{"entity":{"id":"paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988","kind":"paper","name":"Genetic alterations during colorectal-tumor development","aka":[],"tldr":"The 1988 study of 172 bowel tumours that showed cancer is not one mutation but a sequence of them, accumulating as a polyp grows into a cancer. It is the origin of the idea that cancer develops step by step.","summary":"Vogelstein, Fearon, Hamilton, Kern, Preisinger, Leppert, Nakamura, White, Smits and Bos looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17 and 18) in 172 colorectal-tumour specimens representing different stages of neoplastic development: 40 predominantly early-stage adenomas from seven patients with familial adenomatous polyposis, 40 adenomas from 33 patients without polyposis (19 without and 21 with associated foci of carcinoma), and 92 carcinomas resected from 89 patients.\n\nThe four alterations accumulated in a way that paralleled the clinical progression of the tumours, and the authors concluded that the steps to cancer often involve mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumourigenesis. Fearon and Vogelstein set the model out in full two years later in Cell (the corpus holds that record as paper-fearon-cell).","asOf":"2026-09-24","links":[{"label":"N Engl J Med 1988","url":"https://doi.org/10.1056/NEJM198809013190901"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/2841597/"},{"label":"Fearon and Vogelstein: a genetic model for colorectal tumorigenesis (Cell 1990)","url":"https://doi.org/10.1016/0092-8674(90)90186-I"}],"tags":["colorectal-evidence"],"related":["paper-fearon-cell","paper-vogelstein-cancer-genome-landscapes-science-2013","paper-tcga-colon-rectal-molecular-characterization-nature-2012"],"cancers":["colorectal","colon-cancer"],"sections":["early-detection","prevention"],"technologies":["colorectal-screening"],"targets":["kras","tp53","apc","smad4"],"drugs":[],"companies":[],"institutions":["johns-hopkins"],"pathways":["wnt","ras-mapk"],"terms":[],"trials":[],"people":["bert-vogelstein","kenneth-kinzler"],"bottlenecks":["b-early-detection","b-prevention-adoption"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":1988,"doi":"10.1056/NEJM198809013190901","pmid":"2841597","authors":"Vogelstein B, Fearon ER, Hamilton SR, et al.","paperType":"basic","findings":["ras-gene mutations in 58 percent of adenomas larger than 1 cm and 47 percent of carcinomas, but only 9 percent of adenomas under 1 cm.","Chromosome 5 sequences linked to the familial adenomatous polyposis gene were not lost in adenomas from polyposis patients but were lost in 29 to 35 percent of adenomas and carcinomas from others.","A specific region of chromosome 18 was deleted in 73 percent of carcinomas, 47 percent of advanced adenomas and only 11 to 13 percent of earlier-stage adenomas.","Chromosome 17p sequences were usually lost only in carcinomas (75 percent).","The four alterations accumulated in a fashion that paralleled clinical progression."],"whatItMeans":"Every screening programme rests on this paper: if cancer arrives through a polyp that takes years to progress, then finding and removing polyps prevents cancer rather than merely catching it early.","caveats":["Four markers in tumours collected in the 1980s; the full driver set (APC, KRAS, SMAD4, TP53, PIK3CA and the rest) came from the sequencing studies two decades later.","The sequence is typical, not obligatory: the serrated and mismatch repair-deficient routes to colorectal cancer do not follow it."],"changedPractice":true,"participants":172},"route":"/key-papers/paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988/","neighbours":{"paper":[{"id":"paper-fearon-cell","kind":"paper","name":"A genetic model for colorectal tumorigenesis","route":"/key-papers/paper-fearon-cell/"},{"id":"paper-vogelstein-cancer-genome-landscapes-science-2013","kind":"paper","name":"Cancer genome landscapes: about 140 driver genes, and each tumour needs only a handful","route":"/key-papers/paper-vogelstein-cancer-genome-landscapes-science-2013/"},{"id":"paper-zauber-national-polyp-study-colonoscopic-polypectomy-nejm-2012","kind":"paper","name":"Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths (National Polyp Study)","route":"/key-papers/paper-zauber-national-polyp-study-colonoscopic-polypectomy-nejm-2012/"},{"id":"paper-tcga-colon-rectal-molecular-characterization-nature-2012","kind":"paper","name":"Comprehensive molecular characterization of human colon and rectal cancer","route":"/key-papers/paper-tcga-colon-rectal-molecular-characterization-nature-2012/"}],"cancer":[{"id":"colon-cancer","kind":"cancer","name":"Colon cancer (adenocarcinoma of the colon)","route":"/cancers/colon-cancer/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"section":[{"id":"early-detection","kind":"section","name":"Early Detection & Screening","route":"/fronts/early-detection/"},{"id":"prevention","kind":"section","name":"Prevention & Risk","route":"/fronts/prevention/"}],"technology":[{"id":"colorectal-screening","kind":"technology","name":"Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)","route":"/technologies/colorectal-screening/"}],"target":[{"id":"apc","kind":"target","name":"APC","route":"/targets/apc/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"smad4","kind":"target","name":"SMAD4","route":"/targets/smad4/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"institution":[{"id":"johns-hopkins","kind":"institution","name":"Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center","route":"/institutions/johns-hopkins/"}],"pathway":[{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"person":[{"id":"bert-vogelstein","kind":"person","name":"Bert Vogelstein","route":"/people/bert-vogelstein/"},{"id":"kenneth-kinzler","kind":"person","name":"Kenneth W. Kinzler","route":"/people/kenneth-kinzler/"}],"bottleneck":[{"id":"b-prevention-adoption","kind":"bottleneck","name":"Prevention we already have is not deployed","route":"/bottlenecks/b-prevention-adoption/"},{"id":"b-early-detection","kind":"bottleneck","name":"The hardest cancers are found late","route":"/bottlenecks/b-early-detection/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"roadmap":[{"id":"colorectal-roadmap","kind":"roadmap","name":"Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation","route":"/roadmaps/colorectal-roadmap/"}]}}