Intriguing Insights From 100 Consecutive Colorectal Cancer Cases in Mid-Kerala: Sparse BRAF Gene Mutations and Mismatch Repair Deficiency (MMR-D)

Colorectal cancer (CRC) is among the most prevalent types of cancer globally. It is well established that the development of CRC primarily results from the sequential activation of oncogenes and the simultaneous inactivation of tumor suppressor genes. It has also been noted that after the initial oncogenic mutation, many subpopulations with different mutational profiles are created, causing heterogeneity among the tumors. This retrospective study analyzed 100 patients diagnosed with CRC through colectomy over an eighteen-month period at a tertiary referral center in mid-Kerala, India. Pathology records and histological slides were reviewed by two pathologists, and clinicopathological data were collected from pathology reports. Immunohistochemical analysis for BRAF mutation and possible microsatellite instability (MSI) (by mismatch repair (MMR) protein study) was conducted on tumor tissue blocks sent to an external center due to the lack of an automated platform at the hospital. The study utilized Roche's Benchmark XT platform for BRAF analysis and assessed MMR protein expression using antibodies for MLH1, MSH2, MSH6, and PMS2. The mean age of patients was 58.36 years, with a male predominance (58.0%). Most tumors were classified as T3 (71.0%, n-71) and T2/T4a (14.0% each, n-14), while nodal involvement included N0 (35.0%, n-35), N1 (26.0%, n-26), N2 (19.0%, n-19), and NX (20.0%, n-20). Histological examination revealed predominantly well-differentiated tumors (78.0%, n-78), with lymphatic invasion noted in 41.0% (n-41) and vascular invasion in 5.0% (n-5) of cases. Left-sided tumors predominated (33.0%, n-33), followed by rectal carcinoma (37.0%, n-37), and right-sided colon cancers (30.0%, n-30). Genetic profiling showed sparse BRAF mutations (1.0%, n-1) and MSI (1.0%, n-1), with some cases exhibiting loss of MMR proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry (IHC). The study highlights the rarity of BRAF mutations in this cohort and emphasizes the diverse pathological and molecular characteristics observed. The discussion focuses on the implications of these findings, suggesting that CRC in this population exhibits unique clinicopathological features potentially influenced by factors beyond genetic mutations. Further multicentric studies are warranted to comprehensively explore these factors and refine risk stratification and treatment strategies for CRC patients in similar demographics.