IntroductionBreast carcinoma is the most common cancer in women, but its incidence is not increased in Lynch syndrome (LS) and studies on DNA mismatch repair deficiency (MMR) in LS-associated breast cancers have arrived at conflicting results. This study aimed to settle the question as to whether breast carcinoma belongs to the LS tumor spectrum.MethodsMMR status and epigenetic profiles were determined for all available breast carcinomas identified among 200 LS families from a nation-wide registry (23 tumors from mutation carriers and 18 from non-carriers). Sporadic breast carcinomas (n = 49) and other cancers (n = 105) from MMR gene mutation carriers were studied for comparison.ResultsThe proportion of breast carcinomas that were MMR-deficient based on absent MMR protein, presence of microsatellite instability, or both was significantly (P = 0.00016) higher among breast carcinomas from mutation carriers (13/20, 65%) compared to non-carriers (0/14, 0%). While the average age at breast carcinoma diagnosis was similar in carriers (56 years) and non-carriers (54 years), it was lower for MMR-deficient versus proficient tumors in mutation carriers (53 years versus 61 years, P = 0.027). Among mutation carriers, absent MMR protein was less frequent in breast carcinoma (65%) than in any of seven other tumor types studied (75% to 100%). Tumor suppressor promoter methylation patterns were organ-specific and similar between breast carcinomas from mutation carriers and non-carriers.ConclusionsBreast carcinoma from MMR gene mutation carriers resembles common breast carcinoma in many respects (for example, general clinicopathological and epigenetic profiles). MMR status makes a distinction: over half are MMR-deficient typical of LS spectrum tumors, while the remaining subset which is MMR-proficient may develop differently. The results are important for appropriate surveillance in mutation carriers and may be relevant for LS diagnosis in selected cases.

BackgroundAltered expression of microRNAs (miRNAs) commonly accompanies colorectal (CRC) and endometrial carcinoma (EC) development, but the underlying mechanisms and clinicopathological correlations remain to be clarified. We focused on epigenetic mechanisms and aimed to explore if DNA methylation patterns in tumors depend on DNA mismatch repair (MMR) status, sporadic vs. Lynch-associated disease, and geographic origin (Finland vs. Australia). Treatment of cancer cell lines with demethylating agents revealed 109 significantly upregulated miRNAs. Seven met our stringent criteria for possible methylation-sensitive miRNAs and were used to screen patient specimens (205 CRCs and 36 ECs) by methylation-specific multiplex ligation-dependent probe amplification.ResultsThree miRNAs (129-2, 345, and 132) with low methylation levels in normal tissue and frequent hypermethylation in tumors were of particular interest. Hypermethylation of miR-345 and miR-132 associated with MMR deficiency in CRC regardless of geographic origin, and hypermethylation of miR-132 distinguished sporadic MMR-deficient CRC from Lynch-CRC. Finally, hypermethylation of miRNAs stratified 49 endometrial hyperplasias into low-methylator (simple hyperplasia) and high-methylator groups (complex hyperplasia with or without atypia) and suggested that miR-129-2 methylation in particular could serve as a marker of progression in early endometrial tumorigenesis.ConclusionsOur study identifies miR-345 and miR-132 as novel differentially methylated miRNAs in CRC, thereby facilitating sub-classification of CRC and links miR-129-2 methylation to early endometrial tumorigenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0059-3) contains supplementary material, which is available to authorized users.

(GENES CHROM CANCER=250 words)Molecular mechanisms underlying coordinated hypermethylation of multiple CpG islands in cancer remain unclear. In particular, expressional and other studies of methyltransferase enzymes have arrived at conflicting results. We focused on DNMT1 and DNMT3B, DNA methyltransferases responsible for (de novo) methylation, and EZH2, histone (H3K27) methyltransferase, and

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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