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Abstract. Cadmium (Cd2+) is a known carcinogen that inactivates the DNA mismatch repair (MMR) pathway. In this study, we have tested the effect of Cd2+ exp

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Yang et al. identify MSH6 as a negative regulator of cGAS that promotes cGAS nuclear localization by strengthening its interaction with importin-α protein, thereby suppressing cGAS condensation and activity, consequently dampening antiviral and antitumor immunity. In tumors, MSH6 loss enhances the antitumor effect of heat-inactivated MVA.

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...

Read the full paper: MSH6 regulates cGAS activity in antiviral and antitumor signaling pathways by governing its cytosolic/nuclear distribution

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

Blurring the Lines: Co-Occurrence of MSH6 Variant and MLH1 Constitutional Epimutation in a Young Colorectal Cancer Patient

Blurring the Lines: Co-Occurrence of MSH6 Variant and MLH1 Constitutional Epimutation in a Young Colorectal Cancer Patient

Blurring the Lines: Co-Occurrence of MSH6 Variant and MLH1 Constitutional Epimutation in a Young Colorectal Cancer Patient

Blurring the Lines: Co-Occurrence of MSH6 Variant and MLH1 Constitutional Epimutation in a Young Colorectal Cancer Patient

Blurring the Lines: Co-Occurrence of MSH6 Variant and MLH1 Constitutional Epimutation in a Young Colorectal Cancer Patient

Blurring the Lines: Co-Occurrence of MSH6 Variant and MLH1 Constitutional Epimutation in a Young Colorectal Cancer Patient

Lynch syndrome (LS) is an autosomal dominant inherited disease caused by germline pathogenic variants (PVs) in mismatch repair (MMR) genes. LS-associated endometrial cancer (LS-EC) is the most common extraintestinal sentinel cancer caused by germline PVs in MMR genes, including MLH1, MSH2, MSH6 and …

Although RTs insertions do not seem to be a common cause of Lynch syndrome, the number might be underestimated because of the difficulties in detecting these variants with well-established methods lik...