Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features

  • Missiaglia E
  • Jacobs B
  • D'Ario G
 et al. 
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BACKGROUND: Differences exist between the proximal and distal colon in terms of developmental origin, exposure to patterning genes, environmental mutagens and gut flora. Little is known on how these differences may affect mechanisms of tumorigenesis, side specific therapy response or prognosis. We explored systematic differences in pathway activation and their clinical implications.

MATERIALS AND METHODS: Detailed clinico-pathological data for 3045 colon carcinoma patients enrolled in the PETACC3 adjuvant chemotherapy trial were available for analysis. A subset of 1404 samples had molecular data, including gene expression and DNA copy number profiles for 589 and 199 samples, respectively. In addition, 413 colon adenocarcinoma from TCGA collection were also analyzed. Tumor side effect on anti-EGFR therapy was assessed in a cohort of 325 metastatic patients. Outcome variables considered were relapse-free survival (RFS) and survival after relapse (SAR).

RESULTS: Proximal carcinomas were more often mucinous, MSI-high, mutated in key tumorigenic pathways, expressed a BRAF-like and a serrated pathway signature, regardless of histological type. Distal carcinomas were more often chromosome instable and EGFR or HER2 amplified, and more frequently over-expressed epiregulin. While risk of relapse was not different per side, survival after relapse was much poorer for proximal than for distal stage III carcinomas in a multivariable model including BRAF mutation status (N=285; HR=1.95 95% CI(1.6-2.4) P
CONCLUSIONS: Colorectal carcinoma side is associated with differences in key molecular features, some immediately druggable, with important prognostic effects which are maintained in metastatic lesions. Although within side significant molecular heterogeneity remains, our findings justify stratification of patients by side for retrospective and prospective analysis of drug efficacy and prognosis.

Author-supplied keywords

  • colon cancer
  • expression profiling
  • mutations
  • oncogenic pathways
  • survival

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