1. Does multilocus inherited neoplasia alleles syndrome have severe clinical expression?
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Eva Tornero, Gabriel Capellá, Joan Brunet, Matilde Navarro, Conxi Lázaro, Paula Rofes, Angel Izquierdo, Elia Grau Garces, Olga Campos, Angela Velasco, Lídia Feliubadaló, Jesús del Valle, Gardenia Vargas, Marta Pineda, Judith Balmaña-Gelpi, Agostina Stradella, Sara González, Institut Català de la Salut, Stradella A] 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. Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. [del Valle J, Rofes P, Feliubadaló L] 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 (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain. [Grau Garces È] 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. [Velasco À] Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGI, Girona, Spain. [Balmaña-Gelpi J] Grup Alt Risc i Prevenció del Càncer, Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, Hospital Universitari Vall d'Hebron, and Vall d'Hebron Barcelona Hospital Campus
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Male ,0301 basic medicine ,Càncer - Prognosi ,Inheritance Patterns ,030105 genetics & heredity ,Severity of Illness Index ,Genetic analysis ,Neoplasms ,Malalties hereditàries ,Medicine ,Càncer ,Càncer -- Aspectes genètics ,Genetics (clinical) ,Cancer ,Genetics ,medicine.diagnostic_test ,cancer syndromes ,multilocus inherited neoplasia alleles syndrome ,Syndrome ,Middle Aged ,Pedigree ,Phenotype ,Female ,Liver cancer ,Genetic Phenomena::Inheritance Patterns [PHENOMENA AND PROCESSES] ,Genetic diseases ,Adult ,MLH1 ,genetic testing ,Càncer de fetge ,neoplasias [ENFERMEDADES] ,03 medical and health sciences ,Breast cancer ,gene panel ,Biomarkers, Tumor ,Cancer Genetics ,Humans ,Genetic Predisposition to Disease ,MEN1 ,Allele ,CHEK2 ,Alleles ,Genetic Association Studies ,Aged ,Genetic testing ,Gens del càncer ,business.industry ,fenómenos genéticos::patrones de herencia [FENÓMENOS Y PROCESOS] ,medicine.disease ,Cancer -- Genetic aspects ,Neoplasms [DISEASES] ,030104 developmental biology ,Genetic Loci ,business - Abstract
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.