Comprehensive genetic analysis of seven large families with mismatch repair proficient colorectal cancer

✍ Scribed by Anneke Middeldorp; Shantie C. Jagmohan-Changur; Heleen M. van der Klift; Marjo van Puijenbroek; Jeanine J. Houwing-Duistermaat; Emily Webb; Richard Houlston; Carli Tops; Hans F. A. Vasen; Peter Devilee; Hans Morreau; Tom van Wezel; Juul Wijnen

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 222 KB
• Volume: 49
• Category: Article
• ISSN: 1045-2257
• DOI: 10.1002/gcc.20763

✦ Synopsis

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. © 2010 Wiley‐Liss, Inc.