Read the full paper: Reconciling the effects of PMS2 in different repeat expansion disease models supports a common expansion mechanism

Abstract. DNA mismatch repair (MMR) detects and corrects post-replicative DNA alterations; it is deregulated in up to 20% of human cancers. MMR-deficient (MMR-d) cancers display increased tumour mutat...

Read the full paper: Analysis of structure and conservation for supporting functional evaluation of PMS2 missense variants

Mutations in DNA mismatch repair (MMR) pathway genes (MSH2, MSH6, MLH1, and PMS2) are linked to acquired resistance to temozolomide (TMZ) and high tumor mutation burden (TMB) in high-grade gliomas (HGGs), including glioblastomas (GBMs). However, the specific roles of individual MMR genes in the initiation, progression, TMB, microsatellite instability (MSI), and resistance to TMZ in gliomas remain unclear. Here, we developed de novo mouse models of germline and somatic MMR-deficient (MMRd) HGGs. Surprisingly, loss of Msh2 or Msh6 did not lead to high TMB, MSI, nor did it confer a response to anti–programmed cell death 1 (anti–PD-1) in GBM. Similarly, human GBM showed discordance between MMR gene mutations and the TMB and MSI. Germline MMRd promoted the progression from low-grade to HGG and reduced survival compared with MMR-proficient (MMRp) tumor–bearing mice. This effect was not tumor cell intrinsic but was associated with MMRd in the tumor immune microenvironment, driving immunosuppressive myeloid programs, reduced lymphoid infiltration, and CD8+ T cell exhaustion. Both MMR-reduced (MMRr) and MMRd GBM were resistant to TMZ, unlike MMRp tumors. Our study shows that N3-(2-fluoroethyl) imidazotetrazine (KL-50), an imidazotetrazine-based DNA targeting agent that induces MMR-independent cross-link–mediated cytotoxicity, was effective against germline and somatic MMRr and MMRd GBMs, offering a potential therapy for TMZ-resistant HGG with MMR alterations.

Lynch syndrome (MIM #120435) is a heritable condition associated with increased risk of different forms of cancer [1]. It results from a germline inactivating variant causing loss of function of one of four major DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2 [2, 3]. Somatic loss of the wild-type allele causes cellular MMR deficiency and microsatellite instability (MSI) [4]. Although Lynch syndrome confers a strongly elevated cancer risk for the individual, it is difficult to diagnose based on clinical phenotype. This is particularly the case for carriers of PMS2 pathogenic variants (also called path_PMS2), because they have lower penetrance, milder phenotypes, later onset, and reduced familial burden compared to path_MLH1 and path_MSH2 carriers. Moreover, path_PMS2 carriers may have a different tumor spectrum, with elevated prevalence of extra colonic localizations such as breast cancer and prostate cancer [5,6,7,8,9], although other studies have not found increased cancer rates [1, 10]. Notably, despite lower penetrance, PMS2 defects still can cause early-onset cancer [11], and path_PMS2_carriers should therefore be identified for being offered appropriate surveillance measures [12]. The differences in phenotype have been attributed to a potential partial compensation of PMS2 defects by MLH3, which shows some degree of overlap in its...

Lynch syndrome, caused by germline pathogenic variants in mismatch repair genes, markedly increases risks of endometrial, ovarian, and possibly breast…