Suchergebnisse

Síndrome de Lynch; Panell de gens del càncer; Epimutació ; Síndrome de Lynch; Panel de genes del cáncer; Epimutación ; Lynch syndrome; Cancer genes panel; Epimutation ; The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-deficient tumors and no germline MMR mutations were included. Mutational analysis of 26 colorectal cancer (CRC)-associated genes was performed. Pathogenicity of MMR variants was assessed by splicing and multifactorial likelihood analyses. Genome-wide methylome analysis was performed by the Infinium Human Methylation 450K Bead Chip. The multigene panel analysis revealed the presence of two MMR gene truncating mutations not previously found. Of a total of 15 additional MMR variants identified, five -present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes were found in 12 probands. Methylome analysis detected one constitutional MLH1 epimutation, but no additional differentially methylated regions were identified in LLS compared to LS patients or cancer-free individuals. In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allowed the identification of deleterious MMR mutations as well as new LLS candidate causal genes. Constitutional epimutations in non-LS-associated genes are not responsible for LLS. ; This work was funded by the Spanish Ministry of Economy and Competitiveness and cofunded by FEDER funds -a way to build Europe- (grants SAF2012-33636, SAF2015-68016-R and SAF2016-80888-R), CIBERONC, RTICC Network (RD12/0036/0031 and RD12/0036/0008), the Spanish Association Against Cancer (AECC) (080253), the Government of Catalonia (grant 2014SGR338, 2017SGR1282 and PERIS SLT002/16/0037), Fundación Mutua Madrileña (grant AP114252013). We thank CERCA Programme for institutional support. ED was supported by a grant from the Spanish Ministry of Economy and Competitiveness. The AECC fellowship to MG-A. AF was supported by a grant from the Catalonian Health Department (SLT002/16/00409). FM was supported by CIBERONC. The Mexican National Council for Science and Technology (CONACyT) fellowship to GV.

Predisposició al càncer de mama; Factors de risc de càncer de mama; Espectre de mutació ; Predisposición al cáncer de mama; Factores de riesgo de cáncer de mama; Espectro de mutación ; Breast cancer predisposition; Breast cancer risk factors; Mutation spectrum ; 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. ; This research was partially funded by Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732) to P. Peterlongo, a fellowship from Fondazione Umberto Veronesi to G. Figlioli and by the Italian Ministry of Health with Ricerca Corrente and 5x1000 funds. E. Tham is supported by Region Stockholm (ALF). The Czech study was supported by a grant of the Ministry of Health of the Czech Republic NV16-29959A. CNIO study was partially supported by projects PI16/00440 and PI19/00640, supported by the Instituto de Salud Carlos III, cofunded by European Regional Development Fund (ERDF), the Spanish Network on Rare Diseases (CIBERER) and BRIDGES project H2020. Financial support for GENESIS resource and genotyping was provided by the Ligue Nationale contre le Cancer (grants PRE05/DSL, PRE07/DSL, PRE11/NA), the French National Institute of Cancer (INCa grant No b2008-029/LL-LC) and the comprehensive cancer center SiRIC, (Site de Recherche Intégrée sur le Cancer: Grant INCa-DGOS-4654). HEBCS was funded by Helsinki University Hospital Research Fund, Sigrid Juselius Foundation, The cancer Society of Finland. A.Vega is supported by the Spanish Health Research Foundation, Instituto de Salud Carlos III (ISCIII) through Research Activity Intensification Program (contract grant numbers: INT15/00070, INT16/00154, INT17/00133), and through Centro de Investigación Biomédica en Red de Enferemdades Raras CIBERER (ACCI 2016: ER17P1AC7112/2018); Autonomous Government of Galicia (Consolidation and structuring program: IN607B), and by the Fundación Mutua Madrileña (call 2018). This work was supported by the Australian National Health and Medical Research Council (APP1029974 and APP1074383) and by a Victorian Life Sciences Computation Initiative grant (number VR0182) on its Peak Computing Facility, an initiative of the Victorian Government. T.N-D is a Career Development Fellow of the National Breast Cancer Foundation (Australia, ECF-17-001). M.C.S. is a National Health and Medical Research Council (Australia) Senior Research Fellow. The Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745 and NKFI OTKA K-112228 to E. Olah. Lithuanian study was supported by The Research Council of Lithuania grant SEN18/2015 and P-MIP-20-25 to R. Janavicius. The ICO was supported by the Carlos III National Health Institute funded by FEDER funds—a way to build Europe—[PI16/00563, PI19/00553 and CIBERONC]; the Government of Catalonia [Pla estratègic de recerca i innovació en salut (PERIS) Project MedPerCan, 2017SGR1282 and 2017SGR496]; and CERCA program.

