PMS2-associated Lynch syndrome: Past, present and future

Area of Science:

• Genetics and Genomics
• Oncology
• Molecular Biology

Background:

• Mismatch repair (MMR) gene variants traditionally confer similar cancer risks, primarily colorectal cancer (CRC) and endometrial cancer.
• Emerging evidence indicates that the specific MMR gene affected influences cancer risk, spectrum, and Lynch syndrome CRC pathogenesis.
• Significant knowledge gaps persist, particularly regarding pathogenic variants in PMS2 (path_PMS2).

Purpose of the Study:

• To review current knowledge on MMR gene variants and associated cancer risks.
• To highlight clinical challenges and knowledge gaps, especially for path_PMS2 carriers.
• To discuss implications for future research and clinical management.

Main Methods:

• Literature review of current research on MMR gene variants and Lynch syndrome.
• Analysis of recent findings on PMS2-deficient colorectal cancers (CRCs).
• Discussion of molecular pathogenesis and clinical implications.

Main Results:

• Cancer risk and spectrum vary significantly based on the affected MMR gene.
• PMS2-deficient CRCs exhibit more aggressive behavior and poorer prognosis compared to other MMR-deficient CRCs.
• PMS2-deficient CRCs show lower intratumoral immune infiltration, suggesting biological similarities to sporadic MMR-proficient CRCs.

Conclusions:

• Understanding MMR gene-specific differences is crucial for personalized cancer risk assessment and management.
• PMS2 deficiency presents unique biological and clinical characteristics requiring further investigation.
• Findings have potential implications for surveillance, chemoprevention, and therapeutic strategies, including vaccine development.