Risk of second primary tumors in men diagnosed with prostate cancer: A population‐based cohort study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108272/1/cncr28769.pd

Rare germline mutations in African American men diagnosed with earlyâ onset prostate cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142420/1/pros23464_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142420/2/pros23464.pd

Genetic polymorphisms in CYP17 , CYP3A4 , CYP19A1 , SRD5A2 , IGF-1 , and IGFBP-3 and prostate cancer risk in African-American men: The Flint Men's Health Study

BACKGROUND Association studies have examined the significance of several candidate genes based on biological pathways relevant to prostate carcinogenesis, including both the androgen and insulin-like growth factor pathways. Clinical and epidemiologic evidence suggest that androgens, specifically testosterone and dihydrotestosterone (DHT) are important not only in normal prostate growth but in the pathogenesis of prostate cancer. Similarly, the insulin-like growth factor-1 (IGF-1) signaling pathway regulates both cellular proliferation and apoptosis. Therefore, genes involved in the biosynthesis, activation, metabolism and degradation of androgens and the stimulation of mitogenic and antiapoptotic activities of prostate epithelial cells represent important candidates for affecting the development and progression of prostate cancer. METHODS Using resources from the Flint Men's Health Study, a population-based case control study of African-American men aged 40–79, we evaluated the associations between selected single-nucleotide polymorphisms (SNPs) in the CYP17 , CYP3A4 , CYP19A1 , SDR5A2 , IGF1 , and IGFBP3 genes and prostate cancer diagnosis in 473 men (131 prostate cancer cases and 342 disease-free controls). RESULTS We found a significant association between prostate cancer and selected CYP17 SNP genotypes, with the heterozygous genotype conferring decreased risk. Suggestive evidence for association between IGF1 SNPs and prostate cancer were also found. No significant associations were observed between SNPs in the other genes and prostate cancer. CONCLUSIONS These findings suggest that variation in or around CYP17 and/or IGF1 may be associated with prostate cancer development in the African-American population. Additional studies are needed to determine whether these polymorphisms are indeed associated with prostate cancer risk in African Americans. Prostate 68: 296–305, 2008. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57913/1/20696_ftp.pd

Identification of a novel germline SPOP mutation in a family with hereditary prostate cancer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106871/1/pros22818.pd

Comprehensive serial molecular profiling of an “N of 1” exceptional non-responder with metastatic prostate cancer progressing to small cell carcinoma on treatment

Abstract Importance Small cell carcinoma/neuroendocrine prostate cancer (NePC) is a lethal, poorly understood prostate cancer (PCa) subtype. Controversy exists about the origin of NePC in this setting. Objective To molecularly profile archived biopsy specimens from a case of early-onset PCa that rapidly progressed to NePC to identify drivers of the aggressive course and mechanisms of NePC origin and progression. Design, setting, and participants A 47-year-old patient presented with metastatic prostatic adenocarcinoma (Gleason score 9). After a 6-month response to androgen deprivation therapy, the patient developed jaundice and liver biopsy revealed exclusively NePC. Targeted next generation sequencing (NGS) from formalin-fixed paraffin-embedded (FFPE)-isolated DNA was performed from the diagnostic prostate biopsy and the liver biopsy at progression. Intervention Androgen deprivation therapy for adenocarcinoma followed by multiagent chemotherapy for NePC. Main outcomes and measures Identification of the mutational landscape in primary adenocarcinoma and NePC liver metastasis. Whether the NePC arose independently or was derived from the primary adenocarcinoma was considered based on mutational profiles. Results A deleterious somatic SMAD4 L535fs variant was present in both prostate and liver specimens; however, a TP53 R282W mutation was exclusively enriched in the liver specimen. Copy number analysis identified concordant, low-level alterations in both specimens, with focal MYCL amplification and homozygous PTEN, RB1, and MAP2K4 losses identified exclusively in the NePC specimen. Integration with published genomic profiles identified MYCL as a recurrently amplified in NePC. Conclusions and relevance NGS of routine biopsy samples from an exceptional non-responder identified SMAD4 as a driver of the aggressive course and supports derivation of NePC from primary adenocarcinoma (transdifferentiation).http://deepblue.lib.umich.edu/bitstream/2027.42/113670/1/13045_2015_Article_204.pd