Síndromes de càncer; Panell genètic; Proves genètiques ; Síndromes de cáncer; Panel de genes; Prueba genética ; Cancer syndromes; Gene panel; Genetic testing ; Importance Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations. Objective To determine the prevalence and clinical features of MINAS in a large cohort of adult patients with hereditary cancer homogeneously tested with the same gene panel. Patients and methods A cohort of 1023 unrelated patients with suspicion of hereditary cancer was screened using a validated panel including up to 135 genes associated with hereditary cancer and phakomatoses. Results Thirteen (1.37%) patients harbouring two pathogenic mutations in dominant cancer-predisposing genes were identified, representing 5.7% (13/226) of patients with pathogenic mutations. Most (10/13) of these cases presented clinical manifestations associated with only one of the mutations identified. One case showed mutations in MEN1 and MLH1 and developed tumours associated with both cancer syndromes. Interestingly, three of the double mutants had a young age of onset or severe breast cancer phenotype and carried mutations in moderate to low-risk DNA damage repair-associated genes; two of them presented biallelic inactivation of CHEK2. We included these two patients for the sake of their clinical interest although we are aware that they do not exactly fulfil the definition of MINAS since both mutations are in the same gene. Conclusions and relevance Genetic analysis of a broad cancer gene panel identified the largest series of patients with MINAS described in a single study. Overall, our data do not support the existence of more severe manifestations in double mutants at the time of diagnosis although they do confirm previous evidence of severe phenotype in biallelic CHEK2 and other DNA repair cancer-predisposing genes. ; Contract grant sponsor: Supported by the Carlos III National Health Institute and Ministerio de Educación y Ciencia funded by FEDER funds–a way to build Europe (PI16/00563, PI16/01363, SAF2015-68016-R and CIBERONC); the Government of Catalonia (Pla estratègic de recerca i innovació en salut (PERIS), 2017SGR1282 and 2017SGR496); and the scientific foundation Asociación Española Contra el Cáncer.

Cancer hereditario de mama y ovario; Pseudoexones; Variantes intrónicas profundas spliceogénicas ; Càncer hereditari de mama i d'ovari; Pseudoexons; Variants intròniques profundes spliceogèniques ; Hereditary breast ovarian cancer; Pseudoexons; Spliceogenic deep intronic variants ; The contribution of deep intronic splice-altering variants to hereditary breast and ovarian cancer (HBOC) is unknown. Current computational in silico tools to predict spliceogenic variants leading to pseudoexons have limited efficiency. We assessed the performance of the SpliceAI tool combined with ESRseq scores to identify spliceogenic deep intronic variants by affecting cryptic sites or splicing regulatory elements (SREs) using literature and experimental datasets. Our results with 233 published deep intronic variants showed that SpliceAI, with a 0.05 threshold, predicts spliceogenic deep intronic variants affecting cryptic splice sites, but is less effective in detecting those affecting SREs. Next, we characterized the SRE profiles using ESRseq, showing that pseudoexons are significantly enriched in SRE-enhancers compared to adjacent intronic regions. Although the combination of SpliceAI with ESRseq scores (considering ∆ESRseq and SRE landscape) showed higher sensitivity, the global performance did not improve because of the higher number of false positives. The combination of both tools was tested in a tumor RNA dataset with 207 intronic variants disrupting splicing, showing a sensitivity of 86%. Following the pipeline, five spliceogenic deep intronic variants were experimentally identified from 33 variants in HBOC genes. Overall, our results provide a framework to detect deep intronic variants disrupting splicing. ; This research was funded by the Spanish Instituto de Salud Carlos III (ISCIII) funding an initiative of the Spanish Ministry of Economy and Innovation, partially supported by European Regional Development FEDER Funds, grant numbers PI16/01218 and PI19/01303. AM-F contract is supported by the award ERAPERMED2019-215 granted by AECC FC and by ISCIII thorough AES 2019, both within the ERAPerMed framework". J.D.-V. contract is supported by the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia and the European Social Fund.

