Insights into familial colon cancer: The plot thickens

Evidence indicates that colorectal cancer (CRC) risk is conferred by both genetic and environmental factors. A well-described sequence of molecular genetic changes accompany the development and progression of precursor lesions to invasive malignancy.¹ Two major pathways of tumorigenesis have been described and include the chromosomal instability (CIN) pathway that is associated with frequent chromosomal allelic loss and aneuploidy.² The other pathway is characterized by microsatellite instability (MIN; referred to here as MSI). MSI results in numerous mutations that occur in microsatellite sequences consisting of mono- and dinucleotide repeats scattered throughout the genome.³ The promoter regions of the following genes frequently are mutated and include proapoptotic BAX, transforming growth factor β type II receptor, and insulin growth factor receptor type II.³ Sporadic colon cancers with MSI show right-sided colon predominance, as do tumors arising in the syndrome of hereditary nonpolyposis colorectal cancer (HNPCC).⁴ MSI is the hallmark of the syndrome of HNPCC, where it occurs as a consequence of a germline mutation in 1 of 4 DNA mismatch repair genes (hMLH1, hMSH2, hMSH6, and PMS2), with the great majority of mutations occurring in hMLH1 and hMSH2 genes.⁵ HNPCC accounts for 3%–6% of all CRC cases and familial adenomatous polyposis (FAP), owing to germline mutation in APC, accounts for 1% of incident CRCs.⁵ Despite these well-known syndromes, the mechanism(s) underlying the much larger group of suspected familial colon cancer not associated with FAP or HNPCC remains unexplained.