Hereditary Colorectal Cancer: State of the Art in Lynch Syndrome

Abstract

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. Molecular diagnosis is performed to identify pathogenetic variants in MMR genes. However, for many patients with clinically suspected Lynch syndrome, it is not possible to identify a pathogenic variant in MMR genes. Molecular diagnosis is essential for referring patients to specific surveillance to prevent the development of tumors related to Lynch syndrome. This review summarizes the main aspects of Lynch syndrome and recent advances in the field and, in particular, emphasizes the factors that can lead to the loss of expression of MMR genes.

Diagnostic Performance of Immunohistochemistry Compared to Molecular Techniques for Microsatellite Instability and p53 Mutation Detection in Endometrial Cancer

“…Discrepancies can be explained by tumour heterogeneity or by an incomplete sensitivity/specificity of either method: poor DNA quality, insufficient or heterogenous antibody binding and retained expression of mutated proteins [11,14,21,24]. Indeed, analyses performed on gastrointestinal tract tumours indicate a sensitivity of around 90% for each method, and these numbers are lower for EC [12,25].…”

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

“…LS is an autosomal dominant disease characterized by incomplete penetrance and variable expressivity in which a high variability of the risk of developing one of the tumors of the spectrum of the syndrome is also described in carriers of pathogenic variants in one of the MMR genes ( MLH1 , MSH2 , MSH6 , and PMS2 ) [ 1 ]. Therefore, an important aspect to consider in the molecular diagnosis of LS is the evaluation of the possible simultaneous presence of pathogenic variants in other genes beyond the aforementioned MMR when predicting the development of a hereditary tumor.…”

“…Lynch syndrome (LS) is an autosomal dominant inherited disorder that mainly predisposes individuals to colorectal and endometrial cancer but is also associated with other extracolonic malignancies, such as stomach, small intestine, bladder, pancreatic, bile duct, and prostate cancer [ 1 ]. Germline pathogenic variants in DNA mismatch repair ( MMR ) genes such as MLH1 , MSH2 , MSH6 , and PMS2 are associated with a predisposition to this syndrome.…”

Understanding the Genetic Landscape of Pancreatic Ductal Adenocarcinoma to Support Personalized Medicine: A Systematic Review

“…As regards PDAC susceptibility genes, BRCA1 and BRCA2 are considered high penetrance genes in breast and ovarian cancer, and MLH1 and MSH2 are considered high penetrance genes in LS CRC [ 231 ]. On the other hand, ATM and PALB2 are considered moderate penetrance genes in breast and ovarian cancer [ 232 ], and MSH6 , PMS2 , and EPCAM are considered moderate penetrance genes in LS CRC [ 233 ]. Additionally, CDKN2A , STK11 , and TP53 are considered highly penetrant genes in melanoma, juvenile polyposis syndrome (JPS), and Li–Fraumeni syndrome, respectively.…”