Germline Variants in MLH1 and ATM Genes in a Young Patient with MSI-H in a Precancerous Colonic Lesion.

Lynch syndrome (LS) is an autosomal dominant inherited disorder that primarily predisposes individuals to colorectal and endometrial cancer. It is associated with pathogenic variants in DNA mismatch repair (MMR) genes. In this study, we report the case of a 16-year-old boy who developed a precancerous colonic lesion and had a clinical suspicion of LS.

Hereditary Colorectal Cancer: State of the Art in Lynch Syndrome.

Hereditary non-polyposis colorectal cancer is also known as Lynch syndrome. Lynch syndrome is associated with pathogenetic variants in one of the mismatch repair (MMR) genes. In addition to colorectal cancer, the inefficiency of the MMR system leads to a greater predisposition to cancer of the endometrium and other cancers of the abdominal sphere.

Significance of rare variants in genes involved in the pathogenesis of Lynch syndrome.

The molecular characterization of patients with Lynch syndrome (LS) involves germline testing to detect a deleterious mutation in one of the genes of the mismatch repair () pathway. To date, however, a large proportion of patients with a clinical suspicion of LS who undergo genetic testing do not show a germline pathogenetic variant in these genes. Germline DNA from 73 patients with a clinical suspicion of LS was examined with next‑generation sequencing methods, using a multigene custom panel designed and standardized by our research group, that targets a set of 15 genes.

MiR-137 Targets the 3' Untranslated Region of : Potential Implications in Lynch Syndrome-Related Colorectal Cancer.

Mismatch Repair () gene dysregulation plays a fundamental role in Lynch Syndrome (LS) pathogenesis, a form of hereditary colorectal cancer. Loss or overexpression of key genes leads to genome instability and tumorigenesis; however, the mechanisms controlling gene expression are unknown. One such gene, , exerts an important role, not only in MMR, but also in cell proliferation, apoptosis, and cell cycle control.

Sporadic pediatric severe familial adenomatous polyposis: A case report.

Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary precancerous condition caused by germline pathogenetic variants in the tumor suppressor adenomatous polyposis coli () gene. Patients with FAP develop multiple gastrointestinal adenomatous polyps usually at the age of ~20 years, which, if untreated, become cancerous in 100% of cases. Genotype-phenotype associations have been extensively described; however, inter- and intra-familial variability exists.

MSH2 Overexpression Due to an Unclassified Variant in 3'-Untranslated Region in a Patient with Colon Cancer.

Background: The loss or low expression of DNA mismatch repair (MMR) genes can result in genomic instability and tumorigenesis. One such gene, MSH2, is mutated or rearranged in Lynch syndrome (LS), which is characterized by a high risk of tumor development, including colorectal cancer. However, many variants identified in this gene are often defined as variants of uncertain significance (VUS).

Novel variants of unknown significance in the gene identified in patients with hereditary colon cancer.

Lynch syndrome is associated with genetic variants in mismatch repair () genes. Pathogenic variants in the and genes occur in most families in which the phenotype is highly penetrant. These testing criteria are likely to miss individuals with Lynch syndrome due to the less penetrant genes, such as and .

Genetics, diagnosis and treatment of Lynch syndrome: Old lessons and current challenges.

Lynch syndrome (LS) is an autosomal dominant genetic disorder associated with germline mutations in DNA mismatch repair (MMR) genes. The carriers of pathogenic mutations in these genes have an increased risk of developing a colorectal cancer and/or LS-associated cancer. The LS-associated cancer types include carcinomas of the endometrium, small intestine, stomach, pancreas and biliary tract, ovary, brain, upper urinary tract and skin.

Characterisation of mesenchymal colon tumour-derived cells in tumourspheres as a model for colorectal cancer progression.

Cellular plasticity, the ability of cells to switch from an epitheial phenotype to a mesenchymal one and vice versa, plays a crucial role in tumour progression and metastases development. In 20-25% of patients with colon cancer and in 18% of patients with rectal cancer, metastases are present at the time of the first diagnosis. They are the first cause of colorectal cancer (CRC)-related mortality, defining stage IV CRC, which is characterized by a relatively short overall survival.

Novel MSH2 splice-site mutation in a young patient with Lynch syndrome.

Lynch Syndrome (LS) is associated with germline mutations in one of the mismatch repair (MMR) genes, including MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6, PMS1 homolog 2, mismatch repair system component (PMS2), MLH3 and MSH3. The mutations identified in MMR genes are point mutations or large rearrangements. The point mutations are certainly pathogenetic whether they determine formation of truncated protein.

Characterization of novel, large duplications in the MSH2 gene of three unrelated Lynch syndrome patients.

