Lynch Syndrome: From Carcinogenesis to Prevention Interventions

Abstract

Lynch syndrome (LS) is the most common inherited disorder responsible for an increased risk of developing cancers at different sites, most frequently in the gastrointestinal and genitourinary tracts, caused by a germline pathogenic variant affecting the DNA mismatch repair system. Surveillance and risk-reducing procedures are currently available and warranted for LS patients, depending on underlying germline mutation, and are focused on relevant targets for early cancer diagnosis or primary prevention. Although pharmacological approaches for preventing LS-associated cancer development were started many years ago, to date, aspirin remains the most studied drug intervention and the only one suggested by the main surveillance guidelines, despite the conflicting findings. Furthermore, we also note that remarkable advances in anticancer drug discovery have given a significant boost to the application of novel immunological strategies such as immunocheckpoint inhibitors and vaccines, not only for cancer treatment, but also in a preventive setting. In this review, we outline the clinical, biologic, genetic, and morphological features of LS as well as the recent three-pathways carcinogenesis model. Furthermore, we provide an update on the dedicated screening, surveillance, and risk-reducing strategies for LS patients and describe emerging opportunities of harnessing the immune system.

Germline Variants in Sporadic Pituitary Adenomas

“…Finally, MLH1 , MSH2 , and MSH6 are some of the underlying genes for Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC) [ 42 , 43 ]. LS is characterized by an increased risk of developing several types of cancers due to germline mutations in genes involved in DNA mismatch repair ( MSH2 , MLH1 , MSH6 , PMS2 , and EPCAM ) [ 42 ]. Colorectal, endometrial, ovarian, gastric cancers and malignant brain tumors are among the commonly occuring cancers seen in this syndrome [ 42 , 43 ].…”

“…LS is characterized by an increased risk of developing several types of cancers due to germline mutations in genes involved in DNA mismatch repair ( MSH2 , MLH1 , MSH6 , PMS2 , and EPCAM ) [ 42 ]. Colorectal, endometrial, ovarian, gastric cancers and malignant brain tumors are among the commonly occuring cancers seen in this syndrome [ 42 , 43 ]. PA has been associated with LS, and mutations in LS genes have been described in apparently sporadic PA [ 44-46 ].…”

Real-World Data on Institutional Implementation of Screening for Mismatch Repair Deficiency and Lynch Syndrome in Endometrial Cancer Patients

“…For genetic screening, sequence analysis of the coding exons (including exon/intron boundaries, +/−10 base pairs) of the Lynch syndrome-associated mismatch repair genes MLH1, MSH2, MSH6, and PMS2 was performed by high-throughput sequencing, Sanger sequencing of selected exons, and gene dosage analyses by MLPA assays. If no deleterious sequence variant was found in MSH2 despite immunohistochemical loss of MSH2 and/or MSH6, the EPCAM gene was analyzed as its deletion can lead to methylation of the MSH2 promoter, resulting in silencing of the MSH2 gene [4]. Lynch syndrome was diagnosed in all patients with a confirmed pathogenic or likely pathogenic MMR gene variant.…”

“…Lynch syndrome is an autosomal dominant genetic disorder, one of the most common inherited tumor syndromes and the leading cause of hereditary colorectal and endometrial cancer [1][2][3]. It is caused by a heterozygous germline mutation in the genes encoding mismatch repair (MMR) proteins, which results in MMR deficiency when combined with a second-hit mutation of the remaining wild-type allele [4,5]. Such a deficiency in DNA repair mechanisms disrupts the integrity of the cellular genome, leading to increased mutational load, microsatellite instability and consequently increased tumor susceptibility [6,7].…”

Genetically engineered mouse models for hereditary cancer syndromes

“…There is not yet any definite association of other MMR genes such as MSH3 , MSH4 , MSH5 , MLH3 , and PMS1 with LS. 13 , 14 Mutations in both the alleles of MMR genes causes a rare disorder, the constitutional mismatch repair deficiency (CMMRD) syndrome that greatly increases the risk of developing cancer in childhood (before age 18). The tumor spectrum for CMMRD mainly includes hematologic, brain/central nervous system, gastrointestinal (GI), and other malignancies.…”