Characterization of Family History Profiles in a Large Series of Lynch Syndrome Carriers

Abstract

INTRODUCTION: The purpose of this study was to characterize family history profiles of unaffected individuals diagnosed with Lynch syndrome in the absence of a known family mutation. METHODS: We queried our laboratory database for unaffected patients who were positive for Lynch syndrome genetic testing between September 2010 and May 2013. All individuals underwent full sequence and large rearrangement analysis of MLH1 and MSH2 and full sequence analysis of MSH6. Some patients also underwent full sequence and large rearrangement analysis of PMS2 and large rearrangement analysis of MSH6 and EPCAM. We then assessed family history profiles in 200 unaffected patients with genetically confirmed Lynch syndrome. RESULTS: Of the 200 patients, 162 female and 38 male Lynch syndrome carriers were identified. Mutations in MLH1 and MSH2 were the most common (30.0% and 32.5%, respectively). Eighteen patients lacked a first-degree or second-degree relative with colorectal cancer. Only 37.8% (73/193) of individuals had a first-degree or second-degree relative meeting Amsterdam II criteria, whereas 76.8% (149/194) of individuals had a first- or second-degree relative meeting Revised Bethesda criteria. The average PREMM1, 2, 6 score was 10.0% with 43.5% (87/200) falling below 5%. In this large cohort, 15.5% (31/200) had neither a first- or second-degree relative who met the Amsterdam II or Revised Bethesda criteria nor a PREMM1, 2, 6 score of 5% or greater. CONCLUSIONS: To improve detection of Lynch syndrome in the population, it is important to consider genetic testing in unaffected individuals even in the absence of a known family mutation.