Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer

BACKGROUND Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC. METHODS Targeted next‐generation sequencing of 40 genes included in the 5 critical pathways of CRC (WNT, P53, RTK‐RAS, phosphatidylinositol‐4,5‐bisphosphate 3‐kinase [PI3K], and transforming growth factor β [TGF‐β]) was performed for 516 patients with stage III or high‐risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. The associations between critical pathway mutations and relapse‐free survival (RFS) and overall survival were analyzed. The associations were further analyzed according to the tumor location. RESULTS The mutation rates for the WNT, P53, RTK‐RAS, PI3K, and TGF‐β pathways were 84.5%, 69.0%, 60.7%, 30.0%, and 28.9%, respectively. A mutation in the PI3K pathway was associated with longer RFS (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36‐0.99), whereas a mutation in the RTK‐RAS pathway was associated with shorter RFS (adjusted HR, 1.60; 95% CI, 1.01‐2.52). Proximal tumors showed a higher mutation rate than distal tumors, and the mutation profile was different according to the tumor location. The mutation rates of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit α (PIK3CA), and B‐Raf proto‐oncogene serine/threonine kinase (BRAF) were higher in proximal tumors, and the mutation rates of adenomatous polyposis coli (APC), tumor protein 53 (TP53), and neuroblastoma RAS viral oncogene homolog (NRAS) were higher in distal tumors. The better RFS with the PI3K pathway mutation was significant only for proximal tumors, and the worse RFS with the RTK‐RAS pathway mutation was significant only for distal tumors. CONCLUSIONS A PI3K pathway mutation was associated with better RFS for CRC patients treated with adjuvant chemotherapy, and an RTK‐RAS pathway mutation was associated with worse RFS. The significance of the prognostic impact differed according to the tumor location. Cancer 2017;123:3513‐23. © 2017 American Cancer Society. Targeted next‐generation sequencing of 40 genes has demonstrated that identifying a pathway mutation can predict a patient's prognosis. In addition, the prognostic role of these pathway mutations differs with the tumor location.