Lynch syndrome (LS) is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1, MSH2, MSH6, and PMS2. Most of genetic variants in the MMR genes predisposing to LS are point mutations, small deletions and insertions but large genomic rearrangements in the MMR genes also predisposing to Lynch syndrome. In this study, we report a novel, large rearrangement of the MSH2 gene, manifested by a duplication spanning a 14,846-bps region from intron 7 through intron 9.

Same Gene Mutation But Variable Phenotypes in 2 Families With Lynch Syndrome: Two Case Reports and Review of Genotype-Phenotype Correlation.

Lynch syndrome is an autosomal dominant syndrome that can be subdivided into Lynch syndrome I, or site-specific colonic cancer, and Lynch syndrome II, or extracolonic cancers, particularly carcinomas of the stomach, endometrium, biliary and pancreatic systems, and urinary tract. Lynch syndrome is associated with point mutations and large rearrangements in DNA MisMatch Repair () genes. This syndrome shows a variable phenotypic expression in people who carry pathogenetic mutations.

Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome.

Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, involves mutations in mismatch repair genes. The aim of this study was to identify mutations in from 97 subjects negative for mutations in and . By direct sequencing, we identified 27 variants, of which, nine were novel.

Novel Implications in Molecular Diagnosis of Lynch Syndrome.

About 10% of total colorectal cancers are associated with known Mendelian inheritance, as Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). In these cancer types the clinical manifestations of disease are due to mutations in high-risk alleles, with a penetrance at least of 70%. The LS is associated with germline mutations in the DNA mismatch repair (MMR) genes.

Two novel sequence variants in MSH2 gene in a patient who underwent cancer genetic counseling for a very early-onset epithelial ovarian cancer.

Background: Early-onset or hereditary ovarian cancer is mostly associated with BRCA1 or BRCA2 mutations. Mismatch repair genes sequence alteration frequently cause colorectal cancer, and, in less extent, other tumors, such as ovarian cancer. Subjects with personal and/or family history suggestive for hereditary cancer should be addressed to cancer genetic counseling, aimed to the identification, definition and management of hereditary cancer syndrome, by a multidisciplinary approach.

Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability.

Loss of function of mismatch repair (MMR) genes, mainly MLH1 and MSH2, manifests as high levels of microsatellite instability (MSI) that occurs in >90% of carcinomas in patients with Lynch syndrome (LS). The MSI-high status has also been described in sporadic colorectal cancer (CRC) associated with BRAF gene mutation (V600E); this mutation was not present in LS-associated cancers. The present study performed MSI analysis on 39 CRC patients selected according to Bethesda guidelines, and BRAF V600E genotyping was performed in 26 cases classified as MSI-high or MSI-low (15 MSI-H and 11 MSI-L).

Lithium chloride induces mesenchymal‑to‑epithelial reverting transition in primary colon cancer cell cultures.

Epithelial‑to‑mesenchymal transition (EMT) confers stem cell‑like phenotype and more motile properties to carcinoma cells. During EMT, the expression of E‑cadherin decreases, resulting in loss of cell‑cell adhesion and increased migration. Expression of Twist1 and other pleiotropic transcription factors, such as Snail, is known to activate EMT.

Differential expression of PTEN gene correlates with phenotypic heterogeneity in three cases of patients showing clinical manifestations of PTEN hamartoma tumour syndrome.

Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS) and proteus syndrome are disorders known as PTEN hamartoma tumour syndrome (PHTS), that can show remarkable clinical overlap and are all caused by germline PTEN mutations. We here present two families, one affected by CS and the other affected by BRRS, both carriers of specific pathogenetic missense mutation in exon 5 of PTEN gene, within the catalitic domain. Both PHTS families exhibited extremely variable phenotypes, showing inter- and intra- familial variability.

Contribution of large genomic rearrangements in Italian Lynch syndrome patients: characterization of a novel alu-mediated deletion.

Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1 and MSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%.

Association of low-risk MSH3 and MSH2 variant alleles with Lynch syndrome: probability of synergistic effects.

Mutations in the MLH1 and MSH2 genes account for a majority of cases of families with Lynch Syndrome. Germ-line mutations in MSH6, PMS2 and MLH3 are responsible for disease in a minority of cases, usually associated with milder and variable phenotypes. No germ-line mutations in MSH3 have so far been associated with Lynch Syndrome, although it is known that impaired MSH3 activity leads to a partial defect in mismatch repair (MMR), with low levels of microsatellite instability at the loci with dinucleotide repeats in colorectal cancer (CRC), thus suggesting a role for MSH3 in carcinogenesis.