22 results on '"Sami Belhadj"'
Search Results
2. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
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Christopher Hakkaart, John F. Pearson, Louise Marquart, Joe Dennis, George A. R. Wiggins, Daniel R. Barnes, Bridget A. Robinson, Peter D. Mace, Kristiina Aittomäki, Irene L. Andrulis, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Sami Belhadj, Lieke Berger, Marinus J. Blok, Susanne E. Boonen, Julika Borde, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Maria A. Caligo, Ian Campbell, Wendy K. Chung, Kathleen B. M. Claes, GEMO Study Collaborators, EMBRACE Collaborators, Marie-Agnès Collonge-Rame, Jackie Cook, Casey Cosgrove, Fergus J. Couch, Mary B. Daly, Sita Dandiker, Rosemarie Davidson, Miguel de la Hoya, Robin de Putter, Capucine Delnatte, Mallika Dhawan, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Alan Donaldson, Jacqueline Eason, Douglas F. Easton, Hans Ehrencrona, Christoph Engel, D. Gareth Evans, Ulrike Faust, Lidia Feliubadaló, Florentia Fostira, Eitan Friedman, Megan Frone, Debra Frost, Judy Garber, Simon A. Gayther, Andrea Gehrig, Paul Gesta, Andrew K. Godwin, David E. Goldgar, Mark H. Greene, Eric Hahnen, Christopher R. Hake, Ute Hamann, Thomas V. O. Hansen, Jan Hauke, Julia Hentschel, Natalie Herold, Ellen Honisch, Peter J. Hulick, Evgeny N. Imyanitov, SWE-BRCA Investigators, kConFab Investigators, HEBON Investigators, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Zoe Kemp, Judy Kirk, Irene Konstantopoulou, Marco Koudijs, Ava Kwong, Yael Laitman, Fiona Lalloo, Christine Lasset, Charlotte Lautrup, Conxi Lazaro, Clémentine Legrand, Goska Leslie, Fabienne Lesueur, Phuong L. Mai, Siranoush Manoukian, Véronique Mari, John W. M. Martens, Lesley McGuffog, Noura Mebirouk, Alfons Meindl, Austin Miller, Marco Montagna, Lidia Moserle, Emmanuelle Mouret-Fourme, Hannah Musgrave, Sophie Nambot, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Joanne Ngeow Yuen Yie, Tu Nguyen-Dumont, Liene Nikitina-Zake, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Ana Peixoto, Pedro Perez-Segura, Paolo Peterlongo, Timea Pocza, Paolo Radice, Juliane Ramser, Johanna Rantala, Gustavo C. Rodriguez, Karina Rønlund, Efraim H. Rosenberg, Maria Rossing, Rita K. Schmutzler, Payal D. Shah, Saba Sharif, Priyanka Sharma, Lucy E. Side, Jacques Simard, Christian F. Singer, Katie Snape, Doris Steinemann, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Mads Thomassen, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Alison H. Trainer, Vishakha Tripathi, Nadine Tung, Klaartje van Engelen, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Lisa Walker, Jeffrey N. Weitzel, Marike R. Wevers, Georgia Chenevix-Trench, Amanda B. Spurdle, Antonis C. Antoniou, and Logan C. Walker
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Biology (General) ,QH301-705.5 - Abstract
The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.
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- 2022
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3. A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants
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Mariann Unhjem Wiik, Tiffany-Jane Evans, Sami Belhadj, Katherine A. Bolton, Dagmara Dymerska, Shantie Jagmohan-Changur, Gabriel Capellá, Grzegorz Kurzawski, Juul T. Wijnen, Laura Valle, Hans F. A. Vasen, Jan Lubinski, Rodney J. Scott, and Bente A. Talseth-Palmer
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Medicine ,Science - Abstract
Abstract Individuals with Lynch syndrome (LS), have an increased risk of developing cancer. Common genetic variants of telomerase reverse transcriptase (TERT) have been associated with a wide range of cancers, including colorectal cancer (CRC) in LS. We combined genotype data from 1881 LS patients, carrying pathogenic variants in MLH1, MSH2 or MSH6, for rs2075786 (G>A, intronic variant), 1207 LS patients for rs2736108 (C>T, upstream variant) and 1201 LS patients for rs7705526 (C>A, intronic variant). The risk of cancer was estimated by heterozygous/homozygous odds ratio (OR) with mixed-effects logistic regression to adjust for gene/gender/country of sample origin considering family identity. The AA genotype of SNP rs2075786 is associated with 85% higher odds at developing cancer compared to GG genotype in MSH2 pathogenic variant carriers (p = 0.0160). Kaplan–Meier analysis also shows an association for rs2075786; the AA allele for MSH2 variant carriers confers risk for earlier diagnosis of LS cancer (log-rank p = 0.0011). We report a polymorphism in TERT to be a possible modifier of disease risk in MSH2 pathogenic variant carriers. The rs2075786 SNP in TERT is associated with a differential risk of developing cancer for MSH2 pathogenic variant carriers. Use of this information has the potential to personalise screening protocols for LS patients.
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- 2021
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4. Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients
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Jesús del Valle, Paula Rofes, José Marcos Moreno-Cabrera, Adriana López-Dóriga, Sami Belhadj, Gardenia Vargas-Parra, Àlex Teulé, Raquel Cuesta, Xavier Muñoz, Olga Campos, Mónica Salinas, Rafael de Cid, Joan Brunet, Sara González, Gabriel Capellá, Marta Pineda, Lídia Feliubadaló, and Conxi Lázaro
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Breast cancer risk ,Breast and ovarian cancer risk ,Fanconi Anemia ,Hereditary Cancer ,NGS panel sequencing ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Fanconi anemia (FA) is caused by biallelic mutations in FA genes. Monoallelic mutations in five of these genes (BRCA1, BRCA2, PALB2, BRIP1 and RAD51C) increase the susceptibility to breast/ovarian cancer and are used in clinical diagnostics as bona-fide hereditary cancer genes. Increasing evidence suggests that monoallelic mutations in other FA genes could predispose to tumor development, especially breast cancer. The objective of this study is to assess the mutational spectrum of 14 additional FA genes (FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FANCP, FANCQ, FANCR and FANCU) in a cohort of hereditary cancer patients, to compare with local cancer-free controls as well as GnomAD. A total of 1021 hereditary cancer patients and 194 controls were analyzed using our next generation custom sequencing panel. We identified 35 pathogenic variants in eight genes. A significant association with the risk of breast cancer/breast and ovarian cancer was found for carriers of FANCA mutations (odds ratio (OR) = 3.14 95% confidence interval (CI) 1.4–6.17, p = 0.003). Two patients with early-onset cancer showed a pathogenic FA variant in addition to another germline mutation, suggesting a modifier role for FA variants. Our results encourage a comprehensive analysis of FA genes in larger studies to better assess their role in cancer risk.
