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Abstract Title Double Trouble: Lynch syndrome and KRAS Mutation in a Young Male With Stage IV Colon Adenocarcinoma
Background Lynch syndrome is a hereditary cancer syndrome caused by germline mutations in mismatch repair (MMR) genes, resulting in microsatellite instability (MSI) and a significantly increased lifetime risk of early-onset colorectal cancer (50%–70%). KRAS mutations, frequently observed in sporadic colorectal cancers, are less commonly associated with Lynch syndrome. Their presence can influence both prognosis and response to targeted therapies, especially anti-epidermal growth factor receptor (EGFR) agents.
Case Presentation A 35-year-old man with a history of lumbar radiculopathy and diverticulosis presented in August 2020 with diffuse abdominal pain and altered bowel habits. An abdominal CT scan revealed hepatic metastases, and colonoscopy identified a circumferential, partially obstructing mass in the distal descending colon. Biopsy confirmed a moderately differentiated adenocarcinoma, consistent with colorectal cancer (CRC) with distant metastasis (stage IV). In October 2020, immunohistochemistry demonstrated loss of MLH1, MSH6, and PMS2 expression, consistent with deficient mismatch repair (dMMR) and suggestive of Lynch syndrome. Molecular profiling revealed a concurrent KRAS mutation. The patient was initiated on FOLFOX chemotherapy (5-fluorouracil, leucovorin, and oxaliplatin), administered biweekly, and completed five cycles by November 2020. His current status is unknown, as he was lost to follow-up.
Discussion The co-occurrence of dMMR, consistent with Lynch syndrome, and a KRAS mutation presents diagnostic and therapeutic complexity in metastatic CRC. While dMMR or MSI-high (MSI-H) status predicts robust responses to immune checkpoint inhibitors, concurrent KRAS mutations can negate the benefit of anti-EGFR therapies and may influence overall prognosis. In this case, early genomic profiling identified both Lynch syndrome and a somatic KRAS mutation. This guided the decision to initiate FOLFOX chemotherapy, in line with American Society of Clinical Oncology (ASCO) recommendations. However, recent evidence, including the KEYNOTE-177 trial (February 2016-2018) , supports the use of pembrolizumab as first-line therapy in MSI-H/dMMR metastatic CRC, demonstrating superior progression-free survival compared with standard chemotherapy (median, 16.5 vs 8.2 months). Importantly, the presence of a KRAS mutation does not preclude benefit from immune checkpoint inhibitors. Studies demonstrate durable responses in dMMR/MSI-H tumors regardless of KRAS status. Given that KRAS mutations are found in 15% to 35% of Lynch-associated metastatic CRC cases, early and comprehensive molecular testing is essential to guide treatment, assess prognosis, and inform familial risk. This case underscores the evolving role of precision oncology in tailoring individualized treatment by integrating germline and somatic genomic data.
