MALIGNANT AND NONMALIGNANT BRAIN-TISSUES DIFFER IN THEIR MESSENGER-RNA EXPRESSION PATTERNS FOR ERCC1 AND ERCC2

Perturbation of the DNA repair process appears to be responsible for t he occurrence of a number of human diseases, which are usually associa ted with a propensity to develop internal malignancies and/or disorder s of the central nervous system. We have been interested in the possib ility that a subtle abnormality in DNA repair competency might be asso ciated with the transformation of nonmalignant cells to the malignant state. To study this question, we assayed malignant and nonmalignant b rain tissues from 19 individuals for mRNA expression levels of the hum an DNA repair genes ERCC1, ERCC2, and XPAC and for differential splici ng of the ERCC1 transcript. We separately compared expression levels o f these genes in the following situations: concordance of expression w ithin malignant tissues; concordance of expression within nonmalignant tissues; concordance between malignant and nonmalignant tissues withi n individuals of the cohort; and concordance of gene expression betwee n two nonmalignant tissue sites within a single individual. Linear reg ression analyses of mRNA values obtained suggested orderly concordance of these three DNA repair genes in nonmalignant tissues within the pa tient cohort and an excellent concordance of these genes between two s eparate biopsy sites from the same individual. In contrast, malignant tissues showed disruption of concordance between the full-length ERCC1 transcript and ERCC2, which have excision and helicase functions, res pectively. Furthermore, within the same individuals, malignant tissues were discordant with nonmalignant tissues for ERCC1 and ERCC2, althou gh concordance for XPAC was preserved. These data suggest that one mol ecular characteristic of human malignancy may be the disruption of the normal relationship between the excision and the helicase functions o f the nucleotide excision repair pathway.