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- 2020
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5. NBN Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and In Vitro DNA Damage Response Defects
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Sami Belhadj, Aliya Khurram, Chaitanya Bandlamudi, Guillermo Palou-Márquez, Vignesh Ravichandran, Zoe Steinsnyder, Temima Wildman, Amanda Catchings, Yelena Kemel, Semanti Mukherjee, Benjamin Fesko, Kanika Arora, Miika Mehine, Sita Dandiker, Aalin Izhar, John Petrini, Susan Domchek, Katherine L. Nathanson, Jamie Brower, Fergus Couch, Zsofia Stadler, Mark Robson, Michael Walsh, Joseph Vijai, Michael Berger, Fran Supek, Rachid Karam, Sabine Topka, and Kenneth Offit
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Cancer Research ,Oncology - Abstract
Purpose: To explore the role of NBN as a pan-cancer susceptibility gene. Experimental Design: Matched germline and somatic DNA samples from 34,046 patients were sequenced using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and presumed pathogenic germline variants (PGV) identified. Allele-specific and gene-centered analysis of enrichment was conducted and a validation cohort of 26,407 pan-cancer patients was analyzed. Functional studies utilized cellular models with analysis of protein expression, MRN complex formation/localization, and viability assessment following treatment with γ-irradiation. Results: We identified 83 carriers of 32 NBN PGVs (0.25% of the studied series), 40% of which (33/83) carried the Slavic founder p.K219fs. The frequency of PGVs varied across cancer types. Patients harboring NBN PGVs demonstrated increased loss of the wild-type allele in their tumors [OR = 2.7; confidence interval (CI): 1.4–5.5; P = 0.0024; pan-cancer], including lung and pancreatic tumors compared with breast and colorectal cancers. p.K219fs was enriched across all tumor types (OR = 2.22; CI: 1.3–3.6; P = 0.0018). Gene-centered analysis revealed enrichment of PGVs in cases compared with controls in the European population (OR = 1.9; CI: 1.3–2.7; P = 0.0004), a finding confirmed in the replication cohort (OR = 1.8; CI: 1.2–2.6; P = 0.003). Two novel truncating variants, p.L19* and p.N71fs, produced a 45 kDa fragment generated by alternative translation initiation that maintained binding to MRE11. Cells expressing these fragments showed higher sensitivity to γ-irradiation and lower levels of radiation-induced KAP1 phosphorylation. Conclusions: Burden analyses, biallelic inactivation, and functional evidence support the role of NBN as contributing to a broad cancer spectrum. Further studies in large pan-cancer series and the assessment of epistatic and environmental interactions are warranted to further define these associations.
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- 2022
6. Figure S1 from NBN Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and In Vitro DNA Damage Response Defects
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Kenneth Offit, Sabine Topka, Rachid Karam, Fran Supek, Michael Berger, Joseph Vijai, Michael Walsh, Mark Robson, Zsofia Stadler, Fergus Couch, Jamie Brower, Katherine L. Nathanson, Susan Domchek, John Petrini, Aalin Izhar, Sita Dandiker, Miika Mehine, Kanika Arora, Benjamin Fesko, Semanti Mukherjee, Yelena Kemel, Amanda Catchings, Temima Wildman, Zoe Steinsnyder, Vignesh Ravichandran, Guillermo Palou-Márquez, Chaitanya Bandlamudi, Aliya Khurram, and Sami Belhadj
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Supplementary Figure S1. Germline and somatic data from The Cancer Genome Atlas (TCGA) project, representing 10,268 cancer patients with whole exome sequencing data.
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- 2023
7. Data from NBN Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and In Vitro DNA Damage Response Defects
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Kenneth Offit, Sabine Topka, Rachid Karam, Fran Supek, Michael Berger, Joseph Vijai, Michael Walsh, Mark Robson, Zsofia Stadler, Fergus Couch, Jamie Brower, Katherine L. Nathanson, Susan Domchek, John Petrini, Aalin Izhar, Sita Dandiker, Miika Mehine, Kanika Arora, Benjamin Fesko, Semanti Mukherjee, Yelena Kemel, Amanda Catchings, Temima Wildman, Zoe Steinsnyder, Vignesh Ravichandran, Guillermo Palou-Márquez, Chaitanya Bandlamudi, Aliya Khurram, and Sami Belhadj
- Abstract
Purpose:To explore the role of NBN as a pan-cancer susceptibility gene.Experimental Design:Matched germline and somatic DNA samples from 34,046 patients were sequenced using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and presumed pathogenic germline variants (PGV) identified. Allele-specific and gene-centered analysis of enrichment was conducted and a validation cohort of 26,407 pan-cancer patients was analyzed. Functional studies utilized cellular models with analysis of protein expression, MRN complex formation/localization, and viability assessment following treatment with γ-irradiation.Results:We identified 83 carriers of 32 NBN PGVs (0.25% of the studied series), 40% of which (33/83) carried the Slavic founder p.K219fs. The frequency of PGVs varied across cancer types. Patients harboring NBN PGVs demonstrated increased loss of the wild-type allele in their tumors [OR = 2.7; confidence interval (CI): 1.4–5.5; P = 0.0024; pan-cancer], including lung and pancreatic tumors compared with breast and colorectal cancers. p.K219fs was enriched across all tumor types (OR = 2.22; CI: 1.3–3.6; P = 0.0018). Gene-centered analysis revealed enrichment of PGVs in cases compared with controls in the European population (OR = 1.9; CI: 1.3–2.7; P = 0.0004), a finding confirmed in the replication cohort (OR = 1.8; CI: 1.2–2.6; P = 0.003). Two novel truncating variants, p.L19* and p.N71fs, produced a 45 kDa fragment generated by alternative translation initiation that maintained binding to MRE11. Cells expressing these fragments showed higher sensitivity to γ-irradiation and lower levels of radiation-induced KAP1 phosphorylation.Conclusions:Burden analyses, biallelic inactivation, and functional evidence support the role of NBN as contributing to a broad cancer spectrum. Further studies in large pan-cancer series and the assessment of epistatic and environmental interactions are warranted to further define these associations.
