Evidence for breast cancer as an integral part of Lynch syndrome

Department of Obstetrics and Gynecology, Cantonal Hospital of Liestal, Liestal, Switzerland.
Genes Chromosomes and Cancer (Impact Factor: 4.04). 01/2012; 51(1):83-91. DOI: 10.1002/gcc.20935
Source: PubMed


Lynch syndrome, an autosomal dominant cancer predisposition caused by mutations in DNA mismatch repair (MMR) genes, mainly mainly mutL homolog 1, OMIM 120436 (MLH1) and mutS homolog 2, OMIM 609309 (MSH2), encompasses a tumor spectrum including primarily gastrointestinal, endometrial, and ovarian cancer. This study aimed at clarifying the heavily debated issue of breast cancer being part of Lynch syndrome. Detailed clinical data on cancer occurrence in Swiss female MLH1/MSH2 mutation carriers were gathered, all available breast cancer specimens assessed for molecular evidence for MMR deficiency (i.e., microsatellite instability (MSI), MMR protein expression, and somatic (epi)genetic MMR gene alterations) and compiled with the scarce molecular data available from the literature. Seventy unrelated Swiss Lynch syndrome families were investigated comprising 632 female family members at risk of which 92 were genetically verified mutation carriers (52 MLH1 and 40 MSH2). On contrast to endometrial and ovarian cancer, which occurred significantly more often and at younger age in MLH1/MSH2 mutation carriers (median 50.5 and 49.0 years; P < 0.00001), overall cumulative breast cancer incidence closely mirrored the one in the Swiss population (56.5 years). Six (85.7%) of seven breast cancer specimens available for molecular investigations displayed the hallmarks of MMR deficiency. Combined with data from the literature, MSI was present in 26 (70.3%) of 37 and altered MMR protein expression in 16 (72.7%) of 22 breast cancer specimens from MLH1/MSH2 mutation carriers. These findings, thus, provide strong molecular evidence for a pivotal role of MMR deficiency in breast cancer development in Lynch syndrome.

