Very early somatic genetic origins of cancer: Can somatic mosaicism of androgen receptor CAG repeat length in early stages of prostate growth and development be a predictor of future cancer? B. Gottlieb^1,4,6, K. Sircar², C. Alvarado¹, A. Aprikian⁵, L.K. Beitel^1,3, M. Alam-Fahmy², L. Begin⁵, M. Trifiro^1,3,4. 1) Dept Cell Genetics, Lady Davis Institute for Medical Research,; 2) Department of Pathology, McGill University Health Center; 3) Department of Medicine; 4) Human Genetics; 5) Urology, McGill University; 6) Department of Biology, John Abbott College, Montreal, Quebec, Canada.
   In recent years the genetic origins of many cancers have been found to be somatic rather than germline. In particular this is true of prostate cancer (PCa). This has been partly due to the use of techniques such as laser capture microdissection (LCM), which has allowed for genetic analysis of specific cancer tissues. Shorter CAG repeat lengths in the androgen receptor gene (AR) have been correlated with increased AR transactivation activity and are associated with increased risk for PCa. We analyzed and sequenced AR CAG repeat lengths in human prostatic tissues from 13 PCa patients, as well as from disease-free individuals as young as I year old. Microdissected PCa lesions, high grade prostatic intraepithelial neoplasia (HGPIN), benign peripheral, transitional and central prostate zones, as well as leukocytes from peripheral blood were examined. Many prostate sections showed AR CAG repeat length heterogeneity in the form of multiple repeat lengths, i.e. somatic mosaicism. These consisted of normal and shortened CAG repeat lengths and even complete CAG repeat deletions. Blood leukocytes, representing germline DNA, predominately showed a single AR CAG repeat length per patient. CAG repeat length heterogeneity in both histologically benign tissues from diseased prostates and non-diseased prostates suggests that genetic heterogeneity of the AR CAG repeat precedes microscopically recognizable malignant changes and may occur very early in the growth and development of prostate tissue. Whether such genetic heterogeneity is a feature of all prostates must await a much more detailed survey of normal prostate tissues, but it raises some intriguing questions about the very early origins of prostate cancer susceptibility which will be further discussed.