Somatic alterations of the androgen receptor CAG repeat in human colon cancer delineate a novel mutation pathway independent of microsatellite instability

The human androgen receptor gene contains a polymorphic CAG repeat region r anging from 8 to about 35 repeats in the normal human population. The repea t length is inversely related to the transactivation potential of the recep tor. We have analyzed the repeat length in 50 sporadic colon cancer samples in comparison to surrounding healthy mucosa and have found somatic reducti ons of up to 10 repeats in 5 cases (10%), 3 of which were complex, probably involving both alleles. Alterations occurred in tumors with and without mi crosatellite instability indicating that they follow an independent mutatio n pathway. The similar repeat of the huntingtin gene did not show any somat ic alterations in the same cases. No correlation to sex, tumor stage, locat ion, or histology was evident. In the tumors that showed somatic reductions , the reduced allele was present in at least half of the cells and thus in most, if not all, of the tumor component of the sample. Somatic reductions of the androgen receptor CAG repeat thus occur frequently, through a pathwa y distinct from microsatellite instability and early during colon carcinoge nesis. The receptor is expressed in most normal and neoplastic tissue sampl es analyzed. Apparent growth selection of cells bearing shortened AR allele s suggests that androgens contribute to colon carcinogenesis in a yet unkno wn way. (C) 2000 Elsevier Science Inc. All rights reserved.