PMS2 (PMS1 protein homolog 2)

These findings highlight the need to molecularly characterize these lesions as there is no specific histologic finding to identify cases that harbour different pathogenic alterations in specific genes.

This rare case highlights the critical role of histopathological examination. Given the limited body of documented evidence for an association between RASD and MTS, documented, albeit limited, baseline immunohistochemistry and colonoscopy should always be considered to rule out MTS in patients diagnosed with RASD.

This is the first meta-analysis providing stratified cancer risk estimates by cancer site, gene, and study design. These findings support gene-specific surveillance strategies, such as initiating colonoscopy at age 30-35 for MSH6 and PMS2 carriers, postponing hysterectomy after 50 y for PMS2 carriers, and delaying oophorectomy after 45 y for MLH1 and MSH2 PV carriers.

MLH1ph ECs represent a higher-risk molecular subgroup with significantly poorer survival. Our findings support routine MLH1ph testing when MLH1/PMS2 protein loss is identified. Improved recognition of this subgroup is crucial for refining molecular risk stratification and will enable more personalized and effective oncologic management strategies based on tumour biology.

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.

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.

Six PMS2 variants were associated with either early or later-onset CMMRD. Future validation through larger prospective cohort studies is necessary to confirm our findings and better understand the natural history of PMS2-CMMRD to inform clinical decision-making in PMS2-Lynch syndrome (PMS2-LS).

These data highlight the importance of dMMR testing in patients with advanced solid tumors in China to optimize biomarker testing and treatment decisions.

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.

In the studied population, dMMR tumors more frequently exhibited adverse prognostic features of EC, such as advanced stage of disease and lymphovascular space invasion. This suggests the potential for effective immunotherapy in this patient group.