BACKGROUND: With recent advances in genetics research, genetic analysis is increasingly being used in clinical practice. We report a case in which genetic analysis aided in diagnosing a local recurrence of sigmoid colon cancer, initially suspected to be a primary neoplasm of the small intestine. CASE PRESENTATION: A 61-year-old male underwent laparoscopic sigmoidectomy for stage IIIB sigmoid colon cancer, followed by 8 cycles of CAPOX adjuvant chemotherapy, one and a half years prior. A follow-up CT scan performed one and a half years postoperatively revealed a mass in the small intestine near the ileal end, adjacent to the staple line of the previous colonic anastomosis. PET imaging showed high uptake in the small intestine but no significant uptake at the site of the prior anastomotic ring. Based on these findings, a primary small intestine neoplasm was suspected, rather than a local recurrence of the sigmoid cancer, prompting laparoscopic surgery. Intraoperative findings revealed an inflamed mass in the ileum, approximately 30 cm proximal to the cecum, involving staples from the previous anastomotic site. Consequently, an ileocecal resection combined with resection of the prior colonic anastomosis was performed. Macroscopically, the resected specimen revealed a 25-mm Type 2 tumor in the ileum extending into the previous anastomotic site of the large intestine, while the colonic mucosa remained intact. Histopathological examination identified a moderately differentiated tubular adenocarcinoma, consistent with the histology of the primary sigmoid cancer, raising the possibility of local recurrence. To analyze the origin of the ileal tumor, we performed whole-genome sequencing and subsequent PCR direct sequencing. As a result, identical mutations in two key driver genes (KRAS c.35G >
A and PIK3CA c.1624G >
A), as well as a mutation in a passenger gene (BBS9 c.2218_2222del), were identified in the primary and ileal tumors. These findings confirmed that the ileal tumor was a local recurrence rather than a new primary malignancy. CONCLUSIONS: The present case highlights the practical application of genetic analysis in clinical practice, particularly when clinical diagnosis and histopathological findings are inconclusive or conflicting.