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.

Keywords: Lynch syndrome; carcinogenesis; colorectal cancer; endometrial cancer; ovarian cancer; prevention.

Figure 1

A schematic representation of the MMR machinery. In humans, the MMR machinery comprises nine conserved core proteins that are four MutL homologues, MLH1, MLH3, PMS1, and PMS2, and five MutS homologues, MSH2, MSH3, MSH4, MSH5, and MSH6. These proteins form hMutL heterodimers, composed of MLH1-PMS2 (hMutLα), MLH1-PMS1 (hMutLβ), and MLH1-MLH3 (hMutLγ). Both hMutLα and hMutLγ participate in insertion/deletion loop (IDL) repair, but single-base mismatches are mainly repaired by hMutLα. hMutS heterodimers constitute the mismatch-binding factors. Specifically, hMutSα is formed by MSH2 and MSH6 and binds single-base mispairs and IDLs, whereas hMutSβ is composed of MSH2 and MSH3 and mainly acts on IDLs. After binding, MutS undergoes an ATP-driven conformational change, allowing to recruit a hMutL heterodimer. The hMutS–hMutL complex recognizes a mismatched sequence, triggering the degradation of the nascently synthesized DNA by exonuclease I (exo I) and the correct sequence synthesis by polymerase δ.

Figure 2

The three-pathways carcinogenic model in LS. A cartoon represents the hypothetical mechanisms of cancer development in LS with parallel intranuclear genetic events (above) and morphologic lesion in the colorectum (below). The somatic cell harboring a heterozygous germline mismatch repair (MMR) gene mutation is MMR-proficient and thus microsatellite stable (MSS). In the two upper models, the cells first acquire a somatic mutation in the same MMR gene, giving rise to MMRd crypt foci, morphologically normal, or only slightly altered, but with loss of MMR immunohistochemical staining. Then, depending on the further acquired mutation, they can progress to a polypoid lesion (with TGFBR2, RNF43, ARID1A, ATM, or BRCA mutation) or a flat lesion (in case of CTNNB1 or TP53 mutation), and thus becomes invasive. The third model is analogous to the sporadic microsatellite stable process, and MMRd can occur as a late event.

Figure 3

(a) The lifetime risk of cancer in patients with Lynch syndrome based on pathogenic MMR gene and site. The risks of endometrial and ovarian cancer were calculated in a female population. (b) Frequency of cancer by site in 6350 carriers of pathogenic MMR variants from the Prospective Lynch Syndrome Database (skin cancer were excluded) [5].

Figure 4

The diagnostic algorithm for colorectal (CRC) and endometrial cancer. MMR deficiency can be tested with immunohistochemistry (IHC) for MLH1, MSH2, MSH6, and PMS2 or MSI testing, complemented by MLH1 promoter methylation testing, and BRAF mutation analysis for CRCs.