Epidemiologic Approaches to Understanding Advanced Prostate Cancer: Chemoprevention, Genetics and Response to Therapy.

Prostate Cancer Genetics;Public Health;Health Sciences;Epidemiological Science

Ishak, Miriam BahgatLange, Ethan M. ;

University of Michigan

关键词: Prostate Cancer Genetics;    Public Health;    Health Sciences;    Epidemiological Science;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/94049/mshak_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Prostate cancer is the most commonly diagnosed non-cutaneous cancer among men. Statins are widely used cholesterol-lowering drugs. The association between statin use and risk of recurrence after prostatectomy was investigated in men with inherited forms of prostate cancer enrolled in the University of Michigan Prostate Cancer Genetics Project (PCGP). Of 539 men surveyed, 115 (21%) participants experienced recurrence after prostatectomy and 47.9% used statins. Ever-statin use was not associated with recurrence in crude models (HR=1.04, 95% CI=0.72-1.49, p value =0.86) or in models adjusted for clinical characteristics (HR=1.06, 95% CI=0.68-1.64, p value =0.81). Men with a family history of prostate cancer represent a subgroup of men who may benefit from further study of statin medication use to slow or prevent recurrence.Genetic linkage studies have consistently identified the 17q21-22 chromosomal region as a potential prostate cancer susceptibility locus. Three genes in 17q21-22 are potential candidates based on plausible biologic function; MAP3K14, ARHGAP27 and RND2. Using next-generation sequencing techniques, all exons within the 17q21-22 were interrogated in 94 probands from hereditary prostate cancer (HPC) families.Participants were from the PCGP and Johns Hopkins University. Confirmation of mutation status among family members was performed using Sanger sequencing. Five missense variants were identified in the MAP3K14 and ARHGAP27 genes. ARHGAP27 demonstrated evidence of cosegregation within families and was associated with prostate cancer in the presence of linkage (Z Score=2.87, p value=0.004). Further research should investigate these variants in larger studies of HPC families. Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer. Using data from the SWOG-9346 randomized-controlled trial of men receiving ADT, I assessed the role of germline variation in genes involved in androgen synthesis/metabolism in response to ADT. DNA from 210 Caucasian and African-American metastatic prostate cancer patients, 1,536 single nucleotide polymorphisms (SNP) were genotyped. A total of 15 SNPs in SLCO1B1, SRD5A1, SRD5A2, CYP19A1 and ESR2 were associated with response to ADT, after correction for ancestry. Among the associated SNPs is rs2306283, a missense variant (OR = 0.50, 95% C.I.: 0.30-0.89, nominal p value =0.02) in SLCO1B1. Findings from this study may inform prediction of therapeutic outcomes.