Interaction of PTEN deletion and c-MYC gain in prostate cancer progression

Prostate cancer is of significant public health importance since it is the most common non-cutaneous cancer and the second leading cause of cancer death among men in the United States. While the majority of prostate cancer patients will not die of the disease and some may not even need treatment, about 15% of prostate cancer patients may progress to metastatic disease. Therefore, while it is important to diagnose men with prostate cancer, it is probably more important to distinguish which patients will likely progress so they can be aggressively treated and hopefully to improve the survival. Genetic components are important risk factors to be associated with not only prostate carcinogenesis but also prostate cancer progression. PTEN deletion and MYC gain have been individually well-delineated in prostate carcinogenesis/progression. Our preliminary studies showed an association between somatic DNA deletion at PTEN and gain at MYC with prostate cancer-specific death in genome-wide association study (GWAS), independent of grade, stage and pre-operative PSA levels. The goal of this project is to test the hypothesis that somatic PTEN deletion interacts with MYC gain to promote prostate cancer progression, especially prostate cancer-specific death.;We first developed a multi-color fluorescence in situ hybridization (multi-color FISH) technology to simultaneously assess PTEN deletion and MYC gain in prostate cancer formalin-fixed, paraffin-embedded (FFPE) tissues. 20 prostate cancer samples with known DNA copy number status of PTEN and MYC from previous SNP array analysis were evaluated by multi-color FISH. The concordance was excellent between multi-color FISH and SNP array with a concordance rate of 90 % (κ=0.80) for PTEN deletion and 95% (κ=0.90) for MYC gain. In addition, multi-FISH could simultaneously detect PTEN deletion and MYC gain in single cells and showed heterogeneity in prostate cancer. Further validation of multi-color FISH for detecting PTEN deletion and MYC gain in FFPE tissues may allow it to be a reliable prognostic tool for prostate cancer patients in clinical settings.;We continued to generate transgenic mouse models with various combinations of prostate specific Pten deletion and Myc overexpression to study whether and how the two genetic variations accelerate prostate cancer progression. We found that double transgenic mice with Pten heterozygous or homozygous deletion combined with Myc overexpression (Pten+/-; MycT and Pten-/-; MycT) developed more aggressive prostate cancer as compared with mice harboring only Pten deletion or Myc overexpression. Increased tumor growth resulted from significantly increased cell proliferation but not decreased apoptosis. No metastasis was found in lymph nodes, lung, liver, femurs and tibias from 6-month old mice. However, Pten deletion and Myc overexpression cooperatively contributed to decreased survival. Pten +/-;MycT mice had worse survival compared with MycT mice (P=0.0346) or Pten +/- mice (P=0.0797), while Pten -/-;MycT mice had the shortest survival (P<0.05) among all groups. These results suggest that PTEN deletion and MYC overexpression have a joint effect on promoting prostate cancer progression and biological outcome.;In addition to study the cooperation of PTEN deletion and MYC gain in prostate cancer progression, we investigated the role of germ-line genetic changes of PTEN in susceptibility to prostate cancer. Both common (with a minor allele frequency ≥ 5%) and rare (with a minor allele frequency < 5%) germ-line variants of PTEN were comprehensively evaluated. Fifteen germ-line variants were identified by re-sequencing the PTEN gene, including 5' UTR, all 9 exons, exon-intron junctions, and 3' UTR, in 188 probands of hereditary prostate cancer (HPC) families recruited from Johns Hopkins Hospital. Two microsatellite markers surrounding PTEN were used to test the co-segregation of 10 rare variants, which may give rise to highly penetrant in HPC. Two common SNPs were evaluated in the 188 HPC families using a family-based association study approach. To study low penetrant SNPs in prostate cancer susceptibility, 33 SNPs covering PTEN were selected from the GWAS from our available case-control studies in Sweden [Cancer of the Prostate in Sweden (CAPS)] and the publicly available Cancer Genetic Markers of Susceptibility (CGEMS) study. Germ-line copy number variations in PTEN were assessed in CAPS. Co-segregation of germ-line variants and prostate cancer was not observed among HPC families and no significant differences in the allele frequencies were observed in sporadic cases and controls, aggressive and non-aggressive prostate cancer (P>0.05). These results suggest that germ-line variants in PTEN do not play an important role in prostate cancer susceptibility.