S4024 A Rare Presentation of Adenocarcinoma of Rectum With NRAS Mutation

Introduction: Colorectal cancer (CRC) with rhabdoid differentiation is rare and associated with poor prognosis. Synchronous involvement of both rectum and ileum by the same tumor is highly unusual. We present a case of metastatic CRC in a young patient harboring a rare NRAS Q61R mutation and germ line POT1 mutation, complicating management. Case Description/Methods: A 42-year-old man presented with LLQ pain and hematochezia. Imaging and colonoscopy revealed a recto sigmoid mass and omental nodularity; biopsy confirmed poorly differentiated adenocarcinoma with rhabdoid features, involving both rectum and ileum. Positron emission tomography scan showed metastatic disease. Next Generation sequencing (NGS) identified an NRAS Q61R mutation (rare), MSI-stable, and no other actionable mutations. He had a diverting colostomy due to severe constipation and began chemotherapy, showing initial improvement. Disease later progressed; further testing revealed no new targets. A POT1 mutation was also found. He received palliative radiation for pain control. Discussion: NRAS mutations are present in only 2%-5% of CRCs, with the Q61R variant accounting for less than 1%. These mutations activate the MAPK pathway and are associated with resistance to EGFR-targeted therapies, eliminating a major treatment avenue. Their presence often signals a more aggressive tumor biology, as seen in our patient, who demonstrated early and widespread metastasis despite initial response to multi-agent chemotherapy. Rhabdoid differentiation adds to the poor prognostic profile, correlating with dedifferentiation and rapid disease progression. The coexistence of rectal and ileal tumors from a single origin but with differing morphology suggests early dissemination and intratumoral heterogeneity. The discovery of a germ line POT1 mutation, which confers susceptibility to various cancers, further underscores the importance of genetic evaluation in atypical cases. This case emphasizes the need for early genomic profiling to guide personalized treatment in aggressive and rare CRC subtypes.