title: Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing.
abstract: Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1.
authors.affiliation: Department of Molecular and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. anna.rohlin@vgregion.se.
authors.forename: Anna
authors.identifier: 0000-0002-4083-6748
authors.initials: A
authors.lastname: Rohlin
authors.affiliation: Division of Oncology and Pathology Department of Clinical Sciences Lund, Lund University, Medicon Village, 22381, Lund, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Rambech
authors.affiliation: Division of Oncology and Pathology Department of Clinical Sciences Lund, Lund University, Medicon Village, 22381, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Kvist
authors.affiliation: Division of Oncology and Pathology Department of Clinical Sciences Lund, Lund University, Medicon Village, 22381, Lund, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Törngren
authors.affiliation: Department of Molecular and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Frida
authors.initials: F
authors.lastname: Eiengård
authors.affiliation: Department of Surgery, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, 416 85, Gothenburg, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Lundstam
authors.affiliation: Department of Molecular and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Theofanis
authors.initials: T
authors.lastname: Zagoras
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Department of Clinical Genetics, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden.
authors.forename: Samuel
authors.initials: S
authors.lastname: Gebre-Medhin
authors.affiliation: Division of Oncology and Pathology Department of Clinical Sciences Lund, Lund University, Medicon Village, 22381, Lund, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: The Swedish Polyposis Registry, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Björk
authors.affiliation: Division of Oncology and Pathology Department of Clinical Sciences Lund, Lund University, Medicon Village, 22381, Lund, Sweden.|The HNPCC-register, Hvidovre University Hospital, Copenhagen University, Hvidovre, Denmark.
authors.forename: Mef
authors.initials: M
authors.lastname: Nilbert
authors.affiliation: Department of Molecular and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Margareta
authors.initials: M
authors.lastname: Nordling
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D060466:Axin Protein / Q000235:genetics; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D015820:Cadherins / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D051901:Smad4 Protein / Q000235:genetics; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics
chemical_list: C491761:AXIN2 protein, human; D015703:Antigens, CD; D060466:Axin Protein; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D004268:DNA-Binding Proteins; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D051176:beta Catenin; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2
keywords: Colorectal cancer; FAP; Familial adenomatous polyposis; Gene panel; Hereditary; Lynch syndrome