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Using a large adjuvant trial, this study showed that the two ends of the colon behave like two diseases: the right is mucinous, mismatch repair deficient and BRAF-like, the left is chromosomally unstable and dependent on EGFR signalling.
Clinicopathological data for 3,045 colon carcinoma patients enrolled in the PETACC-3 adjuvant chemotherapy trial were analysed, with molecular data for 1,404, gene expression for 589 and DNA copy number for 199, plus 413 TCGA colon adenocarcinomas and a cohort of 325 metastatic patients treated with anti-EGFR therapy. Proximal carcinomas were more often mucinous, microsatellite instability-high, mutated in key tumourigenic pathways, and 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 overexpressed epiregulin. Risk of relapse did not differ by side, but survival after relapse was much poorer for proximal stage III carcinomas in a multivariable model including BRAF status (hazard ratio 1.95). Only patients with metastases from a distal carcinoma responded to anti-EGFR therapy.
It is the molecular case for sidedness, made before the trial meta-analyses that turned it into a treatment rule, and it supplies the mechanism: ligand dependence on the left, pathway mutation on the right.
Shares Sidedness (left vs right colon), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
Shares Sidedness (left vs right colon), BRAF, RAS / RAF / MEK / ERK (MAPK), EGFR.
Shares Chromosomal instability & aneuploidy, Mismatch repair & microsatellite instability, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Colorectal cancer.
Shares Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), BRAF.
Shares Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), BRAF.
Shares Sidedness (left vs right colon), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
Shares Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Colorectal cancer.
Shares Sidedness (left vs right colon), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Colorectal cancer.