Lynch syndrome founder mutations in families of Navajo and German-American heritage

Abstract

9511 Background: Lynch syndrome is caused by mutations in mismatch repair (MMR) genes which confer extraordinarily high risk of colorectal cancer, endometrial, ovarian as well as lesser occurring cancer types. Carriers of these MMR mutations require genetic counseling, clinical surveillance, and targeted management. Methods: An MLH1 mutation among the Navajo consisted of a four basepair deletion beginning at the first nucleotide of codon 727. In Caucasians a deletion encompassing exons 1 - 6 of MSH2 occurred. To facilitate the diagnosis of these mutations, specific PCR-based tests were developed and used for large-scale screening of individuals at risk. An extensive genealogical and historical study was performed in search for a common origin of each mutation and its spread. Results: The MLH1 deletion mutation was found in members of six widely dispersed Navajo families in Arizona. To date, 386 individuals from these families have been identified to be at risk of whom 142 individuals have been tested with 56 harboring the mutation. The MSH2 deletion mutation was found in members of nine Caucasian families living in various parts of the U.S. To date 566 family members of the nine probands have been identified to be at risk and counseled; 137 of these have been tested, and 61 carry the mutation. Carriers of the mutation have already been identified in 14 states. Three of these families have been genealogically shown to descend from a German immigrant family that arrived in Pennsylvania in 1727. Conclusions: The postulated high frequency and continent-wide geographic distribution of these founder mutations beg the suggestion that until more is learned about their occurrences, the routine testing of individuals at risk for Lynch syndrome in the U.S. might include an assay for these mutations in the interest of early cancer detection and improved cancer control. No significant financial relationships to disclose.