Lynch syndrome TACSTD1 family with predominant colorectal cancer.

Abstract

1500 Background: Germline mutations in the mismatch repair (MMR) genes MLH1 and MSH2 cannot be identified in about 30% of families fulfilling Amsterdam I criteria for Lynch syndrome (LS). Recently, deletions in the TACSTD1 gene have also been identified as a cause of LS. Kovacs et al. (Hum Mutat 2009;30:197-203) identified large germline deletions of TACSTD1 upstream of MSH2 among 19% (5/27) of LS families lacking evidence of a mutation in MSH2 or MLH1. TACSTD1 deletions result in hypermethylation and incomplete silencing of MSH2 suggesting that some TACSTD1 mutation carriers may have a different phenotype than carriers of MSH2 or MLH1 mutations, namely an almost exclusive expression of colorectal cancer (CRC) without extracolonic cancers. We evaluated for TACSTD1 mutations in this large LS kindred that was critical in our original description of LS; we initiated study of this family in 1970. Methods: TACSTD1 analysis was performed using a commercially available MLPA kit (P072 version 6, MRC Holland) on patients' DNA. Extensive genealogy, cancer pathology verification, and genetic counseling has been a constant process among consenting family members. We identified a TACSTD1 mutation in this highly extended LS family which had served as LS's phenotypic template since we initiated its study. Results: Family characteristics comprised 605 bloodline relatives, 73% of whom are over the age of 25, living, and eligible for DNA testing. In 2009, a Family Information Service (FIS) was held to educate, counsel, and collect DNA samples on high-risk family members for TACSTD1 testing. Over 70 family members attended this FIS with 45 of them providing DNA samples wherein 14 were confirmed to be TACSTD1 mutation carriers. Affected family members had primarily CRC, and only a few had extracolonic cancers. Conclusions: Identification of TACSTD1 mutations as a cause of LS has important cancer control implications for this and other LS families thereby enabling family members to identify their cancer risk, receive genetic counseling, and enroll in an appropriate cancer surveillance/management program. Extracolonic cancer risk may be decreased in TACSTD1 mutation carriers but this will require further confirmation. No significant financial relationships to disclose.