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- 2023
8. Germline Pathogenic Variants Impact Clinicopathology of Advanced Lung Cancer
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Semanti Mukherjee, Chaitanya Bandlamudi, Matthew D. Hellmann, Yelena Kemel, Esther Drill, Hira Rizvi, Kaitlyn Tkachuk, Aliya Khurram, Michael F. Walsh, Marjorie G. Zauderer, Diana Mandelker, Sabine Topka, Ahmet Zehir, Preethi Srinivasan, Myvizhi Esai Selvan, Maria I. Carlo, Karen A. Cadoo, Alicia Latham, Jada G. Hamilton, Ying L. Liu, Steven M. Lipkin, Sami Belhadj, Gareth L. Bond, Zeynep H. Gümüş, Robert J. Klein, Marc Ladanyi, David B. Solit, Mark E. Robson, David R. Jones, Mark G. Kris, Joseph Vijai, Zsofia K. Stadler, Christopher I. Amos, Barry S. Taylor, Michael F. Berger, Charles M. Rudin, and Kenneth Offit
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Germ Cells ,Lung Neoplasms ,Oncology ,Epidemiology ,Humans ,Genetic Predisposition to Disease ,Prospective Studies ,Germ-Line Mutation ,Article - Abstract
Background: The genetic factors that modulate risk for developing lung cancer have not been fully defined. Here, we sought to determine the prevalence and clinical significance of germline pathogenic/likely pathogenic variants (PV) in patients with advanced lung cancer. Methods: We studied clinical and tumor characteristics of germline PV in 5,118 patients who underwent prospective genomic profiling using paired tumor–normal tissue samples in 468 cancer genes. Results: Germline PV in high/moderate-penetrance genes were observed in 222 (4.3%) patients; of these, 193 patients had PV in DNA damage repair (DDR) pathway genes including BRCA2 (n = 54), CHEK2 (n = 30), and ATM (n = 26) that showed high rate of biallelic inactivation in tumors. BRCA2 heterozygotes with lung adenocarcinoma were more likely to be never smokers and had improved survival compared with noncarriers. Fourteen patients with germline PV in lung cancer predisposing genes (TP53, EGFR, BAP1, and MEN1) were diagnosed at younger age compared with noncarriers, and of tumor suppressors, 75% demonstrated biallelic inactivation in tumors. A significantly higher proportion of germline PV in high/moderate-penetrance genes were detected in high-risk patients who had either a family history of any cancer, multiple primary tumors, or early age at diagnosis compared with unselected patients (10.5% vs. 4.1%; P = 1.7e−04). Conclusions: These data underscore the biological and clinical importance of germline mutations in highly penetrant DDR genes as a risk factor for lung cancer. Impact: The family members of lung cancer patients harboring PV in cancer predisposing genes should be referred for genetic counseling and may benefit from proactive surveillance.
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- 2022
9. Regulation of Laboratory-Developed Tests in Preventive Oncology: Emerging Needs and Opportunities
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Kenneth Offit, Catherine M. Sharkey, Dina Green, Xiaohan Wu, Magan Trottier, Jada G. Hamilton, Michael F. Walsh, Sita Dandiker, Sami Belhadj, Steven M. Lipkin, Thelma Alessandra Sugrañes, Michele Caggana, and Zsofia K. Stadler
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Cancer Research ,Oncology - Abstract
Cancer predictive or diagnostic assays, offered as Laboratory-Developed Tests (LDTs), have been subject to regulatory authority and enforcement discretion by the US Food and Drug Administration. Many LDTs enter the market without US Food and Drug Administration or any regulatory review. The Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Amendments focuses on analytic performance, but has limited oversight of the quality or utility of LDTs, including whether patients have been harmed as a result of their use. Increasingly, LDTs for cancer risk or early detection have been marketed directly to consumers, with many LDT developers depicting these tests, requested by patients but ordered by personal or company-associated physicians, as procedures falling under the practice of medicine. This patchwork of regulation and enforcement uncertainty regarding LDTs and public concerns about accuracy of tests given emergency authorization during the COVID-19 pandemic led to the Verifying Accurate Leading-edge IVCT (in vitro clinical test) Development Act of 2021. This pending federal legislation represents an opportunity to harmonize regulatory policies and address growing concerns over quality, utility, and safety of LDTs for cancer genomics, including tests marketed directly to consumers. We review here questions regarding the potential benefits and harms of some cancer-related LDTs for cancer risk and presymptomatic molecular diagnosis, increasingly marketed to oncologists or directly to the worried well. We offer specific proposals to strengthen oversight of the accuracy and clinical utility of cancer genetic testing to ensure public safety.