Germline genetic variants in men with prostate cancer and one or more additional cancers

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138930/1/cncr30817.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138930/2/cncr30817_am.pd

Mutational landscape of candidate genes in familial prostate cancer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108266/1/pros22849-sm-0001-SupTab-S1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/108266/2/pros22849.pd

Evidence for an association between prostate cancer and chromosome 8q24 and 10q11 genetic variants in African American men: The flint men's health study

Prostate cancer is the most commonly diagnosed non-skin cancer in men in the United States and the second leading cause of cancer-related mortality. African American men have substantially increased risk of both being diagnosed and dying from the disease. Recent genome-wide genetic association studies have identified a number of common single nucleotide genetic polymorphisms (SNPs) that are associated with prostate cancer in men of European descent. Only a small number of studies have evaluated the association between these genetic variants and prostate cancer in African Americans

R726L androgen receptor mutation is uncommon in prostate cancer families in the united states

Background A mutation in the androgen receptor ( AR ) gene, namely AR R726L, was described in 2% of Finnish men with sporadic or familial prostate cancer and was associated with an approximately sixfold increased risk of prostate cancer. We set out to determine the incidence of this mutation in a sample of men with either early-onset and/or familial prostate cancer in the United States. Methods Five hundred forty-eight men with prostate cancer from 411 unrelated families participating in the University of Michigan Prostate Cancer Genetics Project (PCGP) were studied. Allele-specific oligonucleotide hybridization was used to detect the presence of the AR R726L mutation in germline DNA. Results None of the 548 prostate cancer patients studied, including 513 White, 29 African American, 3 Asian, and 3 Hispanic men, were found to carry the AR R726L allele. Therefore, the prevalence of this allele is significantly less than that observed among Finnish men with prostate cancer (Fisher's exact test, P  = 0.002). Conclusions The AR R726L allele does not account for a significant proportion of early-onset and/or familial prostate cancer in the United States. Prostate 54: 306–309, 2003. © 2003 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34764/1/10195_ftp.pd

Genetic variation in Glutathione S-Transferase Omega-1, Arsenic Methyltransferase and Methylene-tetrahydrofolate Reductase, arsenic exposure and bladder cancer: a case–control study

Abstract Background Ingestion of groundwater with high concentrations of inorganic arsenic has been linked to adverse health outcomes, including bladder cancer, however studies have not consistently observed any elevation in risk at lower concentrations. Genetic variability in the metabolism and clearance of arsenic is an important consideration in any investigation of its potential health risks. Therefore, we examined the association between genes thought to play a role in the metabolism of arsenic and bladder cancer. Methods Single nucleotide polymorphisms (SNPs) in GSTO-1, As3MT and MTHFR were genotyped using DNA from 219 bladder cancer cases and 273 controls participating in a case–control study in Southeastern Michigan and exposed to low to moderate (\u3c50 μg/L) levels of arsenic in their drinking water. A time-weighted measure of arsenic exposure was constructed using measures from household water samples combined with past residential history, geocoded and merged with archived arsenic data predicted from multiple resources. Results While no single SNP in As3MT was significantly associated with bladder cancer overall, several SNPs were associated with bladder cancer among those exposed to higher arsenic levels. Individuals with one or more copies of the C allele in rs11191439 (the Met287Thr polymorphism) had an elevated risk of bladder cancer (OR = 1.17; 95% CI = 1.04-1.32 per 1 μg/L increase in average exposure). However, no association was observed between average arsenic exposure and bladder cancer among TT homozygotes in the same SNP. Bladder cancer cases were also 60% less likely to be homozygotes for the A allele in rs1476413 in MTHFR compared to controls (OR = 0.40; 95% CI = 0.18-0.88). Conclusions Variation in As3MT and MTHFR is associated with bladder cancer among those exposed to relatively low concentrations of inorganic arsenic. Further investigation is warranted to confirm these findings