MUTATIONS IN THE ANDROGEN RECEPTOR GENE ARE ASSOCIATED WITH PROGRESSION OF HUMAN PROSTATE-CANCER TO ANDROGEN INDEPENDENCE

Progression to androgen-independent growth of human prostate cancers m ay be mediated by alterations in the structure and/or expression of th e androgen receptor (AR) gene, To date, mutations in the AR gene have largely been identified in hormone refractory tumors, In this study, s ingle-strand conformational polymorphism analysis and DNA sequencing o f the entire AR gene coding region was performed on 25 primary prostat e tumors sampled prior to initiation of hormonal (i.e., androgen ablat ion) therapy. Base changes leading to amino acid substitutions in the AR were identified in 11 (44%) tumors, The presence of AR amino acid s ubstitutions was associated with decreased immunohistochemical stainin g for AR in tumor cells and the rapid failure of subsequent hormonal t herapies, Single-strand conformational polymorphism analysis of exons 2, 3, and 8 of the X-linked hypoxanthine guanine phosphoribosyl transf erase (HPRT) gene in the same samples revealed no bandshifts, suggesti ng that the high frequency of AR gene mutations detected was not a con sequence of generalized genetic instability. These data indicate that AR gene mutations occur commonly in advanced prostate cancers prior to endocrine treatment of disease and may contribute to altered androgen responsiveness of the tumors.