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- 2022
10. Role of POLE and POLD1 in familial cancer
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Pau M. Munoz-Torres, Joan Brunet, Rebeca Sanz-Pamplona, August Vidal, Gemma Llort, Esther Darder, Victor Moreno, Teresa Ramón y Cajal, Laura Valle, Judith Balmaña, Marta Pineda, Tirso Pons, Xavier Matias-Guiu, Jesús del Valle, Lorena Magraner-Pardo, Rosa Aligué, Pilar Mur, Giacomo Cinnirella, Josep M. Piulats, Elia Grau, Lídia Feliubadaló, Sami Belhadj, Adriana Lopez-Doriga, Matilde Navarro, Conxi Lázaro, Sandra García-Mulero, Judit Sanz, Gabriel Capellá, Edgar Martin-Ramos, [Mur P, Del Valle J, Pineda M] Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. [García-Mulero S] Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. [Magraner-Pardo L] Prostate Cancer Clinical Research Unit. Spanish National Cancer Research Center (CNIO), Madrid, Spain. [Vidal A] Department of Pathology, Bellvitge University Hospital, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. [Balmana J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Generalitat de Catalunya, Fundación Olga Torres, and European Cooperation in Science and Technology
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fenómenos genéticos::variación genética::mutación::mutación de la línea germinal [FENÓMENOS Y PROCESOS] ,Proband ,Polymerase proofreading–associated polyposis ,Recte - Càncer - Aspectes genètics ,Colorectal cancer ,Genetic counseling ,Population ,Còlon - Càncer - Aspectes genètics ,Biology ,Article ,Genetic Phenomena::Genetic Variation::Mutation::Germ-Line Mutation [PHENOMENA AND PROCESSES] ,Germline ,PPAP ,Endometrial cancer ,Càncer colorectal ,Malalties hereditàries ,Ultramutated phenotype ,medicine ,Humans ,Missense mutation ,Poly-ADP-Ribose Binding Proteins ,education ,Allele frequency ,Germ-Line Mutation ,Genetics (clinical) ,Exonuclease domain ,DNA Polymerase III ,Genetics ,education.field_of_study ,Malalties transmissibles - Teoria germinal ,POLD1 ,ultramutated phenotype ,DNA Polymerase II ,medicine.disease ,polymerase proofreading–associated polyposis ,Càncer d'endometri ,Neoplasms::Neoplasms::Neoplastic Syndromes, Hereditary::Colorectal Neoplasms, Hereditary Nonpolyposis [DISEASES] ,Hereditary colorectal cancer ,Mutation ,hereditary colorectal cancer ,neoplasias::neoplasias::síndromes neoplásicos hereditarios::neoplasias colorrectales hereditarias sin poliposis [ENFERMEDADES] ,exonuclease domain ,Colorectal Neoplasms ,Genetic diseases - Abstract
[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, 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).
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- 2020
11. TP53, a gene for colorectal cancer predisposition in the absence of Li-Fraumeni-associated phenotypes
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Emma R. Woodward, Conxi Lázaro, D. Gareth Evans, Pau M. Munoz-Torres, George J Burghel, Gabriel Capellá, Mariona Terradas, Matilde Navarro, Marta Pineda, Isabel Quintana, Laura Valle, Victor Moreno, Pilar Mur, Sami Belhadj, and Joan Brunet
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,education.field_of_study ,medicine.diagnostic_test ,Molecular pathology ,business.industry ,Colorectal cancer ,Population ,Gastroenterology ,Cancer ,Gene mutation ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Medical genetics ,Missense mutation ,business ,education ,Genetic testing - Abstract
ObjectiveGermline TP53 pathogenic (P) variants cause Li-Fraumeni syndrome (LFS), an aggressive multitumor-predisposing condition. Due to the implementation of multigene panel testing, TP53 variants have been detected in individuals without LFS suspicion, for example, patients with colorectal cancer (CRC). We aimed to decipher whether these findings are the result of detecting the background population prevalence or the aetiological basis of CRC.DesignWe analysed TP53 in 473 familial/early-onset CRC cases and evaluated the results together with five additional studies performed in patients with CRC (total n=6200). Control population and LFS data were obtained from Genome Aggregation Database (gnomAD V.2.1.1) and the International Agency for Research on Cancer (IARC) TP53 database, respectively. All variants were reclassified according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), following the ClinGen TP53 Expert Panel specifications.ResultsP or likely pathogenic (LP) variants were identified in 0.05% of controls (n=27/59 095) and 0.26% of patients with CRC (n=16/6200) (pTP53 testing. This association was still detected when patients with CRC diagnosed at more advanced ages (>50 and>60 years) were excluded from the analysis to minimise the inclusion of variants caused by clonal haematopoiesis. Loss-of-function and missense variants were strongly associated with CRC as compared with controls (OR=25.44, 95% CI 6.10 to 149.03, for loss of function and splice-site alleles, and OR=3.58, 95% CI 1.46 to 7.98, for missense P or LP variants).ConclusionTP53 P variants should not be unequivocally associated with LFS. Prospective follow-up of carriers of germline TP53 P variants in the absence of LFS phenotypes will define how surveillance and clinical management of these individuals should be performed.
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- 2020
12. Candidate genes for hereditary colorectal cancer: Mutational screening and systematic review
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Gabriel Capellá, Laura Valle, Matilde Navarro, Mariona Terradas, Gemma Aiza, Sami Belhadj, and Pau M. Munoz-Torres
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Adult ,Candidate gene ,Adolescent ,Colorectal cancer ,DNA Mutational Analysis ,Biology ,Cohort Studies ,Young Adult ,03 medical and health sciences ,Germline mutation ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Epigenetics ,Promoter Regions, Genetic ,Allele frequency ,Interleukin 12 receptor, beta 1 subunit ,Gene ,Early Detection of Cancer ,Genetics (clinical) ,Aged ,030304 developmental biology ,Aged, 80 and over ,0303 health sciences ,FAN1 ,Receptor-Like Protein Tyrosine Phosphatases, Class 3 ,030305 genetics & heredity ,DNA Methylation ,Middle Aged ,medicine.disease ,Colorectal Neoplasms - Abstract
Genome-wide approaches applied for the identification of new hereditary colorectal cancer (CRC) genes, identified several potential causal genes, including RPS20, IL12RB1, LIMK2, POLE2, MRE11, POT1, FAN1, WIF1, HNRNPA0, SEMA4A, FOCAD, PTPN12, LRP6, POLQ, BLM, MCM9, and the epigenetic inactivation of PTPRJ. Here we attempted to validate the association between variants in these genes and nonpolyposis CRC by performing a mutational screening of the genes and PTPRJ promoter methylation analysis in 473 familial/early-onset CRC cases, a systematic review of the published cases, and assessment of allele frequencies in control population. In the studied cohort, 24 (5%) carriers of (predicted) deleterious variants in the studied genes and no constitutional PTPRJ epimutations were identified. Assessment of allele frequencies in controls compared with familial/early-onset patients with CRC showed association with increased nonpolyposis CRC risk of disruptive variants in RPS20, IL12RB1, POLE2, MRE11 and POT1, and of FAN1 c.149T>G (p.Met50Arg). Lack of association was demonstrated for LIMK2, PTPN12, LRP6, PTPRJ, POLQ, BLM, MCM9 and FOCAD variants. Additional studies are required to provide conclusive evidence for SEMA4A, WIF1, HNRNPA0 c.-110G>C, and FOCAD large deletions.
