MSH3 (MutS Homolog 3)

Functionally, KLM exhibited dose-dependent cytotoxicity against MDA-MB-231 breast cancer cells and showed strong synergy with doxorubicin. qPCR analysis further confirmed significant downregulation of AKT1, BCRP, and MRP1 expression following KLM treatment. Collectively, these findings indicate that K. laciniata phytochemicals may act as effective chemosensitizing agents to overcome ABC transporter-mediated drug resistance in breast cancer.

This commentary underscores the need for functional assays and validation through multi-center studies to establish the pathogenicity and clinical relevance of non-EDMs. Furthermore, it advocates for the incorporation of comprehensive POLE sequencing, including non-EDM regions, into standard molecular subtyping frameworks for CRC to refine personalized treatment strategies.

Germline DDR alterations-most notably in BRCA2, CHEK2, and ATM-were present in a substantial subset of Turkish men with PCa and showed a non-significant trend toward clustering in higher-grade disease. The high prevalence of VUS reflects limited genomic annotation in under-represented populations and underscores the need for longitudinal reinterpretation. These data support the clinical value of incorporating germline DDR testing into risk assessment and familial counseling, while larger cohorts integrating somatic profiling are needed to refine genotype-phenotype associations.

Germline mutations in the APC gene were confirmed in more than 90% of Hungarian patients with clinically suspected FAP. Although the role of VUS genes is unclear, they are highly likely to play a role in the development of CRC.

Although several DNA repair gene polymorphisms have been explored, findings remain inconsistent and limited by populations and SNPs studied. Larger, well-designed studies with standardized methodologies are needed to confirm these associations and identify genetic markers for predicting high-risk patients for CIO.

We further reveal that the peptide is able to inhibit the latent endonuclease activity of recombinant MutLα, possibly via competing with a putative MIM within PMS2. Our findings define key PPI interfaces within the MLH1(CTD) that govern MMR activity and may offer novel therapeutic opportunities to exploit MMRd in cancer and HD.

In conclusion, discordance between IHC- and NGS-based MMR/MSI detection is primarily attributable to MSH6 loss with MSH3 compensation and MLH1 promoter methylation. Recognizing these mechanisms is essential for accurate molecular subtyping and clinical decision-making in EC.

POLE mutations, especially non-EDMs, are frequent in MSI-L CRC and often co-occur with MLH3, MSH3, KRAS, PIK3CA, and BRAF, highlighting their potential role in tumor biology and as biomarkers for personalized treatment. Functional validation and multicenter studies are needed.

Using cell models we demonstrate IL-6-induced binding of wild type and Δ27bpMSH3 to the NFκB activating complex NEMO/IKKγ which stabilizes MSH3 after disengaging from its nuclear partner MSH2, linking inflammation with DNA repair protein stability. Additional NLS modifications using MSH3-FLAG mimics cytosolic Δ27bpMSH3 retention to cause loss-of-function after inflammation.

Thus, naturally occurring and in silico informed mutations negatively affect As(GS)3 transport by MRP1. Individuals with R230Q-, R433S-, and A989T-MRP1 mutations may be more susceptible to arsenic-induced diseases.

As for dMMR subgroups (MLH1 me+, Lynch and Lynch-like), KEAP1 and FBXW7 mutations, which may have potential predictive effect of immunotherapy, were enriched in the Lynch subgroup. dMMR ECs has distinctive genomic profile with molecular heterogeneity, which may have potential prognostic and therapeutic implications.

The background of chronic inflammation, advanced lipomatous atrophy, and environmental exposures may have facilitated this transformation. This case underscores the need to consider alternative, nonlinear pathways of PDAC development in genetically predisposed individuals and highlights the potential utility of molecular surveillance for early detection and risk stratification.