Abstract 5018: Genetic and epigenetic investigation of breast carcinoma arising in Lynch syndrome families

Breast carcinoma is the most common cancer type in females, but its incidence is generally not increased in Lynch syndrome (LS). Deficient DNA mismatch repair (MMR) is a hallmark of LS tumors that are unequivocal manifestations of the syndrome (e.g., colorectal and breast carcinoma). Because of controversial study results, it is unclear at present whether or not breast carcinoma is specifically associated with LS. We addressed this question by determining the genetic and epigenetic profiles for all available breast carcinomas from LS families from a nation-wide registry, including 24 tumors from MMR gene mutation carriers and 17 tumors from non-carriers. The average age at breast carcinoma diagnosis was similar in mutation carriers and non-carriers (56 years for each). Among breast carcinomas from mutation carriers, 43% showed loss of MMR protein corresponding to the germline mutation, and high-degree microsatellite instability (MSI-H) was present in 36%. Moreover, in mutation carriers, the age at diagnosis was lower for breast carcinomas that were MMR-deficient (by absent MMR protein and/or MSI present) compared to MMR proficient tumors (51 vs. 60 years, p= 0.031). Breast carcinomas showed frequent inactivation of tumor suppressor genes (TSG) by promoter methylation. The average number of methylated TSGs out of 24 per tumor was 3.1 for mutation carriers and 2.8 for non-carriers. The gene-specific distribution of methylation was also similar between the two breast tumor sets. In mutation carriers, the most frequently methylated TSGs were RASSF1 (77%), APC (45%), CDH13 (45%), GSTP1 (32%) and CDKN2B (27%). In non-carriers, the respective frequencies were 75%, 47%, 59%, 35%, and 29%. When compared to tumors arising in other organs from LS mutation carriers, methylation of CDKN2B was seen as a particular characteristic of breast tumorigenesis. Our investigation shows that TSG promoter methylation is a common characteristic of breast carcinomas arising in LS and affects mutation carriers and non-carriers with comparable overall rates and gene-specific distributions. Analysis of MMR protein expression and MSI revealed that while many breast carcinomas from LS mutation carriers follow MMR-driven tumorigenesis characteristic of tumors of the LS spectrum in general, a significant subset of breast tumors also exists that appears to arise and progress along separate pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5018. doi:1538-7445.AM2012-5018