemotherapy resistance correlates with HR proficiency and is a major clinical problem. Results obtained with HR-proficient and deficient HGSOC cell lines show a 50-85% increase of sensitivity by the combination treatment. Our data raise the possibility of successful targeting of treatment-resistant HR-proficient cancers.
  • ENIGMA Consortium; ENIGMA Consortium; GENESIS Study Collaborators; SWE-BRCA Grp; Figlioli, Gisella; Kvist, Anders; Tham, Emma; Muranen, Taru A.; Kiiski, Johanna; Nevanlinna, Heli (2020)
    Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.