Cases and controls were similar in age (mean in cases, 57 years; in controls, 57 years). Cases were more likely to report a family history of prostate cancer, history of benign prostatic hyperplasia (BPH), and history of PSA tests (). The majority of prostate cancers were local stage tumors with low/moderate Gleason scores. All SNPs included in this study were statistically consistent (P > 0.05) with the Hardy-Weinberg equilibrium (HWE).
Selected characteristics of Caucasian prostate cancer cases and controls.
There was no strong evidence of altered risk of developing prostate cancer for any of the htSNPs evaluated (). Two SNPs (rs3944004, rs2268373) showed slightly lower relative risks of prostate cancer for the homozygous variant carriers versus homozygous wildtype carriers. Two SNPs (rs2239598, rs831003) showed slightly increased relative risks for the heterozygote carriers as compared to homozygous wildtype carriers. However, the P for trend for all four of these SNPs was >0.05 and after adjustment for multiple comparisons none of these associations remained significant. When we assessed risk estimates by measures of tumor aggressiveness (Gleason score, stage, and composite score) we found no differences in risk estimates for any of the polymorphisms examined.
Genotype distribution and odds ratios (95% CI) for the association between megalin htSNPs and prostate cancer risk.
Within the forty htSNPs included in this study, we defined 8 haplotype blocks (A-H, see ) ranging from 2 to 5 htSNPs. Thirteen htSNPs did not fall into any haplotype block structure. We found no evidence of altered relative risks of prostate cancer for any of the haplotypes in any of the blocks. The four SNPs that showed slightly altered risks at the individual level (rs3944004, rs2268373, rs2239595, and rs831003), displayed no evidence of altered risks for prostate cancer when a haplotype containing only these four htSNPs was considered.
There were 86 cases with physician-diagnosed recurrence/progression, with an average 8.8 years of follow-up (range 0.2–11.9 years) after diagnosis. Of these 86 cases, 67 (78%) were diagnosed at low/moderate Gleason score, 55 (64%) were diagnosed at a localized stage, and 14 (16%) were treated with primary ADT. Eight htSNPs showed altered risks of disease recurrence/progression overall (). When these SNPs were adjusted for multiple comparisons, only three SNPs (rs830994, rs830995, and 831003), all within the same haplotype block “E”, retained significance. We then considered all eight SNPs and then only the three block “E” SNPs using stepwise regression and found that only rs830994 remained significant at p = 0.001, independent of all other SNPs in the model. An additional six htSNPs, while not demonstrating altered risks for all cases combined, did show some evidence of different risks of recurrence/progression by ADT ().
Association of megalin htSNPs genotypes with prostate cancer recurrence/progression by primary androgen deprivation therapy (ADT).
There were 33 cases who died of prostate cancer in the average 10.4 years of follow-up (range 1.3–13.4 years). Of these 33 cases, 12 (36%) were diagnosed at low/moderate Gleason score (2–6 or 7 (3+4)), 6 (18%) were diagnosed at a localized stage, and 26 (79%) were treated with primary ADT. Five htSNPs were significantly associated with altered risks of death from prostate cancer, with no evidence of interaction with ADT (). None of these 5 SNPs remained significant after adjustment for multiple comparisons. Using stepwise regression, we observed independence for only two SNPs, rs2300446 at p = 0.02 and rs830094 at p = 0.03. The htSNP rs830994 was found to have genotypes that had altered risks of both recurrence/progression and mortality independent of all other SNPs under the uncorrected multiple comparison models.
Association of megalin htSNPs genotypes with prostate cancer-specific mortality by primary androgen deprivation therapy (ADT).