{"entity":{"id":"paper-missiaglia-distal-proximal-colon-cancers-ann-oncol-2014","kind":"paper","name":"Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-24","links":[{"label":"Missiaglia et al., Ann Oncol 2014: distal and proximal colon cancers differ molecularly and clinically (PETACC-3, 3,045 patients)","url":"https://doi.org/10.1093/annonc/mdu275"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25057166/"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":[],"targets":["egfr","her2","braf","mmr"],"drugs":[],"companies":[],"institutions":[],"pathways":["ras-mapk","chromosomal-instability","mismatch-repair-msi"],"terms":["sidedness","msi"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2014,"doi":"10.1093/annonc/mdu275","pmid":"25057166","authors":"Missiaglia E, Jacobs B, D'Ario G, et al.","paperType":"observational","findings":["Proximal tumours: mucinous, MSI-high, BRAF-like and serrated signature.","Distal tumours: chromosome instable, EGFR or HER2 amplified, epiregulin overexpressing.","Survival after relapse worse for proximal stage III disease (hazard ratio 1.95); only distal metastases responded to anti-EGFR therapy."],"whatItMeans":"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.","caveats":["Retrospective analyses of a trial population.","Molecular data available for fewer than half the patients.","The anti-EGFR cohort was small (325 patients) and not randomised by side."],"changedPractice":false,"participants":3045},"route":"/key-papers/paper-missiaglia-distal-proximal-colon-cancers-ann-oncol-2014/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","route":"/targets/mmr/"}],"pathway":[{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"},{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"sidedness","kind":"term","name":"Sidedness (left vs right colon)","route":"/terms/sidedness/"}],"journal":[{"id":"annals-of-oncology","kind":"journal","name":"Annals of Oncology","route":"/journals/annals-of-oncology/"}]}}