Abstract 5758: Deletions of olfactomedin 4 gene is associated with progression of prostate cancer

Abstract

Abstract The human olfactomedin 4 gene (OLFM4) encodes an olfactomedin-related glycoprotein, which our group first cloned and characterized in myeloid cells and mapped to chromosome 13q14.3. In a subsequent study, we have found that OLFM4 was expressed in normal prostate tissue, but its expression was lost in 10.9% (6/55) of well-differentiated prostate caner (Gleason score 4-6), 22.2% (8/36) of intermediately differentiated prostate cancer (Gleason score 7) and 58.8% (40/68) of advanced prostate cancer tissues (Gleason score 8-10). The loss of expression of OLFM4 was significantly associated with a higher Gleason score for prostate cancer (p<0.001). To study the mechanisms of loss of expression of OLMF4 gene in prostate cancer, we investigated alterations in the genetics and epigenetics of the OLFM4 gene in human prostate cancer patients. We looked for deletions and mutations of the OLFM4 gene and the status of methylation of the OLFM4 promoter region in benign and malignant prostate cell lines and in the paired normal and cancerous prostate epithelial cells that were obtained from whole mount prostate tissues by laser capture microdissection (LCM). The results showed that deletions and mutations of the OLFM4 gene is the primary cause of loss of expression of OLFM4 gene in human prostate cancer. We found that 28% (4/14) of primary prostate cancer cells had loss of heterozygosity (LOH) at rs 2298231 of the OLFM4 gene and 14% (2/14) of primary prostate cancer cells revealed deletion in exon 5 of the OLFM4 gene. We also found deletions in the promoter region in tumor cell lines, LNCaP and DU145, as well as exon 5 deletions in DU145 cells. There were no significant differences in the methylation status compared to adjacent normal (n=8), Prostatic Intraepithelial Neoplasia (PIN, n=3), low grade prostate cancer cells (Gleason score 4-7) and high grade prostate cancer cells (Gleason score 8-10, n=7) from the LCM samples studied. To further explore the function of the OLMF4 gene in prostate cancer, we have developed and studied the pathological changes in an OLFM4 knockout mouse model. Histopathological analysis of prostate tissue from OLMF4 wild type mice revealed the following: 5 out of 5 mice were normal at ages of 10 to 12 months, and 1 out of 5 showed prostate dysplastic changes at 18-20 month of age. The prostate from OLFM4 homozygous knock-out (KO) mice revealed that 7 out of 9 mice developed prostatic epithelial hyperplasia, and lower grade prostatic intraepithelial neoplasia (low-grade PIN) in mice at age of 10 to 12 months. By the age of 18 to 20 months, we found that 12 out of 18 KO mice developed high grade prostate intraepithelial neoplasia (high-grade PIN) in which 4 out of 18 developed into prostate cancer and 1 out of 18 showed evidence of lung metastasis. Our results suggest that OLFM4 gene is a candidate for the putative prostate cancer likely tumor suppressor gene located on chromosome 13q and is involved in the progression of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5758.