# Lynch Syndrome as a Spectrum of Four Distinct Genetic Disorders: Toward Genotype-Guided Precision Management in the NGS Era

## TL;DR

Lynch syndrome is redefined as four distinct genetic disorders requiring tailored management based on the specific mismatch repair gene involved.

## Contribution

The paper proposes a genotype-guided framework for precision management of Lynch syndrome based on the specific MMR gene affected.

## Key findings

- MLH1 and MSH2 mutations require intensive monitoring from age 25 due to aggressive cancer progression.
- MSH6 and PMS2 mutations allow for less frequent surveillance starting at age 35–40 due to slower progression.
- Immune checkpoint inhibitors are effective across all four MMR genotypes in dMMR/MSI-H tumors.

## Abstract

Lynch syndrome (LS) is the most common inherited cancer predisposition. Traditionally managed as a single disease, emerging evidence revealed that LS comprises four distinct conditions based on which mismatch repair (MMR) gene is affected. MLH1 and MSH2 mutations cause aggressive, rapidly progressing cancers requiring intensive monitoring from age 25, while MSH6 and PMS2 mutations lead to slower progression with later onset, allowing for less frequent surveillance starting at age 35–40. This review synthesizes current evidence to propose a genotype-guided framework where each subtype receives tailored management strategies for screening, surgery, immunotherapy, and prevention. Understanding LS as four separate conditions enables personalized care, avoiding unnecessary interventions in lower-risk patients while ensuring adequate protection for high-risk carriers, thereby improving outcomes for patients and families.

Background/Objectives: Lynch syndrome (LS), is traditionally managed uniformly despite being caused by pathogenic variants in four distinct mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). This approach fails to leverage gene-specific characteristics for precision healthcare delivery. This review redefines LS as four distinct genetic syndromes and establishes a genotype-guided precision management framework to optimize risk stratification, surveillance, and therapeutic interventions. Methods: We synthesized molecular, clinical, and outcomes data from the Prospective Lynch Syndrome Database (8500+ carriers; 70,000 person-years), genomic studies characterizing gene-specific mutational patterns, and immunotherapy trials while referencing international guidelines [National Comprehensive Cancer Network (NCCN), European Hereditary Tumour Group (EHTG)/European Society of Coloproctology (ESCP), and European Society for Medical Oncology (ESMO)] to formulate genotype-stratified recommendations. Results: Fundamental molecular differences necessitate differentiated management strategies. MLH1 deficiency exhibits unique “two-in-one hit” mechanisms driving aggressive tumorigenesis with high interval cancer rates. MSH2 deficiency presents the highest tumor mutational burden (≈47 mutations per megabase; Mut/Mb) and broadest cancer spectrum. MSH6 deficiency displays distinctive high-single-nucleotide variant (SNV)/low-insertion–deletion (Indel) patterns often presenting as microsatellite instability-low (MSI-low) or microsatellite stable (MSS), complicating conventional detection. PMS2 deficiency demonstrates substantial attenuation due to redundancy. These translate into precision interventions: MLH1/MSH2 carriers require colonoscopy from age 25 at 1–2-year intervals with extended colectomy preferred, while MSH6/PMS2 carriers can defer surveillance to age 35–40 with longer intervals and undergo segmental resection. Immune checkpoint inhibitors (ICIs) are effective in deficient MMR (dMMR)/microsatellite instability-high (MSI-H) tumors across all four MMR genotypes. Conclusions: Genotype-specific precision management optimizes the benefit–burden balance, enhances early cancer detection, reduces overtreatment, and enables personalized genetic counseling, advancing precision healthcare for LS families and addressing critical gaps in hereditary cancer care.