Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer

Background: The incidence of colorectal cancer in persons under 46 years of age is substantially higher in Hong Kong than in Scotland and many other c ountries. Consequently, we examined whether there is a hereditary predispos ition for colorectal cancer in this Southern Chinese population. Methods: W e investigated the incidence of microsatellite instability (MSI) at 10 DNA sites in 117 colorectal cancer specimens from Chinese patients of various a ges. Those tumors with new alleles at 40% or more of the sites investigated were identified as highly unstable MSI (MSI-H). In young patients, we also searched for germline mutations in three mismatch repair genes (hMSH2, hML H1, and hMSH6), Results: The incidence of MSI-H varied statistically signif icantly with age, being observed in more than 60% of those younger than age 31 years at diagnosis and in fewer than 15% of those age 46 years or older . In 15 patients (<46 years old) whose colorectal cancers showed MSI-H, eig ht possessed germline mutations in either hMSH2 or hMLH1, When mutations in hMSH6 were included, more than 80% of Chinese colorectal cancer patients y ounger than 31 years had germline mutations in mismatch repair genes. We fo und a novel germline missense mutation in hMSH6 in a 29-year-old man whose tumor showed no MSI, Two patients had a 4-base-pair insertion in exon 10 ca using a truncated protein; this insertion is a common polymorphism with a p opulation allele frequency in Chinese of 5.6%. Conclusions: Our results ind icate that germline mutations in mismatch repair genes contribute substanti ally to the pathogenesis and high incidence of colorectal cancer in young H ong Kong Chinese. However, because young Chinese and Caucasians show simila r proportions of colorectal cancers with MSI-H, despite the higher incidenc e in the former, additional factors may underlie the high susceptibility of young Chinese to colorectal cancer.