Appearance of epithelial and stromal genomic instability in background colorectal mucosa of sporadic colorectal cancer patients: relation to age and gender

We have previously demonstrated that not only epithelial but also stromal genetic instability possibly contributes to colorectal tumorigenesis. To assess the increasing risk of carcinogenesis in the colorectum with aging, we examined genomic instability in both epithelia and stroma in the background noncancerous mucosa of patients with colorectal carcinomas. In 213 noncancerous colorectal mucosa samples from colorectal cancer cases and 51 normal mucosa specimens of diverticulosis cases, epithelial and stromal genomic instability was analyzed with National Cancer Institute standard microsatellite markers, chromosome 17 (Chr.17) markers and tumor suppressor gene-related markers, using a combination of laser-capture microdissection and GeneScan approaches. Results were compared with immunohistochemically demonstrated expression of FHIT, Rb, WT1, hMLH1 and hMSH2. Genomic instability (MSI and LOH) in both epithelia and stroma appeared after around 40 years of age and remained relatively constant thereafter at relatively low frequencies (4.8-30.4%). The Epithelial LOH tended to show a stepwise increase in people in their 40s and 50s along with aging, especially in males. Overall frequencies of both epithelial MSI and LOH in left-side colon and LOH in right-side colon were significantly higher in males than in females. Epithelial hMLH1 expression in MSI (-) cases tended to be reduced with aging. Genomic instability of both MSI and LOH in noncancerous colonic mucosa, and more particularly epithelial and stromal LOH, appears relatively early in adults, suggesting age-related changes which increase the risk of cancer development, particularly in males.