Context-dependent effects of genome-wide association study genotypes and macroenvironment on time to biochemical (prostate specific antigen) failure after prostatectomy.
BACKGROUND
Disparities in cancer defined by race, age, or gender are well established. However, demographic metrics are surrogates for the complex contributions of genotypes, exposures, health care, socioeconomic and sociocultural environment, and many other factors. Macroenvironmental factors represent novel surrogates for exposures, lifestyle, and other factors that are difficult to measure but might influence cancer outcomes.


METHODS
We applied a "multilevel molecular epidemiology" approach using a prospective cohort of 444 White prostate cancer cases who underwent prostatectomy and were followed until biochemical failure (BF) or censoring without BF. We applied Cox regression models to test for joint effects of 86 genome-wide association study-identified genotypes and macroenvironment contextual effects after geocoding all cases to their residential census tracts. All analyses were adjusted for age at diagnosis and tumor aggressiveness.


RESULTS
Residents living in census tracts with a high proportion of older single heads of household, high rates of vacant housing, or high unemployment had shorter time until BF postsurgery after adjustment for patient age and tumor aggressiveness. After correction for multiple testing, genotypes alone did not predict time to BF, but interactions predicting time to BF were observed for MSMB (rs10993994) and percentage of older single heads of households (P = 0.0004), and for HNF1B/TCF2 (rs4430796) and census tract per capita income (P = 0.0002).


CONCLUSIONS
The context-specific macroenvironmental effects of genotype might improve the ability to identify groups that might experience poor prostate cancer outcomes.


CONCLUSIONS
Risk estimation and clinical translation of genotype information might require an understanding of both individual- and macroenvironment-level context.
Rebbeck
Timothy R
TR
Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, 217 Blockley Hall, 423 Guardian Drive, Philadelphia, Pennsylvania 19104-6021, USA. rebbeck@mail.med.upenn.edu
Weber
Anita L
AL
Walker
Amy H
AH
Stefflova
Klara
K
Tran
Teo V
TV
Spangler
Elaine
E
Chang
Bao-Li
BL
Zeigler-Johnson
Charnita M
CM
D000368:Aged; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D017720:Molecular Epidemiology; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000453:epidemiology* / Q000235:genetics* / Q000601:surgery; D012307:Risk Factors; D017211:Treatment Failure; D014481:United States / Q000453:epidemiology
D017430:Prostate-Specific Antigen
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