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Association of HPC2/ELAC2 Polymorphisms with Risk of Prostate Cancer in a Population-based Study¹

Divisions of Public Health Sciences [J. L. S., E. A. N., L. I., J. S., Z. F.] and Clinical Research and Human Biology [L. P. S., E. A. O.], Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, and Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, Washington 98195 [J. L. S.]

Genetic polymorphism in HPC2/ELAC2 was recently associated with risk of sporadic prostate cancer. To determine the contribution of two HPC2/ELAC2 missense variants (Ser²¹⁷Leu and Ala⁵⁴¹Thr) to the risk of developing prostate cancer, we conducted a population-based case-control study of middle-aged men (40–64 years). Cases (n = 591) were ascertained from the Seattle-Puget Sound Surveillance, Epidemiology, and End Results Cancer Registry and Controls (n = 538) from the same general population were identified through random-digit dialing. Subjects were residents of King County, Washington, and were frequency matched on age. Cases (32%) had a slightly higher frequency of the Leu²¹⁷ variant compared with controls (29%), but there were no differences in the frequency of the Thr⁵⁴¹ allele (4%). When considering joint genotypes, white men homozygous for the Leu²¹⁷ variant on an Ala⁵⁴¹/Ala⁵⁴¹ background had an increased risk of prostate cancer [odds ratio (OR) = 1.84; 95% confidence interval (CI), 1.11–3.06]. Different risk profiles were also observed when cases were stratified by disease aggressiveness. Men with at least one Leu²¹⁷ allele had an elevated risk (OR = 1.34; 95% CI, 1.02–1.76) of less aggressive prostate cancer (localized stage and Gleason score 7), with a stronger association among men with two Leu²¹⁷ alleles (OR = 1.73; 95% CI, 1.08–2.77). The Ala⁵⁴¹Thr polymorphism was not associated with risk, and neither variant was associated with more aggressive prostate cancer phenotypes. We estimate that the Ser²¹⁷Leu genotype may account for 14% of less aggressive prostate cancer cases and 9% of all sporadic cases in the general United States population of white men <age 65 years.

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