Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset.

Abstract

The androgen receptor (AR) is a structurally conserved member of the nuclear receptor superfamily. The amino-terminal domain is required for transcriptional activation and contains a region of polyglutamine encoded by CAG trinucleotide repeats. In humans, the number of CAG repeats is polymorphic; the average number is 22 in Caucasian males. Expansion of CAG repeats in the AR has clinical implications for human disease. As androgen influences prostate cancer growth, polymorphisms in CAG repeat length may affect the clinical course of patients with prostate cancer. To test for an association between clinical parameters of human prostate cancer and CAG repeat length, we analyzed normal lymphocyte DNA from 109 patients. The CAG region of the AR was amplified by the PCR. Reaction products were then amplified using end-labeled internal primers, cut at the internal PstI site and assayed on sequencing gels using a sequence ladder as a size standard. Sequence analysis of several samples validated this method for measurement of CAG repeat number. The median age of patients was 63 yr (range, 42-83), with 104 Caucasian, 2 African American, 1 Asian, and 2 other racial origin. The median repeat length was 25 for patients with stage A, 22 for patients with stage B, 22 for patients with stage C, and 23 for patients presenting with stage D disease. A significant correlation between CAG repeat length and age at onset was observed, whereas correlations with stage, level of prostate-specific antigen at diagnosis, and time to prostate-specific antigen relapse were not significant. Shorter CAG repeat lengths may be associated with the development of prostate cancer in men at a younger age. These data suggest that CAG repeat length can affect the risk of developing prostate cancer.

The CAG repeat within the androgen receptor gene and its relationship to prostate cancer

“…A study of 109 men referred to a medical oncology practice at Memorial Sloan-Kettering Cancer Center found that shorter repeat lengths were significantly correlated with younger age of diagnosis of prostate cancer (26). Most known germ-line mutations that confer higher risk of cancer (e.g., BRCA1 in breast cancer, mismatch repair genes in colon cancer) are characterized by early age of disease onset, high population attributable risk at young ages, but a relatively low population attributable risk due to the sharply increasing incidence of ''sporadic'' cancers that occurs with advancing age.…”

Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells

“…Amplifications of the AR gene in hormone refractory CaP represent yet another scenario where gain of AR functions may be associated with tumor progression (Visakorpi et al, 1995). Germ-line alterations of CAG repeat length in AR may influence the risk of CaP (Hakimi et al, 1996;Hardy et al, 1996;Stanford et al, 1997). Growth factors commonly involved in cell proliferation and tumorigenesis, e.g., IGF I, EGF and KGF have been shown to activate the transcription transactivation functions of the AR (Culig et al, 1994).…”

Mechanistic Relationship between Androgen Receptor Polyglutamine Tract Truncation and Androgen-dependent Transcriptional Hyperactivity in Prostate Cancer Cells

“…Short poly(Q) repeats (Յ19) have been clinically correlated with a higher risk of prostate cancer, an earlier age of onset, and a higher grade and more advanced stage of prostate cancer at the time of diagnosis (37)(38)(39)(40)(41)(42)(43)(44). Several studies have demonstrated an inverse correlation between the length of the poly(Q) region and AR transcriptional activity (45)(46)(47)(48).…”