Evidence for breast cancer as an integral part of lynch syndrome

Abstract

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.

Predicting the evolution of Escherichia coli by a data-driven approach

“…As expected, the gene gyrB which encodes for a subunit of the DNA gyrase is mutated in half of the mutator strains. This is similar to the malfunction in mismatch repair system that was found to contribute to the evolution of cancer cells in mammalian systems 55–59 .…”

MutSα and MutLα immunoexpression analysis in diagnostic grading of oral epithelial dysplasia and squamous cell carcinoma

“…[7][8][9] Nomenclature and structure of two MMR proteins (MutS and MutL) are conserved from prokaryotes to eukaryotes, but in contrast to bacterial Mut proteins, eukaryotic Mut proteins are heterodimers of two related but distinct proteins. 10 The current study focused on one form of both the major Mut proteins: MutSα and MutLα, in each case using antibodies against both of their constituent proteins.…”

Patients Tested at a Laboratory for Hereditary Cancer Syndromes Show an Overlap for Multiple Syndromes in Their Personal and Familial Cancer Histories

“…Although several studies have suggested there is no increased risk for breast cancer with LS, there has been no consensus to date on the correlation between breast cancer and LS [11,12,13,19,20]. This study revealed that 22.4% of the LS patients meeting NCCN criteria for HBOC had a personal history of breast cancer and a family history of early-onset breast cancer.…”