PMS2-associated Lynch syndrome: Past, present and future

Abstract

Carriers of any pathogenic variant in one of the MMR genes (path_MMR carriers) were traditionally thought to be at comparable risk of developing a range of different malignancies, foremost colorectal cancer (CRC) and endometrial cancer. However, it is now widely accepted that their cancer risk and cancer spectrum range notably depending on which MMR gene is affected. Moreover, there is increasing evidence that the MMR gene affected also influences the molecular pathogenesis of Lynch syndrome CRC. Although substantial progress has been made over the past decade in understanding these differences, many questions remain unanswered, especially pertaining to path_PMS2 carriers. Recent findings show that, while the cancer risk is relatively low, PMS2-deficient CRCs tend to show more aggressive behaviour and have a worse prognosis than other MMR-deficient CRCs. This, together with lower intratumoral immune infiltration, suggests that PMS2-deficient CRCs might have more in common biologically with sporadic MMR-proficient CRCs than with other MMR-deficient CRCs. These findings could have important consequences for surveillance, chemoprevention and therapeutic strategies (e.g. vaccines). In this review we discuss the current knowledge, current (clinical) challenges and knowledge gaps that should be targeted by future studies.

Fucoxanthin Inhibits Development of Sigmoid Colorectal Cancer in a PDX Model With Alterations of Growth, Adhesion, and Cell Cycle Signals

“…Increasing evidence suggests that the gene mutations in TP53, ARID1A, NRAS, and PMS2 are frequent in patients with CRC (42,43). Therefore, we speculated that the TP53, ARID1A, NRAS, and PMS2-associated signals, such as EGFR, PI3K/AKT, MAPK, NF-kB, EMT, p53, WNT/β-catenin, DNA mismatch repair, angiogenesis, apoptosis, and others, might be key regulators for tumor development in the CRC-PDX mice (42,(44)(45)(46).…”

Personalised neoantigen‐based therapy in colorectal cancer

“…The most important components of the MMR system are the MutS and MutL complexes (MSH2 and MSH6 form MutSα; MSH2 and MSH3 form MutSβ; MLH1 and PMS2 form MutLα; MLH1 and PMS1 form MutLβ; MLH1 and MLH3 form MutLγ). As MSH2 and MLH1 are proteins shared by MutS and MutL complexes, gene mutations will completely delay all MMR activities, resulting in the accumulation of insertion/deletion mutations in the repetitive nucleotide sequence regions of coding and non‐coding microsatellites 16–19 . Template and primer chains easily slip during replication, and this mismatch cannot be repaired in MMR defective cells.…”

“…As MSH2 and MLH1 are proteins shared by MutS and MutL complexes, gene mutations will completely delay all MMR activities, resulting in the accumulation of insertion/deletion mutations in the repetitive nucleotide sequence regions of coding and non-coding microsatellites. [16][17][18][19] Template and primer chains easily slip during replication, and this mismatch cannot be repaired in MMR defective cells. Thus, the number of duplicate units between the template and the newly synthesised chain is incorrect.…”

In silico Splicing Analysis of the PMS2 Gene: Exploring Alternative Molecular Mechanisms in PMS2-Associated Lynch Syndrome

“…pediatric cancer syndrome [1,3,7]. In heterozygous state, PMS2 pathogenic variants are associated with Lynch-related cancers, mainly colorectal and endometrial cancers [8]. However, the low penetrance phenotype and late-onset disease associated with heterozygous PMS2 variants are contributing factors that might impede accurately determining of the true prevalence of healthy carriers in population [5,9,10].…”