142 SOMATIC AND GENOMIC INSTABILITY OF ANDROGEN RECEPTOR IN AFRICAN AMERICANS WITH PROSTATE CANCER

Abstract

INTRODUCTION AND OBJECTIVES: Androgen receptor (AR)-dependent signaling is an important element in prostate carcinogenesis and its progression to metastatic disease. AR has also been suggested as a prostate cancer (PCa) susceptibility gene. Alterations in the AR gene can have profound effects on AR expression, the activity of its target genes, and its responsiveness to androgens, non-androgenic steroids, and anti-androgens during the natural history of PCa. Limited information is available on the genetic alterations in the AR in African American men. We investigated somatic and genomic changes in the AR in association with sporadic and familial PCa in African Americans. METHODS: We studied the genomic DNAs of 60 PCa-affected patients from African Americans and Caucasians with a history of familial PCa, 150 normal unrelated individuals, and radical prostatectomy specimens of 91 patients with organ-confined primary PCa (57 African Americans and 34 Caucasians), exon-specific PCR, bi-directional automated sequencing, and restriction enzyme genotyping to identify mutations in the coding region, 5 -UTR, and 3 -UTR of the AR gene. RESULTS: We discovered a novel germline AR-A1675T (T559S) substitution mutation in the DNA-binding domain in four PCaaffected members of a nuclear African American family with a history of early-onset disease, referring to the X-linked transmission pattern. In our data, no linkage disequilibrium existed between the AR-1675(A/T) alleles and the AR-CAG ( 22 vs 22) /GGC ( 16 vs 16) repeat length polymorphisms in African Americans. However, a linkage may exist (p 0.06) between the AR-A1675T mutation and the CAG repeat length ( 22 vs 22). This novel germline mutation was not detected in any of the 150 unrelated normal individuals or 91 patients with primary PCa. In our analyses of radical prosatatectomy samples, we also identified 7 somatic mutations and 1 germline mutation in African American patients, but no mutations in the Caucasian patients. Furthermore, our analyses of genomic DNA extracted from the white blood cells of 88 African Americans and 74 Caucasian Americans with PCa showed a high incidence rate of genomic alterations in the AR in the form of mutations and single nucleotide polymorphisms in African Americans (10.2%) as compared with Caucasians (2.7%). CONCLUSIONS: Our data indicate the potential for a “hypermutator phenotype” of the AR gene that either alone or in combination with other genes might serve risk factors that could contribute to ethnic differences in PCa incidence and outcome in the high-risk, African American population.