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- 2020
13. Multiple Primary Cancers in Patients Undergoing Tumor-Normal Sequencing Define Novel Associations
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Ying L Liu, Michael F. Berger, Marc Ladanyi, Ahmet Zehir, Erin E. Salo-Mullen, Alicia Latham, Joseph Vijai, Karen Cadoo, Yuhan Wang, Michael Walsh, Yelena Kemel, A. Rose Brannon, Zsofia K. Stadler, Anna Maio, Venkatraman E. Seshan, Chaitanya Bandlamudi, Diana Mandelker, Sami Belhadj, Margaret Sheehan, Marianne E Dubard-Gault, Dean F. Bajorin, Sita Dandiker, Semanti Mukherjee, Maria I. Carlo, Kenneth Offit, David B. Solit, Mark E. Robson, Bryan Devolder, Kaitlyn Tkachuk, Vignesh Ravichandran, Aliya Khurram, and Elise Fiala
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Oncology ,Male ,medicine.medical_specialty ,Epidemiology ,Germline ,Article ,Loss of heterozygosity ,Neoplasms, Multiple Primary ,Prostate ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Melanoma ,Germ-Line Mutation ,business.industry ,Incidence (epidemiology) ,Confounding ,Cancer ,Prostatic Neoplasms ,Neoplasms, Second Primary ,medicine.disease ,Phenotype ,medicine.anatomical_structure ,business - Abstract
Background: Cancer survivors are developing more subsequent tumors. We sought to characterize patients with multiple (≥2) primary cancers (MPC) to assess associations and genetic mechanisms. Methods: Patients were prospectively consented (01/2013–02/2019) to tumor-normal sequencing via a custom targeted panel (MSK-IMPACT). A subset consented to return of results of ≥76 cancer predisposition genes. International Agency for Research on Cancer (IARC) 2004 rules for defining MPC were applied. Tumor pairs were created to assess relationships between cancers. Age-adjusted, sex-specific, standardized incidence ratios (SIR) for first to second cancer event combinations were calculated using SEER rates, adjusting for confounders and time of ascertainment. Associations were made with germline and somatic variants. Results: Of 24,241 patients, 4,340 had MPC (18%); 20% were synchronous. Most (80%) had two primaries; however, 4% had ≥4 cancers. SIR analysis found lymphoma–lung, lymphoma–uterine, breast–brain, and melanoma–lung pairs in women and prostate–mesothelioma, prostate–sarcoma, melanoma–stomach, and prostate–brain pairs in men in excess of expected after accounting for synchronous tumors, known inherited cancer syndromes, and environmental exposures. Of 1,580 (36%) patients who received germline results, 324 (21%) had 361 pathogenic/likely pathogenic variants (PV), 159 (44%) in high penetrance genes. Of tumor samples analyzed, 55% exhibited loss of heterozygosity at the germline variant. In those with negative germline findings, melanoma, prostate, and breast cancers were common. Conclusions: We identified tumor pairs without known predisposing mutations that merit confirmation and will require novel strategies to elucidate genetic mechanisms of shared susceptibilities. Impact: If verified, patients with MPC with novel phenotypes may benefit from targeted cancer surveillance.
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- 2021
14. A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants
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Dagmara Dymerska, Grzegorz Kurzawski, Gabriel Capellá, Katherine A. Bolton, Hans F. A. Vasen, Juul T. Wijnen, Rodney J. Scott, Shantie Jagmohan-Changur, Tiffany-Jane Evans, Bente A. Talseth-Palmer, Jan Lubinski, Mariann Unhjem Wiik, Sami Belhadj, and Laura Valle
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Male ,0301 basic medicine ,0302 clinical medicine ,Genotype ,Malalties hereditàries ,Càncer ,Cancer genetics ,Telomerase ,Cancer ,Aged, 80 and over ,Genetics ,Multidisciplinary ,Factors de risc en les malalties ,RNA-Directed DNA Polymerase ,Middle Aged ,Lynch syndrome ,MutS Homolog 2 Protein ,030220 oncology & carcinogenesis ,Chromosomes, Human, Pair 5 ,Medicine ,Female ,Colorectal Neoplasms ,Genetic diseases ,Adult ,Adolescent ,Risk factors in diseases ,Science ,MLH1 ,Polymorphism, Single Nucleotide ,Article ,Young Adult ,03 medical and health sciences ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Aged ,business.industry ,Odds ratio ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,digestive system diseases ,MSH6 ,030104 developmental biology ,MSH2 ,business - Abstract
Individuals with Lynch syndrome (LS), have an increased risk of developing cancer. Common genetic variants of telomerase reverse transcriptase (TERT) have been associated with a wide range of cancers, including colorectal cancer (CRC) in LS. We combined genotype data from 1881 LS patients, carrying pathogenic variants in MLH1, MSH2 or MSH6, for rs2075786 (G>A, intronic variant), 1207 LS patients for rs2736108 (C>T, upstream variant) and 1201 LS patients for rs7705526 (C>A, intronic variant). The risk of cancer was estimated by heterozygous/homozygous odds ratio (OR) with mixed-effects logistic regression to adjust for gene/gender/country of sample origin considering family identity. The AA genotype of SNP rs2075786 is associated with 85% higher odds at developing cancer compared to GG genotype in MSH2 pathogenic variant carriers (p = 0.0160). Kaplan–Meier analysis also shows an association for rs2075786; the AA allele for MSH2 variant carriers confers risk for earlier diagnosis of LS cancer (log-rank p = 0.0011). We report a polymorphism in TERT to be a possible modifier of disease risk in MSH2 pathogenic variant carriers. The rs2075786 SNP in TERT is associated with a differential risk of developing cancer for MSH2 pathogenic variant carriers. Use of this information has the potential to personalise screening protocols for LS patients.
