Lynch Syndrome Subtypes

Colorectal cancer is a significant global health concern, accounting for a substantial number of cancer-related deaths. Lynch syndrome (LS), previously known as Hereditary nonpolyposis colorectal cancer (HNPCC), is the most common hereditary form of colorectal cancer, contributing to a significant proportion of familial cases. LS is associated with germline mutations in DNA mismatch repair (MMR) genes, resulting in a higher risk of developing colorectal cancer at an early age.

While it is generally understood that the risk of colorectal cancer is higher in individuals with Lynch syndrome, the likelihood still varies depending on the subtype that the individual is diagnosed with. This article provides an overview of the subtypes of LS based on the underlying genetic mutations, highlighting their distinct clinical features, management strategies and implications for genetic counseling.

LS cases linked to mutations in the MSH2 gene account for approximately 40-50% of all HNPCC cases. Patients with MSH2 mutations tend to have an increased risk of developing colorectal cancer, as well as extracolonic malignancies such as endometrial, ovarian, gastric, and urinary tract cancers.

MSH2-related LS is typically characterized by an earlier age of onset compared to sporadic colorectal cancer, emphasizing the importance of early surveillance and regular screening for affected individuals and their at-risk family members.

Mutations in the MLH1 gene constitute approximately 30% of LS cases. Individuals with MLH1 mutations have a higher risk of developing colorectal cancer, particularly involving the proximal colon. This subtype is also associated with an increased risk of endometrial and ovarian cancers.

LS cases associated with MSH6 gene mutations comprise approximately 10-20% of all LS cases. MSH6 mutations tend to be associated with a milder phenotype, characterized by a later age of colorectal cancer onset and a lower cumulative risk of developing CRC compared to other LS subtypes. However, the risk of extracolonic cancers, particularly endometrial and ovarian cancers, remains significant.

Mutations in the PMS2 gene account for a small proportion (2-5%) of LS cases. PMS2-related LS is associated with a relatively lower risk of colorectal cancer compared to other subtypes. However, individuals with PMS2 mutations have an increased risk of developing extracolonic malignancies, particularly endometrial and ovarian cancers.

Molecular testing and genetic counseling are vital for accurate diagnosis, appropriate surveillance, and personalized management of individuals with PMS2-related LS.

Germline mutations in the EPCAM gene, which leads to the epigenetic silencing of the neighboring MSH2 gene, are responsible for a small subset of LS cases. Individuals with EPCAM mutations show a high lifetime risk of colorectal cancer, similar to MSH2 mutation carriers.

Genetic testing strategies, including deletion analysis and methylation-specific polymerase chain reaction (PCR), are necessary to identify EPCAM-related LS cases. Prophylactic surgeries and regular surveillance are recommended to manage the increased cancer risks associated with this subtype.

Understanding the subtypes of LS is essential for accurate diagnosis, risk assessment, and appropriate management of affected individuals and their families. Identification of specific genetic mutations associated with LS subtypes helps tailor personalized surveillance programs, guide surgical interventions, and inform genetic counseling.

As described, many of the LS subtypes predisposes an individual not only to colorectal cancer, but also various other cancers including gynecologic cancers in women. The compounded risk of multiple cancers means that collaboration between healthcare providers, geneticists, and genetic counselors is crucial in providing comprehensive care to individuals with LS and their families, aiming to reduce the burden of colorectal cancer and associated malignancies.