Intratumoral Heterogeneity of Genetic Changes in Primary Colorectal Carcinomas with Metastasis

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Abstract
Purpose. To elucidate the intratumoral distribution of genetic changes, surgically resected colorectal carcinomas were investigated regarding their loss of heterozygosity in the regions of tumor suppressor genes and the mutation of ras genes. Methods. Full-thickness fresh tumor slices from 23 colorectal carcinomas were removed and divided into multiple specimens, which were then submitted separately for DNA and histopathological analyses. The loss of heterozygosity was analyzed in 23 primary carcinomas and 9 metastasized carcinomas by the use of restriction fragment-length polymorphism markers on chromosome 1p, 5q, 17p, 18q, and 22q. Results. Intratumoral heterogeneity was identified in 11 of 23 primary carcinomas (47.8%) and we could successfully map the regional genetic variation. In both stages I and II, 1 of 5 cases (20%); in stage III, 3 of 6 cases (50%); and in stage IV, 6 of 7 cases (85.7%) were heterogeneous. With respect to venous invasion positive primary carcinomas, hepatic metastasis occurred in 75% (6/8) of the heterogeneous carcinomas, whereas hepatic metastasis occurred in only 12.5% (1/8) of homogeneous carcinomas. Conclusion. The present results suggest that the existence of intratumoral heterogeneity, which may reflect genetic instability, may thus play a role in the enhancement of aggressive progression and the metastasis of colorectal carcimomas.

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