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- 2021
15. Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients
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Lídia Feliubadaló, Raquel Cuesta, Paula Rofes, Sami Belhadj, Rafael de Cid, Mónica Salinas, Gardenia Vargas-Parra, Alex Teulé, Olga Campos, Joan Brunet, Conxi Lázaro, José Marcos Moreno-Cabrera, Adriana Lopez-Doriga, Xavier Muñoz, Jesús del Valle, Gabriel Capellá, Sara González, and Marta Pineda
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0301 basic medicine ,Cancer Research ,Càncer d'ovari ,Anèmia ,lcsh:RC254-282 ,Article ,Càncer de mama ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,FANCF ,FANCG ,Fanconi anemia ,Ovarian cancer ,hemic and lymphatic diseases ,FANCD2 ,medicine ,business.industry ,Cancer ,Hereditary Cancer ,Anemia ,NGS panel sequencing ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,FANCA ,FANCB ,030104 developmental biology ,Fanconi Anemia ,Oncology ,030220 oncology & carcinogenesis ,Breast and ovarian cancer risk ,Cancer research ,business ,Breast cancer risk - Abstract
Fanconi anemia (FA) is caused by biallelic mutations in FA genes. Monoallelic mutations in five of these genes (BRCA1, BRCA2, PALB2, BRIP1 and RAD51C) increase the susceptibility to breast/ovarian cancer and are used in clinical diagnostics as bona-fide hereditary cancer genes. Increasing evidence suggests that monoallelic mutations in other FA genes could predispose to tumor development, especially breast cancer. The objective of this study is to assess the mutational spectrum of 14 additional FA genes (FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FANCP, FANCQ, FANCR and FANCU) in a cohort of hereditary cancer patients, to compare with local cancer-free controls as well as GnomAD. A total of 1021 hereditary cancer patients and 194 controls were analyzed using our next generation custom sequencing panel. We identified 35 pathogenic variants in eight genes. A significant association with the risk of breast cancer/breast and ovarian cancer was found for carriers of FANCA mutations (odds ratio (OR) = 3.14 95% confidence interval (CI) 1.4&ndash, 6.17, p = 0.003). Two patients with early-onset cancer showed a pathogenic FA variant in addition to another germline mutation, suggesting a modifier role for FA variants. Our results encourage a comprehensive analysis of FA genes in larger studies to better assess their role in cancer risk.
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- 2020
16. Germline Mutations in FAF1 Are Associated With Hereditary Colorectal Cancer
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Anna Gratacós-Mulleras, Cristina Herrera-Pariente, Gabriel Capellá, Miriam Cuatrecasas, Jenifer Muñoz, Giulia Raimondi, Trinidad Caldés, Sebastià Franch-Expósito, Clara Esteban-Jurado, Sami Belhadj, Laia Bonjoch, Sergi Castellví-Bel, Francesc Balaguer, Marcos Díaz-Gay, Yasmin Soares de Lima, Laura Valle, Cristina Fillat, Pilar Garre, Antoni Castells, Teresa Ocaña, and Coral Arnau-Collell
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0301 basic medicine ,Male ,Cell death ,Colorectal cancer ,DNA Mutational Analysis ,Single-nucleotide polymorphism ,Apoptosis ,Biology ,Germline ,law.invention ,03 medical and health sciences ,Gene Knockout Techniques ,0302 clinical medicine ,Germline mutation ,law ,Neoplastic Syndromes, Hereditary ,Càncer colorectal ,Cell Line, Tumor ,Exome Sequencing ,medicine ,Missense mutation ,Humans ,Genetic Predisposition to Disease ,Gene ,Wnt Signaling Pathway ,Polymerase chain reaction ,Germ-Line Mutation ,beta Catenin ,Adaptor Proteins, Signal Transducing ,Aged ,Genetics ,Hepatology ,Gastroenterology ,NF-kappa B ,Genomics ,Middle Aged ,medicine.disease ,3. Good health ,Pedigree ,Genòmica ,030104 developmental biology ,Mort cel·lular ,Mutagenesis, Site-Directed ,030211 gastroenterology & hepatology ,DNA mismatch repair ,Female ,Apoptosis Regulatory Proteins ,Colorectal Neoplasms - Abstract
Background & Aims A significant proportion of colorectal cancer (CRC) cases have familial aggregation but little is known about the genetic factors that contribute to these cases. We performed an exhaustive functional characterization of genetic variants associated with familial CRC. Methods We performed whole-exome sequencing analyses of 75 patients from 40 families with a history of CRC (including early-onset cases) of an unknown germline basis (discovery cohort). We also sequenced specific genes in DNA from an external replication cohort of 473 families, including 488 patients with colorectal tumors that had normal expression of mismatch repair proteins (validation cohort). We disrupted the Fas-associated factor 1 gene (FAF1) in DLD-1 CRC cells using CRISPR/Cas9 gene editing; some cells were transfected with plasmids that express FAF1 missense variants. Cells were analyzed by immunoblots, quantitative real-time polymerase chain reaction, and functional assays monitoring apoptosis, proliferation, and assays for Wnt signaling or nuclear factor (NF)-kappa-B activity. Results We identified predicted pathogenic variant in the FAF1 gene (c.1111G>A; p.Asp371Asn) in the discovery cohort; it was present in 4 patients of the same family. We identified a second variant in FAF1 in the validation cohort (c.254G>C; p.Arg85Pro). Both variants encoded unstable FAF1 proteins. Expression of these variants in CRC cells caused them to become resistant to apoptosis, accumulate beta-catenin in the cytoplasm, and translocate NF-kappa-B to the nucleus. Conclusions In whole-exome sequencing analyses of patients from families with a history of CRC, we identified variants in FAF1 that associate with development of CRC. These variants encode unstable forms of FAF1 that increase resistance of CRC cells to apoptosis and increase activity of beta-catenin and NF-kappa-B.
