title: Comprehensive genetic analysis of seven large families with mismatch repair proficient colorectal cancer.
abstract: Approximately 40% of colorectal cancer (CRC) families with a diagnosis of hereditary nonpolyposis CRC on the basis of clinical criteria are not a consequence of mismatch repair (MMR) deficiency. Such families provide supporting evidence for the existence of a hitherto unidentified highly penetrant gene mutation. To gain further understanding of MMR-competent familial colorectal cancer (FCC), we studied seven large families with an unexplained predisposition for CRC to identify genetic regions that could harbor CRC risk factors. First, we conducted a genome-wide linkage scan using 10K single-nucleotide polymorphism (SNP) arrays to search for disease loci. Second, we studied the genomic profiles of the tumors of affected family members to identify commonly altered genomic regions likely to harbor tumor suppressor genes. Finally, we studied the possible role of recently identified low-risk variants in the familial aggregation of CRC in these families. Linkage analysis did not reveal clear regions of linkage to CRC. However, our results provide support linkage to 3q, a region that has previously been linked to CRC susceptibility. Tumor profiling did not reveal any genomic regions commonly targeted in the tumors studied here. Overall, the genomic profiles of the tumors show some resemblance to sporadic CRC, but additional aberrations were also present. Furthermore, the FCC families did not appear to have an enrichment of low-risk CRC susceptibility loci. These data suggest that factors other than a highly penetrant risk factor, such as low or moderate-penetrance risk factors, may explain the increased cancer risk in a subset of familial CRCs.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Middeldorp
authors.forename: Shantie C
authors.initials: SC
authors.lastname: Jagmohan-Changur
authors.forename: Heleen M
authors.initials: HM
authors.lastname: van der Klift
authors.forename: Marjo
authors.initials: M
authors.lastname: van Puijenbroek
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Emily
authors.initials: E
authors.lastname: Webb
authors.forename: Richard
authors.initials: R
authors.lastname: Houlston
authors.forename: Carli
authors.initials: C
authors.lastname: Tops
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Juul
authors.initials: J
authors.lastname: Wijnen
mesh_terms: D000236:Adenoma / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002893:Chromosomes, Human, Pair 3; D015179:Colorectal Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations; D053843:DNA Mismatch Repair; D005192:Family Health; D006651:Histocytochemistry; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide