The Clinical Outcomes Among Patients Under 60 Years Old with Lynch Syndrome: Variations Based on Different Mutation Patterns.

Abstract

Lynch syndrome (LS)-also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC)-is caused by pathogenic germline mutations in DNA mismatch repair (MMR) genes such as <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i>, and <i>PMS2</i>. Although it accounts for only 1-5% of all colorectal cancers (CRCs), LS presents with a particularly high lifetime cancer risk and often occurs at younger ages. Identifying LS in patients under 60 years old is crucial for targeted surveillance and early interventions. Variations in clinical presentation and prognosis may exist based on the specific gene mutated, yet these patterns are not fully elucidated. This review aims to synthesize data on clinical outcomes among LS patients under 60, with an emphasis on how different MMR gene mutation patterns might influence prognosis, survival, and treatment decisions. Five population-based studies examining CRC patients younger than 60 years were included according to predefined eligibility criteria. Two independent reviewers screened and extracted data focusing on MMR deficiency detection methods (microsatellite instability [MSI] and/or immunohistochemistry [IHC]), rates of confirmed germline mutations, frequency of BRAF testing, and clinical endpoints such as stage distribution, survival outcomes, and recurrence. Risk of bias was assessed using standardized tools appropriate to each study design. The synthesis focused on comparing outcomes among individuals with <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i>, and <i>PMS2</i> mutations, as well as delineating the proportion of patients with sporadic MSI under 60 years of age. Across the five studies, MSI positivity in CRC patients under 60 years ranged from 7.5% to 13%. The frequency of confirmed germline MMR mutations varied between 0.8% and 5.2% in specific cohorts, aligning with LS prevalence estimates of 1-5%. Different mutation patterns correlated with some variation in clinical presentation. Cases with <i>MSH2</i> and <i>MLH1</i> mutations more frequently exhibited synchronous or metachronous tumors, while <i>MSH6</i> and <i>PMS2</i> mutations displayed more heterogeneous IHC patterns. Where survival data were provided, LS patients under 60 years had better overall survival compared to MMR-proficient individuals, though some studies also noted a potential lack of benefit from standard 5-fluorouracil adjuvant therapy in MMR-deficient tumors. Screening by MSI or by IHC-supplemented with BRAF mutation testing to exclude sporadic MSI-facilitates early detection of LS in CRC patients under 60 and highlights notable differences between mutation types. Although overall outcomes for LS patients can be favorable, especially for stage II disease, the precise impact of each specific mutated gene on clinical course remains heterogeneous. Future large-scale prospective studies are needed to clarify optimal screening protocols and individualized treatment strategies for LS patients under 60.