Review article: Lynch Syndrome-a mechanistic and clinical management update

Abstract

Background: Lynch syndrome (LS) is an autosomal dominant familial condition caused by a pathogenic variant (PV) in a DNA mismatch repair gene, which then predisposes carriers to various cancers.

Aim: To review the pathogenesis, clinical presentation, differential diagnosis and clinical strategies for detection and management of LS.

Methods: A narrative review synthesising knowledge from published literature, as well as current National Comprehensive Cancer Network guidelines for management of LS was conducted.

Results: LS tumours are characterised by unique pathogenesis, ultimately resulting in hypermutation, microsatellite instability and high immunogenicity that has significant implications for cancer risk, clinical presentation, treatment and surveillance. LS is one of the most common hereditary causes of cancer, and about 1 in 279 individuals carry a PV in an LS gene that predisposes to associated cancers. Individuals with LS have increased risks for colorectal, endometrial and other cancers, with significant variation in lifetime risk by LS-associated gene.

Conclusions: As genetic testing becomes more widespread, the number of individuals identified with LS is expected to increase in the population. Understanding the pathogenesis of LS informs current strategies for detection and clinical management, and also guides future areas for clinical innovation. Unravelling the mechanisms by which these tumours evolve may help to more precisely tailor management by the gene involved.

Figure 1:

The DNA mismatch repair (MMR) system. A) The MutS MMR proteins recognize DNA errors (mispairs and loop-outs) made during S phase. They are only stable as heterodimers (MSH2 + MSH6 [MutSα] or MSH2 + MSH3 [MutSβ]). B) MutL (MutLa here) heterodimers bind to the MutS proteins and act as recruitment proteins for the DNA repair process. C) Enzymes such as exonuclease 1 (EXO1), DNA polymerase, and proliferating cell nuclear antigen (PCNA) serving as a sliding clamp, perform long patch excision to remove the error, and then enable resynthesis and ligation. D) The daughter strand is resynthesized, which results in correction of the DNA error. Figure created using BioRender.com.

Figure 2:

Cumulative colorectal cancer (CRC) incidence by age, shown for males (blue) and females (red) in separate panels for each specified MMR gene mutation, as determined using the Prospective Lynch Syndrome Database (PLSD). Data for carriers of PMS2 PVs were combined for males and females (purple) due to limited total follow-up years within the data

Figure 3:

Three potential pathways for CRC evolution in LS ^,. Based on molecular and clinical evidence (see text for details), multiple pathways for CRC carcinogenesis in LS have been suggested that vary in placement of the timing of mismatch repair (MMR) deficiency and the growth of polyp precursors. A) Adenomas can first develop via traditional mutations such as APC inactivation followed by MMR loss and accumulations of additional driver mutations leading to CRC. The theoretical basis of this is that APC inactivation leads to the formation of an elevated lesion (benign polyp) that can be detected and removed by colonoscopy. This pathway is proposed to be common in LS associated with germline PVs in MSH6 and PMS2, but is the rarest scenario found in molecular studies of Lynch associated-adenomas. B) Inactivating mutations in the MMR gene can occur as the first step producing MMR-deficient (dMMR) crypts, followed by inactivating mutations in APC, leading to an elevated lesion in the colon. Subsequent accumulation of mutations lead to CRCs, and this pathway is proposed to be most common in LS-MSH2. C) MMR-deficient crypts may accumulate driver mutations such as activation of CTNNB1 and serve as the precursor to a flat CRC, without necessarily initiating precursor elevated adenomas, confounding the beneficial effects of surveillance colonoscopy, as may occur in LS-MLH1. This figure was adapted from “Colon Cancer Progression” by BioRender.com (2022)