title: Familial colorectal cancer: eleven years of data from a registry program in Switzerland.
abstract: Deleterious germ-line variants involving the DNA mismatch repair (MMR) genes have been identified as the cause of the hereditary nonpolyposis colorectal cancer syndrome known as the Lynch syndrome, but in numerous familial clusters of colon cancer, the cause remains obscure. We analyzed data for 235 German-speaking Swiss families with nonpolyposis forms of colorectal cancer (one of the largest and most ethnically homogeneous cohorts of its kind) to identify the phenotypic features of forms that cannot be explained by MMR deficiency. Based on the results of microsatellite instability analysis and immunostaining of proband tumor samples, the kindreds were classified as MMR-proficient (n = 134, 57%) or MMR-deficient (n = 101, 43%). In 81 of the latter kindreds, deleterious germ-line MMR-gene variants have already been found (62 different variants, including 13 that have not been previously reported), confirming the diagnosis of Lynch syndrome. Compared with MMR-deficient kindreds, the 134 who were MMR proficient were less likely to meet the Amsterdam Criteria II regarding autosomal dominant transmission. They also had primary cancers with later onset and colon-segment distribution patterns resembling those of sporadic colorectal cancers, and they had lower frequencies of metachronous colorectal cancers and extracolonic cancers in general. Although the predisposition to colorectal cancer in these kindreds is probably etiologically heterogeneous, we were unable to identify distinct phenotypic subgroups solely on the basis of the clinical data collected in this study. Further insight, however, is expected to emerge from the molecular characterization of their tumors.
authors.affiliation: Research Group Human Genetics, Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland.
authors.forename: Michal
authors.initials: M
authors.lastname: Kovac
authors.forename: Endre
authors.initials: E
authors.lastname: Laczko
authors.forename: Ritva
authors.initials: R
authors.lastname: Haider
authors.forename: Josef
authors.initials: J
authors.lastname: Jiricny
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Mueller
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marra
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012042:Registries; D013557:Switzerland; D013997:Time Factors; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; D009363:Neoplasm Proteins