The American founder mutation for Lynch syndrome: Prevalence and cancer control implications

Abstract

9505 Background: We have recently reported a new founder mutation, namely, an exon 1–6 deletion in the MSH2 gene detectable by a recently designed single PCR reaction in 9 kindreds with Lynch Syndrome. In 3 of the kindreds this mutation has been traced through genealogy 12 to 13 generations back to a common founder and thus termed the American Founder Mutation (AFM). We have since identified 11 additional apparently unrelated kindreds with AFM. The new PCR test might serve as first-line screening for Lynch syndrome provided the mutation were prevalent and widespread, which we assess in this study. Methods: With the genealogy data, the expected number of AFM carriers at generation k is E(mk)= mk-1sk/2, where k is number of generations that had passed since the founder had settled in the US, and skis the number of reproductive offspring per mutation carrier at generation k-1. The 95% C.I. was computed based on the probability distribution of mk with simulation of 1 million replicates. From E(mk) we estimated the recent annual incidence of Lynch syndrome caused by AFM. The incidence was also estimated based on published proportion of mismatch repair gene mutation-negative (MMR-MN) cases with Lynch syndrome among all colorectal cancer cases, and the recently reported proportion of AFM carriers among MMR-MN cases with Lynch syndrome (13%). Results: There are 1595 members from 256 nuclear families over 12 to 13 generations with relatively reliable data concerning the number of reproductive offspring per individual in the initial 9 pedigrees. Based on genealogy data, there are 15460 (95% C.I, 5670, 25270) current AFM carriers, or 156 (95% C.I., 58, 258) Lynch syndrome cases/y due to AFM, assuming the last two generations (median age 17 and 41 yrs) and half of the earlier generation are alive. Based on data of the random sample, the incidence of Lynch syndrome caused by AFM is 113 to 396 cases/y. Conclusions: A large number of AFM carriers exist in the US. Further studies will define the proportion and geographic distribution of Lynch syndrome cases due to AFM. Testing for AFM may become the first choice in mutation screening of Lynch syndrome. Expanding the 9 original and 11 “new” AFM pedigrees for AFM carriers should be extremely effective for cancer control. No significant financial relationships to disclose.