MSH6 (MutS homolog 6)

In our cohort, the addition of MLPA provided an incremental yield of seven pathogenic CNVs, representing an 11.6% absolute increase in diagnostic sensitivity (from 16.7% to 28.3%) over the NGS-alone workflow, with CNVs accounting for 41% of all pathogenic findings. Our results show that MLPA is a very useful method in molecular diagnostics of LS and its implementation in routine genetic testing in combination with NGS using multigene panel testing would benefit both patients and health care providers.

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.

Segmental and total colectomy offer similar survival and quality-adjusted life year outcomes. With decreased risk of metachronous cancers, patients with MSH6 mutations across all ages may prefer segmental resection due to higher quality-adjusted life years and lower survival benefits from total colectomy compared with MLH1 and MSH2 patients. Operative strategy in patients with hereditary nonpolyposis colorectal cancer should be individualized, and this study shows that mutation-specific differences in survival and quality-adjusted life years are small. See Video Abstract.

This case underscores the importance of comprehensive assessment integrating tumor and germline molecular data, particularly when clinical or molecular findings are atypical or discordant. The digenic etiology also raises questions regarding cancer surveillance and management strategies in such individuals.

Comprehensive molecular profiling can help guide personalized immunotherapy decisions. Further studies are needed to confirm long-term benefits, optimize treatment duration and dosing, and identify predictive biomarkers for high-risk CRC.

While not significantly associated with tumor grade or patient demographics, MMRD may have clinical relevance in specific subgroups. NGS findings highlight the potential utility of integrating molecular diagnostics for identifying MSI and guiding immunotherapy decisions.

P=N/A, N=310, Recruiting, Washington University School of Medicine | Trial completion date: Jan 2028 --> Jan 2027 | Trial primary completion date: Jan 2028 --> Jan 2027

Cascade testing achieved remarkable uptake, with >20 relatives tested in family A-over tenfold higher than typical reports-facilitated by direct clinician contact and streamlined logistics such as convenient blood collection. This is the first documented EPCAM-MSH2 deletion reported from the Middle East and North Africa region (MENA).

IHC testing can discriminate between sporadic and MTS-associated sebaceous neoplasms, but diagnostic utility is limited by low specificity. Most MMR-deficient cases are not due to MTS.

No associations were found between hMSH2 and hMSH6 expression and tumor staging, HER2, ER, PR, or Ki-67 expression. Our results suggest that the expression of the proposed markers is decreased in breast tumorigenesis.

This study contributes to advancing precision medicine strategies that aim to optimize patient outcomes. Future research into genetic and epigenetic modifiers of GD will further refine this framework and enhance individualized therapeutic approaches.