{"entity":{"id":"paper-vogelstein-genetic-alterations-colorectal-development-nejm-1988","kind":"paper","name":"Genetic alterations during colorectal-tumor development","aka":[],"tldr":"By counting four genetic changes in 172 bowel growths at every stage from small polyp to cancer, this study showed that the changes pile up in step with the disease, and gave cancer research its first map of how one cancer forms.","summary":"Four genetic alterations, ras-gene mutations and allelic deletions of chromosomes 5, 17 and 18, were sought in 172 colorectal tumour specimens: 40 mostly early adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas from 33 patients without polyposis and 92 carcinomas from 89 patients. Ras mutations occurred in 58% of adenomas larger than 1 cm and 47% of carcinomas, but in only 9% of adenomas under 1 cm. Chromosome 5 sequences linked to the polyposis gene were not lost in the polyposis adenomas but were lost in 29% of other adenomas and 35% of carcinomas. A specific region of chromosome 18 was deleted in 73% of carcinomas and 47% of advanced adenomas but only 11 to 13% of earlier adenomas, and chromosome 17p sequences were usually lost only in carcinomas, at 75%. The four alterations accumulated in a fashion that paralleled clinical progression.","asOf":"2026-09-24","links":[{"label":"Vogelstein et al., N Engl J Med 1988: genetic alterations during colorectal tumour development (172 specimens)","url":"https://doi.org/10.1056/NEJM198809013190901"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/2841597/"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":[],"targets":["kras","tp53","apc","smad4"],"drugs":[],"companies":[],"institutions":["johns-hopkins"],"pathways":["colorectal-cancer-signalling","chromosomal-instability"],"terms":["driver-mutation"],"trials":[],"people":["bert-vogelstein","eric-fearon"],"bottlenecks":[],"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":"translational","findings":["Ras mutations in 58% of adenomas over 1 cm against 9% of adenomas under 1 cm.","18q deletion in 73% of carcinomas, 47% of advanced adenomas, 11 to 13% of early adenomas.","17p loss almost confined to carcinomas, 75%."],"whatItMeans":"It is the origin of the multistep model of carcinogenesis. Every later colorectal genomic paper, and much of the logic of screening (removing the adenoma removes the cancer), rests on the ordering it established.","caveats":["Four alterations only, at 1980s resolution; APC itself had not yet been cloned.","Cross-sectional, so the order is inferred from prevalence across stages rather than followed in one lesion.","The ordering has since been shown to be looser than the picture suggests, and normal crypts already carry drivers (Lee-Six 2019)."],"changedPractice":false,"participants":172},"route":"/key-papers/paper-vogelstein-genetic-alterations-colorectal-development-nejm-1988/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"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":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"},{"id":"colorectal-cancer-signalling","kind":"pathway","name":"Colorectal cancer (KEGG map)","route":"/pathways/colorectal-cancer-signalling/"}],"term":[{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"}],"person":[{"id":"bert-vogelstein","kind":"person","name":"Bert Vogelstein","route":"/people/bert-vogelstein/"},{"id":"eric-fearon","kind":"person","name":"Eric R. Fearon","route":"/people/eric-fearon/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}]}}