Prostate Cancer Studies The overarching goal of our work is to find genes and variants associated with prostate cancer (PCa) risk, particularly in men with aggressive disease. We participated in several collaborations to complete whole genome analysis studies (GWAS) to find new loci and develop new methods. We also participated in studies of expression and methylation to find new risk variants. We initiated and completed studies of BRCA2 mutations in PCa tumors and found previously undiscovered mutation profiles in the evolving tumor. Finally, we began new studies aimed at exome sequencing of families, followed by analysis for putative mutations in population-based, case--controls studies. Epigenome Studies In collaboration with Dr. Janet Stanford from the Fred Hutchinson Cancer Research Center (FHCRC) we have contributed to an understanding of the role of tumor DNA methylation as a predictor of metastatic lethal disease in men with clinically localized PCa. Our work demonstrated the existence of, and validated, eight differentially methylated CpGs that distinguish men with metastatic lethal from non-recurrent tumors (Zhao et al., 2016). In another collaborative study, led by Drs. Milan Geybels and Janet Stanford, studies of epigenomic profiling of prostate tumors identified differentially methylated genes in TMPRSS2:ERG fusion protein positive versus fusion-negative tumors (Geybels et al., 2015a). By extension, studies of DNA methylation profiling in paired PCa versus adjacent benign tissue highlighted many differentially methylated CpGs, suggesting that these findings could contribute to an epigenetic-based diagnostic test (Geybels et al., 2015b). Other Population-Based Collaborations In a recent study of cell cycle-regulated genes and prostate cancer prognosis, again in a population based cohort, our collaboration demonstrated that gene expression studies in tumor tissues obtained at radical prostatectomy are an important consideration in PCa risk. The overall mean and individual transcript levels of 30-selected cell cycle genes were compared between patients with no evidence of recurrence (73%) and those who recurred (27%) or died (7%) from PCa. While the data showed that the mean expression level for the 30 selected cell cycle genes was unrelated to recurrence, it was associated with a twofold increase the risk of lethal cancer (Rubicz et al., 2015). We also participated in a study of PCa risk variants and disease aggressiveness in the context of the NCI-SPORE Genetic Working Group, which includes 18,343 cases. This study retrospectively collected clinicopathologic and genotype data for 36 SNPs, the results of which were validated in a study of 25,674 cases. Statistical analyses indicated that only one PCa-risk SNP was significantly and inversely associated with aggressive and high-grade disease in both European and African American men.The SNP was adjacent to the KLK3 gene on chromosome 19q13, suggesting that this excellent candidate gene may be associated with aggressive and high-grade PCa (Helfand et al., 2015). Finally, we collaborated with Steven Chanock and the African Ancestry Prostate Cancer GWAS Consortium to contribute data to a multistage, GWAS for aggressive disease, showing that RASA1 and NAALADL2 may contribute specifically to aggressive disease risk (Berndt et al., 2015). High-Risk Family Studies We have initiated studies aimed at confirming the existence of variants putatively associated with PCa in men from hereditary prostate cancer (HPC) families. Led by Ostrander Staff Scientist Dr. Danielle Karyadi, we studied 957 patients from 270 families of European ancestry using a panel of 22 previously PCa-specific mortality (PCSM) associated SNPs. Variant allele carriers for three SNPs had a significantly altered risk for PCSM including those at RNASEL, XRCC1 and AKT1. All are outstanding candidate genes and undergoing follow-up (Karyadi et al., 2015). African American Studies Our studies also addressed issues in African American PCa patients. Our collaboration used tumor tissue from 76 African American diagnosed with PCa who had radical prostatectomy as their primary treatment and profiled their DNA methylation levels on an epigenome-wide basis. Twenty-three CpGs were differentially methylated at a statistically significant in patients with vs. without recurrence. Methylation differences were also observed between men with metastatic-lethal prostate cancer vs. no recurrence, regional vs. local pathological stage, and higher vs. lower tumor aggressiveness (Rubicz et al., 2016). We have also participated in studies aimed at methods development, particularly as it pertains to the role of cryptic relatedness among participants GWAS (Chen et al., 2015). Prostate Tumor Sequencing Study Ostrander lab M.D./Ph.D. student Brennan Decker led one of our most extensive studies. We sought to identify clinically relevant molecular subtypes of PCa. We characterized the somatic landscape of aggressive tumors using deep whole genome sequence. Our initial discovery set included ten tumor/normal pairs with Gleason scores of 8-10 at diagnosis. We analyzed for all types of variants including single nucleotide variants (SNVs), indels, and structural variants (SVs) in both the germline and tumor DNA. We found that PCa BRCA2-deficient tumors exhibited a complex and highly specific mutation signature featuring a 2.88-fold increased somatic mutation rate, depletion of context-specific C>T substitutions, and an enrichment for deletions, especially those longer than 10 bp. We next did a BRCA2 deficiency targeted reanalysis of 150 metastatic PCa tumors, of which 18 were BRCA2 carriers, showing that the same mutations signature was observed. Interestingly, among BRCA2 carriers half carried one germline mutation and one somatic mutation. The rest carried two somatic mutations. We propose that future tests be designed to leverage BRCA2 status as a biomarker and that equal consideration be given to both germline and somatic mutations (Decker et al., 2016). Consortia We remain active in several PCa Consortia. The International Consortium of Prostate Cancer Genetics (ICPCG) has continued to produce papers heralding advances or approaches for examining risk susceptibility (Larson et al., 2016;Teerlink et al., 2016). In addition we also collaborate with the PRACTICAL consortium. This year the group undertook a follow-up study to the many GWAS studies that have identified putative loci. A total of 25 loci were genotyped in 40,414 individuals and a polygenic risk score (PRS) was calculated. Empirical odds ratios for PCa were associated with different risk strata. PCa risk for men in the top risk strata, as defined by PRS was 31% while it was only 3.7% for men in the bottom percent. Surprisingly, the PRS score did not correlate well with PSA level. This large study has particular applicability for screening programs (Amin Al Olama et al., 2015). Finally we have several additional studies nearing completion. For instance, led by Ostrander lab staff scientist Dr. Karyadi we recently completed a study focused on identification of PCa disease variants that are low frequency and moderately penetrant. Recognizing that PCa susceptibility really defines a continuum from rare, highly penetrant to common low penetrant alleles, we took aim at the middle of the continuum to find variants that are likely important in both HPC families and men from the general population who do not identify themselves as high risk. We performed rigorous disease model-based variant filtering of whole exome sequence data from 75 heredity PCa families. The identified variants were then tested in two case control studies for evidence of association, resulting in replication of three variants in both studies that can be taken forward for functional studies.
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