S3940 Metastatic Colon Cancer With DNMT3A Mutation

Introduction: DNMT3A mutations disrupt DNA methylation in colon cancer, driving tumorigenesis via epigenetic dysregulation. These alterations are linked to aggressive disease and poor prognosis, highlighting potential for targeted therapies. Case Description/Methods: A 52-year-old woman with a history of systemic lupus erythematosus (SLE) and end-stage renal disease (status post living donor transplant on immunosuppression) presented with significant weight loss and lethargy. Laboratory workup revealed iron deficiency anemia, for which endoscopy and colonoscopy were performed, revealing masses in the stomach, duodenum, and ascending colon. Pathology confirmed a poorly differentiated adenocarcinoma, and genetic profiling identified a DNMT3A Q886 variant. She was subsequently hospitalized due to confusion and hemoptysis. Brain magnetic resonance imaging showed a 5 mm enhancing lesion in the frontal lobe with minimal surrounding edema. Further imaging revealed bilateral pulmonary nodules, celiac lymphadenopathy, and extensive muscular involvement. During her hospital stay, she developed septic and hemorrhagic shock, requiring ICU admission, vasopressors, and broad-spectrum antibiotics. She received 3 cycles of CAPEOX chemotherapy, followed by palliative radiotherapy targeting muscular metastases. Brain metastasis was managed with steroids and stereotactic radiosurgery. Discussion: This case highlights an exceptionally rare presentation of DNMT3A-mutated colorectal cancer (CRC) with metastases to the brain, duodenum, stomach, and thoracic muscle. DNMT3A mutations, typically seen in hematologic malignancies, are uncommon in CRC and associated with aggressive disease and poor prognosis. Brain metastases occur in <3% of CRC cases, while duodenal involvement is even rarer. The patient’s rapid decline and unusual metastatic pattern suggest a potential link between DNMT3A and atypical dissemination. Given her critical illness, treatment was palliative. This case highlights the need for vigilant screening in high-risk patients and comprehensive genomic profiling to uncover rare variants that may influence disease behavior. Further research is warranted to explore DNMT3A’s role in CRC metastasis.