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    • "The mechanistic insights obtained by these studies did advance our understanding on how hereditary sequence variants in the minimal human MMR system affect the MMR function and hence predispose to the DNA instabilities linked to cancer predisposition. The list of cancer types where MMR malfunction has been observed expanded to include the most frequent hereditary predisposition to colorectal cancer along with increased risk for development of endometrial, ovarian, gastric, small bowel, urothelial, brain, hepatobiliary, pancreatic, bladder, kidney, prostate and breast cancers, and hematological malignances (Scott et al., 2001; Umar et al., 2004; Grindedal et al., 2009; van Oers et al., 2010; Wimmer and Kratz, 2010; Buerki et al., 2012; Win et al., 2012a,b; Vasen et al., 2013). The ability to predict cancer predisposition by analyzing the sequence variants for the MMR genes also contributed to better management of patients and their relatives and resulted in reduced mortality (Jarvinen et al., 2009). "
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    ABSTRACT: DNA is constantly under attack by a number of both exogenous and endogenous agents that challenge its integrity. Among the mechanisms that have evolved to counteract this deleterious action, mismatch repair (MMR) has specialized in removing DNA biosynthetic errors that occur when replicating the genome. Malfunction or inactivation of this system results in an increase in spontaneous mutability and a strong predisposition to tumor development. Besides this key corrective role, MMR proteins are involved in other pathways of DNA metabolism such as mitotic and meiotic recombination and processing of oxidative damage. Surprisingly, MMR is also required for certain mutagenic processes. The mutagenic MMR has beneficial consequences contributing to the generation of a vast repertoire of antibodies through class switch recombination and somatic hypermutation processes. However, this non-canonical mutagenic MMR also has detrimental effects; it promotes repeat expansions associated with neuromuscular and neurodegenerative diseases and may contribute to cancer/disease-related aberrant mutations and translocations. The reaction responsible for replication error correction has been the most thoroughly studied and it is the subject to numerous reviews. This review describes briefly the biochemistry of MMR and focuses primarily on the non-canonical MMR activities described in mammals as well as emerging research implicating interplay of MMR and chromatin.
    Frontiers in Genetics 08/2014; 5:287. DOI:10.3389/fgene.2014.00287
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    • "Most of the previous studies estimated risk of breast cancer for all MMR gene mutation carriers combined. Some studies [37,53,55,58,59,62,64,65] attempted to test for differences in breast cancer risk by MMR genes; for example, Scott et al. [58] observed an increased risk of breast cancer for MLH1 mutation-carrying families but not in MSH2 families (see Additional file 1 for details). Although there is indeed some suggestion that breast cancer risk may vary by gene, there have been no formal attempts by the previous studies to examine gene- and age-specific risks for breast cancer. "
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    ABSTRACT: Introduction Lynch syndrome is an autosomal dominantly inherited disorder of cancer susceptibility caused by germline mutations in the DNA mismatch repair (MMR) genes. Mutation carriers have a substantial burden of increased risks of cancers of the colon, rectum, endometrium and several other organs which generally occur at younger ages than for the general population. The issue of whether breast cancer risk is increased for MMR gene mutation carriers has been debated with evidence for and against this association. Methods Using the PUBMED, we identified all relevant studies of breast cancer associated with Lynch syndrome that were published by 15 December 2012. In the review, we included: (i) molecular studies that reported microsatellite instability and/or immunohistochemistry in breast cancer tumors of MMR gene mutation carriers; and (ii) risk studies that investigated risk of breast cancer for confirmed MMR gene mutation carriers or families or clinically and/or pathologically defined Lynch syndrome families. Results We identified 15 molecular studies and, when combined, observed 62 of 122 (51%; 95% CI 42 to 60%) breast cancers in MMR gene mutation carriers were MMR-deficient. Of the 21 risk studies identified, 13 did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome while 8 studies found an increased risk of breast cancer ranging from 2- to 18-fold compared with the general population (or non-carriers). There is only one prospective study demonstrating an elevated risk of breast cancer for MMR gene mutation carriers compared with the general population (standardized incidence ratio 3.95; 95% CI 1.59, 8.13). Conclusions Since breast cancer is a relatively common disease in the general population, more precise estimates of risk and gene-specific risks will need to utilize large prospective cohort studies with a long follow-up. While current data are inconclusive at a population level, individual tumor testing results suggest that MMR deficiency is involved with breast cancers in some individuals with Lynch syndrome.
    Breast cancer research: BCR 03/2013; 15(2):R27. DOI:10.1186/bcr3405 · 5.49 Impact Factor
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    • "No consensus exists regarding the association of breast cancer with Lynch Syndrome. Although MSI has been described in most breast cancers of HNPCC kindreds, the risk for breast cancer is not elevated in most families [5,19-23]. However, a recent prospective study revealed an almost four-fold increase of breast cancer incidence in carriers of a mutation in the HNPCC-genes [24]. "
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    ABSTRACT: Background Hereditary Breast and Ovarian Cancer Syndrome (HBOCS) and Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC, Lynch Syndrome) are two tumor predisposition syndromes responsible for the majority of hereditary breast and colorectal cancers. Carriers of both germline mutations in breast cancer genes BRCA1 or BRCA2 and in mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2 are very rare. Case presentation We identified germline mutations in BRCA1 and in MSH6 in a patient with increased risk for HBOC diagnosed with endometrial cancer at the age of 46 years. Conclusions Although carriers of mutations in both MMR and BRCA genes are rare in Caucasian populations and anamnestical and histopathological findings may guide clinicians to identify these families, both syndromes can only be diagnosed through a complete gene analysis of the respective genes.
    BMC Cancer 11/2012; 12(1):531. DOI:10.1186/1471-2407-12-531 · 3.36 Impact Factor
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