Exploring PDB Structure 2O8B

Lynch syndrome, previously known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common inherited form of colorectal cancer (CRC), affecting more than one million people in the United States^[1]MD Anderson Cancer Center. It results from harmful germline mutations in one of the four DNA mismatch repair (MMR) genes—MLH1, MSH2 (or EPCAM deletions affecting MSH2), MSH6, or PMS2. Among these, mutations in MLH1 and MSH2 account for over half of all confirmed cases^[2]citation needed. Individuals with Lynch syndrome have substantially elevated cancer risks: depending on the specific MMR gene involved, the lifetime risk of CRC can approach 60 - 80% for men, and 40 - 60% for women, and risks for additional cancers, including endometrial, ovarian, urinary tract, and several gastrointestinal cancers are also significantly increased^[3]MD Anderson Cancer Center.

Lynch syndrome “mutation-positive” refers to individuals who carry a pathogenic germline MMR gene alteration confirmed through clinical genetic testing. We also classify a related group as having “mutation-negative” Lynch syndrome, or Lynch-like syndrome. These individuals meet clinical criteria for Lynch syndrome, present with non-sporadic MSI-high tumors (demonstrating microsatellite instability but without MLH1 promoter hypermethylation or a BRAF mutation), yet have either negative, inconclusive, or likely benign results on genetic testing or they may have declined genetic testing altogether.

Although they lack an identifiable pathogenic variant, individuals with Lynch-like syndrome require close clinical monitoring due to their elevated cancer risk. As a result, they typically undergo intensified surveillance, which often includes annual or semiannual colonoscopy as well as additional screening based on personal and family history.

Our cells contain a built-in “proofreading” mechanism that corrects mistakes made during DNA replication. This is called the Mismatch Repair (MMR) system. In this case, the MMR genes include: MLH1, MSH2, MSH6, PMS2, EPCAM (deletions in EPCAM affect MSH2 expression). These proteins work together in pairs to scan DNA, identify mismatched bases, and fix them. In this project, we focused on SMH 2 and SMH 6.

In this case, cancer develops through a “second hit” of MMR mismatch, as the working copy of the MMR gene in a particular cell becomes inactivated (due to somatic mutation). As a result, that cell loses mismatch repair ability. This causes DNA errors to accumulate rapidly, especially in short repetitive regions called microsatellites. The majority of Lynch syndrome (LS)-related cancers are characterized by mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H). Microsatellite Instability (MSI-H) is a hallmark of Lynch syndrome cancers indicating Indicate defective mismatch repair (dMMR). The dMMR/MSI-H molecular phenotype is characterized by an exceptionally high tumor mutation burden, driven by numerous small insertion-deletion frameshift mutations (1-4 bp) and single-nucleotide missense mutations, which collectively lead to the formation of novel tumor-associated proteins.

Currently, there are two pharmacological agents that have been shown to reduce the risk of colorectal cancer in Lynch syndrome patients: Aspirin and Naproxen. NSAIDs like Aleve (Naproxen) and Aspirin help reduce inflammation and may lower the risk of colorectal cancer (CRC), especially in Lynch syndrome. Their effect is tied to how they block cyclooxygenase (COX) enzymes, especially COX-2.

COX enzymes (COX-1 and COX-2) make prostaglandins (PGs), which are molecules involved in inflammation and cell growth.

1. COX-1 is always active and handles normal body functions (“housekeeping” prostaglandins).
2. COX-2 is normally turned off, but becomes highly active during inflammation and cancer. COX-2 is over-expressed in ~85% of colorectal cancers and ~50% of adenomas.

One of the prostaglandins produced, PGE2, promotes:

• Inflammation
• Tumor growth
• Blood vessel formation
• Suppression of the immune system
• Prevention of cell death

Early diagnosis paired with routine screening dramatically reduces mortality. Localized tumors often carry a five-year survival rate above 90% when detected before metastasis.

Genetic counseling helps families understand inherited risk, document variants, and enroll in surveillance programs. Informed monitoring remains the key to improving long-term outcomes.