title: Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review.
abstract: Mendelian causes of inherited cancer susceptibility are mostly rare and characterized by variable expression and incomplete penetrance. Phenotypic variability may result from a range of causes including locus heterogeneity, allelic heterogeneity, genetic and environmental modifier effects, or chance. Another potential cause is the presence of 2 or more inherited cancer predisposition alleles in the same individual. Although the frequency of such occurrences might be predicted to be low, such cases have probably been underascertained because standard clinical practice has been to test candidate inherited cancer genes sequentially until a pathogenic mutation is detected. However, recent advances in next-generation sequencing technologies now provide the opportunity to perform simultaneous parallel testing of large numbers of inherited cancer genes. Herein we provide examples of patients who harbor pathogenic mutations in multiple inherited cancer genes and review previously published examples to illustrate the complex genotype-phenotype relationships in these cases. We suggest that clinicians should proactively consider the likelihood of this phenomenon (referred to herein as multilocus inherited neoplasia alleles syndrome [MINAS]) in patients with unusual inherited cancer syndrome phenotypes. To facilitate the clinical management of novel cases of MINAS, we have established a database to collect information on what is likely to be an increasingly recognized cohort of such individuals.
authors.affiliation: Department of Medical Genetics, University of Cambridge and Cambridge NIHR Biomedical Research Centre, Cambridge, England.
authors.forename: James
authors.initials: J
authors.lastname: Whitworth
authors.affiliation: Department of Clinical Genetics, Aarhus University Hospital, Denmark.
authors.forename: Anne-Bine
authors.initials: AB
authors.lastname: Skytte
authors.affiliation: Department of Clinical Genetics, Aarhus University Hospital, Denmark.
authors.forename: Lone
authors.initials: L
authors.lastname: Sunde
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's Hospital NHS Trust, Birmingham, England.
authors.forename: Derek H
authors.initials: DH
authors.lastname: Lim
authors.affiliation: Division of Pathology, University of Edinburgh and Institute for Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.affiliation: Department of Pathology, Addenbrooke's Hospital, Hills Road, Cambridge, England.
authors.forename: Lisa
authors.initials: L
authors.lastname: Happerfield
authors.affiliation: Institute of Cancer and Genetics, Cardiff University School of Medicine, Wales.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Frayling
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: van Minkelen
authors.affiliation: Department of Genomic Medicine, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, England.
authors.forename: Emma R
authors.initials: ER
authors.lastname: Woodward
authors.affiliation: Department of Medical Genetics, University of Cambridge and Cambridge NIHR Biomedical Research Centre, Cambridge, England.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Tischkowitz
authors.affiliation: Department of Medical Genetics, University of Cambridge and Cambridge NIHR Biomedical Research Centre, Cambridge, England.
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D016208:Databases, Factual; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D013577:Syndrome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein