Lynch or not Lynch? Is that always a question?

Area of Science:

• Oncology
• Genetics
• Cancer Research

Background:

• Lynch syndrome (LS), previously known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common inherited predisposition for colorectal cancer (CRC).
• LS is also associated with an increased risk of endometrial and gastric cancers, though its exact prevalence and diagnostic criteria remain debated.
• Tumors arising from LS are challenging to identify clinically and molecularly, contributing to a wide estimated prevalence range of 2%–7% of all CRCs.

Purpose of the Study:

• To review the defining characteristics of LS tumors.
• To differentiate LS tumors from non-LS inherited tumors and non-inherited microsatellite instability (MSI) tumors.
• To clarify the relationship between LS, HNPCC, and the MSI phenotype.

Main Methods:

• Review of existing literature and clinical data on Lynch syndrome and colorectal cancer.
• Analysis of molecular characteristics, specifically DNA mismatch repair (MMR) gene defects and microsatellite instability (MSI).
• Comparison of clinical and molecular features of LS-associated tumors versus other cancer types.

Main Results:

• LS is characterized by germline defects in DNA mismatch repair (MMR) genes, leading to microsatellite instability (MSI) in tumors.
• While LS tumors exhibit the MSI phenotype, not all MSI tumors are associated with LS, and some HNPCC cases occur in non-LS patients.
• LS tumors represent a distinct category at the intersection of inherited predispositions and MSI-positive cancers.

Conclusions:

• LS patients inherit a predisposition to develop specific cancers, linked to MMR gene defects.
• The MSI phenotype is a hallmark of LS tumors but can also occur in sporadic cancers.
• Distinguishing LS tumors based on specific characteristics is essential for accurate diagnosis and management.