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- 2020
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17. Evidence suggests that germline RNF43 mutations are a rare cause of serrated polyposis
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Sami Belhadj, Laura Valle, Esther Darder, Mariona Terradas, Raquel Mejías-Luque, Ares Solanes, Matilde Navarro, Elia Grau, Isabel Quintana, Virginia Piñol, Markus Gerhard, Pilar Mur, Joan Brunet, and Gabriel Capellá
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Genetics ,Sanger sequencing ,Sequence analysis ,Colorectal cancer ,education ,Deleterious Germline Mutation ,Gastroenterology ,Biology ,medicine.disease ,Germline ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Germline mutation ,030220 oncology & carcinogenesis ,Mutation (genetic algorithm) ,medicine ,symbols ,Missense mutation ,030211 gastroenterology & hepatology - Abstract
We read with interest the work by Yan et al published in Gut .1 The serrated (hyperplastic) polyposis syndrome (SPS) is a heterogeneous disease defined by the presence of multiple serrated polyps throughout the colon,2 causing an increased risk (16%) of colorectal cancer (CRC).3 By performing whole-exome sequencing in 20 SPS families, Gala et al identified a germline mutation, c.338C>A (p.R113*), in the RING-type E3 ubiquitin ligase RNF43, an inhibitor of the Wnt pathway, in two independent families.4 The c.394C>T (p.R132*) mutation was subsequently identified in two SPS-affected members of one family, supporting a causal role in SPS.5 In the study by Yan et al whole-exome sequence analysis of four SPS families identified a deleterious germline mutation, c.953–1G>A (p.E318fs), in six members of one family, five fulfilling the WHO criteria for SPS.1 Buchanan et al assessed the mutation status of RNF43 in 74 selected SPS families, identifying two rare missense variants, c.443C>G (p.A148G) and c.640C>G (p.L214V), predicted deleterious by in silico algorithms, in two families. No carriers of p.R113* or p.R132* were detected in 221 additional patients with SPS.6 Mutation screening of RNF43 was carried out by Sanger sequencing in …
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- 2018
18. Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer
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Pere Llinàs-Arias, Catia Moutinho, Fernando Setien, Joan Brunet, Laura Valle, Manel Esteller, Pilar Mur, Tirso Pons, Marta Pineda, Montserrat Pérez-Salvia, Gabriel Capellá, Sami Belhadj, Matilde Navarro, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Generalitat de Catalunya, Fundación Olga Torres, and European Cooperation in Science and Technology
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0301 basic medicine ,Cancer Research ,Colorectal cancer ,Somatic cell ,Reparació de l'ADN ,DNA repair ,Biology ,medicine.disease_cause ,DNA methyltransferase ,Methylation ,Germline ,03 medical and health sciences ,Recte -- Càncer -- Aspectes genètics ,0302 clinical medicine ,Germline mutation ,Càncer colorectal ,medicine ,Genetics ,Germ cells ,Epimutation ,Epigenetics ,Càncer -- Aspectes genètics ,Cancer genetics ,neoplasms ,Mutation ,Rectum -- Cancer -- Genetic aspects ,Cancer ,Epigenètica ,medicine.disease ,Cancer -- Genetic aspects ,digestive system diseases ,Hereditary cancer ,Cèl·lules germinals ,Promoter hypermethylation ,030104 developmental biology ,Oncology ,Mutagenesis ,030220 oncology & carcinogenesis ,Mutagènesi ,Cancer research ,MGMT ,Metilació ,Genètica - Abstract
© 2019 The Authors., Somatic epigenetic inactivation of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) is frequent in colorectal cancer (CRC); however, its involvement in CRC predisposition remains unexplored. We assessed the role and relevance of MGMT germline mutations and epimutations in familial and early-onset CRC. Mutation and promoter methylation screenings were performed in 473 familial and/or early-onset mismatch repair-proficient nonpolyposis CRC cases. No constitutional MGMT inactivation by promoter methylation was observed. Of six rare heterozygous germline variants identified, c.346C > T (p.H116Y) and c.476G > A (p.R159Q), detected in three and one families respectively, affected highly conserved residues and showed segregation with cancer in available family members. In vitro, neither p.H116Y nor p.R159Q caused statistically significant reduction of MGMT repair activity. No evidence of somatic second hits was found in the studied tumors. Case-control data showed over-representation of c.346C > T (p.H116Y) in familial CRC compared to controls, but no overall association of MGMT mutations with CRC predisposition. In conclusion, germline mutations and constitutional epimutations in MGMT are not major players in hereditary CRC. Nevertheless, the over-representation of c.346C > T (p.H116Y) in our familial CRC cohort warrants further research., This work was funded by the Spanish Ministry of Science, Innovation and Universities, co-funded by FEDER funds -a way to build Europe- [SAF2016-80888-R (LV), SAF2014-55000-R (ME), SAF2015-68016-R (GC/MP), Juan de la Cierva and Sara Borrell postdoctoral contracts (PM)]; Instituto de Salud Carlos III [DTS16/00153 (ME) and CIBERONC CB16/12/00234]; the Government of Catalonia [Pla Estratègic de Recerca i Innovació en Salut SLT002/16/0037, 2017SGR1282, 2017SGR1080, 2014SGR633 and 2009SGR1315]; and Fundación Olga Torres. We thank the CERCA/Generalitat de Catalunya Program for institutional support. This study has been enabled by COST Action CA17118.
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- 2019
19. Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1- and MSH3-associated polyposes
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Laura Valle, Gabriel Capellá, Pau M. Munoz-Torres, Mariona Terradas, Sami Belhadj, Matilde Navarro, Gemma Aiza, and Joan Brunet
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Candidate gene ,Pharmacogenomic Variants ,Ubiquitin-Protein Ligases ,DNA-Directed DNA Polymerase ,Biology ,Germline ,03 medical and health sciences ,Deoxyribonuclease (Pyrimidine Dimer) ,Genetics ,Genetic predisposition ,Prevalence ,Humans ,Genetic Predisposition to Disease ,Mutation frequency ,Gene ,Genetics (clinical) ,Genetic Association Studies ,030304 developmental biology ,0303 health sciences ,Tumor Suppressor Proteins ,030305 genetics & heredity ,Serrated polyposis ,MSH3 ,Adenomatous Polyposis Coli ,Causal association ,MutS Homolog 3 Protein ,Mutation ,Biomarkers - Abstract
Technological advances have allowed the identification of new adenomatous and serrated polyposis genes, and of several candidate genes that require additional supporting evidence of causality. Through an exhaustive literature review and mutational screening of 177 unrelated polyposis patients, we assessed the involvement of MCM9, FOCAD, POLQ, and RNF43 in the predisposition to (nonserrated) colonic polyposis, as well as the prevalence of NTHL1 and MSH3 mutations among genetically unexplained polyposis patients. Our results, together with previously reported data and mutation frequency in controls, indicate that: MCM9 and POLQ mutations are not associated with polyposis; germline RNF43 mutations, with a prevalence of 1.5-2.5% among serrated polyposis patients, do not cause nonserrated polyposis; MSH3 biallelic mutations are highly infrequent among European polyposis patients, and the prevalence of NTHL1 biallelic mutations among unexplained polyposes is ~2%. Although nonsignificant, FOCAD predicted deleterious variants are overrepresented in polyposis patients compared to controls, warranting larger studies to provide definite evidence in favor or against their causal association with polyposis predisposition.