Domini de l'exonucleasa; Càncer colorectal hereditari; Fenotip ultramutat ; Dominio exonucleasa; Cáncer colorrectal hereditario; Fenotipo ultramutado ; Exonuclease domain; Hereditary colorectal cancer; Ultramutated phenotype ; Purpose Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study. Methods POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case–control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation. Results Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies <1%, were identified. One ED variant (POLE p.Met294Arg) was classified as likely pathogenic, four as likely benign, and seven as variants of unknown significance. The most commonly associated tumor types were colorectal, endometrial and ovarian cancers. Loss-of-function and outside-ED variants are likely not pathogenic for this syndrome. Conclusions Polymerase proofreading–associated syndrome constitutes 0.1–0.4% of familial cancer cases, reaching 0.3–0.7% when only CRC and polyposis are considered. ED variant interpretation is challenging and should include multiple pieces of evidence. ; We thank Gemma Aiza, Mireia Menéndez, Sara González, and Xavier Muñoz for support, and Biobanc HUB-ICO-IDIBELL, integrated in the Spanish Platform Biobanks Network and funded by Instituto de Salud Carlos III (PT17/0015/0024) and Xarxa Bancs de Tumors de Catalunya sponsored by Pla Director d'Oncologia de Catalunya. This work was funded by the Spanish Ministry of Science and Innovation, cofunded by FEDER funds (SAF2016-80888-R, SAF2015-68016-R, Severo Ochoa SVP-2014-068895 contract [L.M.-P.]); Instituto de Salud Carlos III (PI16/00563, PI16/00588, PI14/00613, PI19/00553, CIBERONC CB16/12/00234, CIBERESP, Sara Borrell contract [P.M.]); Government of Catalonia [AGAUR 2017SGR1282, CERCA Program]; and Fundación Olga Torres. This study was facilitated by COST Action CA17118, supported by COST (European Cooperation in Science and Technology).

BARD1; Càncer hereditari de mama i ovari; Risc moderat de càncer ; BARD1; Cáncer de mama y ovario hereditario; Riesgo de cáncer moderado ; BARD1; Hereditary breast and ovarian cancer; Moderate cancer risk ; Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (BRCA1 and BRCA2). BRCA1-associated ring domain 1 (BARD1), nuclear partner of BRCA1, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of BARD1 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive BARD1 screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous BARD1 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating BARD1 variants with overall risk (odds ratio (OR) = 3.78; CI = 2.10–6.48; p = 1.16 × 10−5). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18; CI = 2.10–7.70; p = 5.45 × 10−5). Furthermore, deleterious BARD1 variants were enriched among triple-negative BC patients (OR = 5.40; CI = 1.77–18.15; p = 0.001) compared to other BC subtypes. Our results support the role of BARD1 as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors. ; Contract grant sponsor: Supported by the Carlos III National Health Institute funded by FEDER funds—a way to build Europe—(PI19/00553; PI16/00563; PI16/01898; PI16/11363; PI15/00355; PI12/02585; SAF2015-68016-R and CIBERONC); the Government of ...