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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.
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.
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.
Shares Eric R. Fearon, APC, Chromosomal instability & aneuploidy, Bert Vogelstein.
Shares APC, Bert Vogelstein, SMAD4, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Bert Vogelstein, SMAD4, Driver mutation, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Chromosomal instability & aneuploidy, Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center, Colorectal cancer.
Shares Bert Vogelstein, SMAD4, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center, TP53.
Shares SMAD4, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center, TP53, KRAS.
Shares APC, Chromosomal instability & aneuploidy, SMAD4, Colorectal cancer (KEGG map).