Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis

Chromosomal instability is believed to be a common feature of most human tu mors, but the stage at which such instability originates has not been defin ed. At the molecular level, chromosomal instability is characterized by all elic imbalance (AI), representing losses or gains of defined chromosomal re gions. We have assessed AI in early colorectal tumors using newly developed methods for assessing AI in complex cell populations. A total of 32 adenom as of average size (2 mm; range, 1-3 mm) were studied. AI of chromosome 5q markers occurred in 55% of tumors analyzed, consistent with a gatekeeping r ole of the adenomatous polyposis coli tumor suppressor gene located at chro mosomal position 5q21. AI was also detected in each of the other four chrom osomes tested. The fractions of adenomas with AI of chromosomes 1p, 8p, 15q , and 18q were 10, 19, 28, and 28%, respectively, Over 90% of the tumors ex hibited AI of at least one chromosome, and 67% had allelic imbalance of a c hromosome other than 5q. These findings demonstrate that AI is a common eve nt, even in very small tumors, and suggest that chromosomal instability occ urs very early during colorectal neoplasia.