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- 2019
20. NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas
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M. Henar Alonso, Pau M. Munoz-Torres, Isabel Quintana, Virginia Piñol, Conxi Lázaro, Matilde Navarro, Pilar Mur, Victor Moreno, Sami Belhadj, Gabriel Capellá, Laura Valle, Mariona Terradas, and Joan Brunet
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0301 basic medicine ,Biallelic Mutation ,Male ,Colorectal cancer ,Polyps (Pathology) ,lcsh:Medicine ,Disease ,medicine.disease_cause ,0302 clinical medicine ,Family history ,Pòlips (Patologia) ,lcsh:Science ,Cancer genetics ,Aged, 80 and over ,Rectum -- Cancer ,Mutation ,Multidisciplinary ,Middle Aged ,Pedigree ,Phenotype ,Adenomatous Polyposis Coli ,Female ,Colorectal Neoplasms ,Adenoma ,Adult ,Article ,Meningioma ,03 medical and health sciences ,Deoxyribonuclease (Pyrimidine Dimer) ,Càncer colorectal ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Allele ,Alleles ,Aged ,Tumors ,Genetic counselling ,business.industry ,Mutació (Biologia) ,lcsh:R ,Cancer ,Mutation (Biology) ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,digestive system diseases ,030104 developmental biology ,Cancer research ,lcsh:Q ,Recte -- Càncer ,business ,030217 neurology & neurosurgery - Abstract
The cancer-predisposing syndrome caused by biallelic mutations in NTHL1 may not be a solely colorectal cancer (CRC) and polyposis syndrome but rather a multi-tumor recessive disease. The presence of ≤10 adenomas in several mutation carriers suggests a possible causal role of NTHL1 in hereditary or early-onset nonpolyposis CRC. The involvement of NTHL1 in serrated/hyperplastic polyposis remains unexplored. The aim of our study is to elucidate the role of NTHL1 in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated polyposis. NTHL1 mutational screening was performed in 312 cancer patients with personal or family history of multiple tumor types, 488 with hereditary nonpolyposis CRC, and 96 with serrated/hyperplastic polyposis. While no biallelic mutation carriers were identified in patients with personal and/or family history of multiple tumor types or with serrated polyposis, one was identified among the 488 nonpolyposis CRC patients. The carrier of c.268C>T (p.Q90*) and 550-1G>A was diagnosed with CRC and meningioma at ages 37 and 45 respectively, being reclassified as attenuated adenomatous polyposis after the cumulative detection of 26 adenomas. Our findings suggest that biallelic mutations in NTHL1 rarely cause CRC, a personal/familial multi-tumor history, or serrated polyposis, in absence of adenomas Tis study was funded by the Spanish Ministry of Science, Innovation and Universities, co-funded by FEDER funds- a way to build Europe, [SAF2016-80888-R (LV), SAF2015-68016-R (GC), Formación de Personal Investigador (IQ)]; Instituto de Salud Carlos III [CIBERONC CB16/12/00234, PI16/00563 (CL), Sara Borrell postdoctoral contract (PM)], the Government of Catalonia [Department of Health PERIS SLT002/16/0037, SLT002/16/00164 “Acció instrumental d’incorporació de científcs i tecnòlegs” (MT)], AGAUR 2017SGR1282 and CERCA Program] and Fundación Olga Torres. Tis study has been enabled by COST Action CA17118
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- 2019
21. Germline variation in O
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Sami, Belhadj, Cátia, Moutinho, Pilar, Mur, Fernando, Setien, Pere, Llinàs-Arias, Montserrat, Pérez-Salvia, Tirso, Pons, Marta, Pineda, Joan, Brunet, Matilde, Navarro, Gabriel, Capellá, Manel, Esteller, and Laura, Valle
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Adult ,Aged, 80 and over ,Male ,Adolescent ,Tumor Suppressor Proteins ,DNA Methylation ,Middle Aged ,Gene Expression Regulation, Neoplastic ,Young Adult ,DNA Repair Enzymes ,Germ Cells ,Case-Control Studies ,Humans ,Female ,Colorectal Neoplasms ,Promoter Regions, Genetic ,DNA Modification Methylases ,Germ-Line Mutation ,Aged - Abstract
Somatic epigenetic inactivation of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) is frequent in colorectal cancer (CRC); however, its involvement in CRC predisposition remains unexplored. We assessed the role and relevance of MGMT germline mutations and epimutations in familial and early-onset CRC. Mutation and promoter methylation screenings were performed in 473 familial and/or early-onset mismatch repair-proficient nonpolyposis CRC cases. No constitutional MGMT inactivation by promoter methylation was observed. Of six rare heterozygous germline variants identified, c.346C T (p.H116Y) and c.476G A (p.R159Q), detected in three and one families respectively, affected highly conserved residues and showed segregation with cancer in available family members. In vitro, neither p.H116Y nor p.R159Q caused statistically significant reduction of MGMT repair activity. No evidence of somatic second hits was found in the studied tumors. Case-control data showed over-representation of c.346C T (p.H116Y) in familial CRC compared to controls, but no overall association of MGMT mutations with CRC predisposition. In conclusion, germline mutations and constitutional epimutations in MGMT are not major players in hereditary CRC. Nevertheless, the over-representation of c.346C T (p.H116Y) in our familial CRC cohort warrants further research.
- Published
- 2018
22. Delineating the Phenotypic Spectrum of the NTHL1-Associated Polyposis
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Gabriel Capellá, Matilde Navarro, Laura Valle, Victor Moreno, Sara González, Sami Belhadj, and Pilar Mur
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0301 basic medicine ,Genetics ,Hepatology ,biology ,Adenomatous polyposis coli ,Colorectal cancer ,business.industry ,Gastroenterology ,medicine.disease ,Phenotype ,03 medical and health sciences ,030104 developmental biology ,Deoxyribonuclease (Pyrimidine Dimer) ,biology.protein ,medicine ,business ,Genotyping Techniques - Published
- 2017
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