Two percent of Finnish prostate cancer patients have a germ-line mutation in the hormone-binding domain of the androgen receptor gene

Mutations of the androgen receptor (AR) gene have been reported in prostate cancer, usually from tumor tissue specimens from late-stage, androgen-inde pendent cancer. Occasionally, germ-line mutations have been found, but a li nk between AR mutations and predisposition to human prostate cancer has not been firmly established. Recently, two independent studies reported the sa me germ-line mutation at codon 726 in exon E (CGC to CTC) in two apparently unrelated Finnish prostate cancer patients. This arginine to leucine subst itution was reported to alter the transactivational specificity of the AR p rotein. In the present study, the R726L mutation was analyzed by allele-spe cific oligohybridization in DNA specimens from 418 consecutive prostate can cer patients who reported a negative family history (sporadic group) and fr om 106 patients with a positive family history (hereditary group), The popu lation frequency of the R726L mutation in blood donors was 3 of 900 (0.33%) , In contrast, eight (1.91%) mutations (odds ratio = 5.8; P = 0.006) were f ound in the sporadic group, and two (1.89%) mutations were found in the her editary group (odds ratio = 5.8; P = 0.09), Suggestive evidence of the segr egation of the mutation with prostate cancer was seen in these two families . The present study indicates that the R726L substitution in the AR may con fer an up to 6-fold increased risk of prostate cancer and may contribute to cancer development in up to 2% of Finnish prostate cancer patients. These results warrant additional large-scale studies of the significance of rare mutations and polymorphisms in candidate genes along the androgen signaling pathway as risk factors for prostate cancer.