Prostate Cancer, Hereditary, 15

For a general discussion of hereditary prostate cancer, see 176807.

Eeles et al. (2008) conducted a genomewide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at or before the age of 60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (less than 0.5 ng/ml). They analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. They identified 3 single-nucleotide polymorphisms (SNPs) on chromosome 19 that were significantly associated with prostate cancer. Of these, the most significantly associated (p = 1.5 x 10(-18)) was rs2735839. This SNP is located between KLK2 (147960), encoding prostatic kallikrein, and KLK3 (176820), encoding prostate-specific antigen (PSA), a serine protease that liquifies semen and is used as a serum marker in screening and disease progression.

Following up on the paper by Eeles et al. (2008), Ahn et al. (2008) evaluated the association of 24 tag SNPs in the KLK region, including SNPs in KLK3 and nearby genes KLK1 (147910), KLK2, and KLK15 (610601), with prostate cancer risk in 1,172 prostate cancer cases and 1,157 controls in men of European ancestry from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, in which serum PSA was used in screening for this disease. Ahn et al. (2008) also examined the prostate cancer risk relationship for 12 of these tag SNPs in the KLK3 region in 4 independent studies from diverse populations including 4,020 prostate cancer cases and 4,028 controls, as a component of Cancer Genetic Markers of Susceptibility (CGEMS) GWAS. Ahn et al. (2008) found that none of the 24 tag SNPs in the KLK region showed strong evidence for association with prostate cancer in the PLCO study, and none of the SNPs in the KLK3 region were significant in the CGEMS combined analyses. However, 2 of the tag SNPs (rs1058205 and rs2735839), located in the 3-prime untranslated region of KLK3 and in high linkage disequilibrium (LD), along with 4 other variants upstream of the gene and several downstream in high LD, were strongly associated with serum PSA concentrations. Only rs2735839 remained significantly associated with PSA concentration when all these SNPs were simultaneously included in the multivariate model. When Ahn et al. (2008) preferentially limited the men in the control group in the PLCO Trial GWAS to those with PSA less than 0.5 ng/ml, prostate cancer risk associations were greater by more than 5-fold for some genotypes, even though the same SNPs showed no clear association when the full control group was used. KLK SNPs were not associated with prostate cancer risk in PLCO when only cases and controls with high PSA levels or only cases and controls with low PSA levels were compared. Ahn et al. (2008) concluded that SNPs in the KLK3 region were not associated with prostate cancer risk in their series of 5 case-control studies. Furthermore, with widespread use of PSA in clinical practice, even modest associations observed between KLK3 SNPs and prostate cancer risk in some epidemiologic studies may be due to PSA-directed differential identification of prostate cancer cases with particular KLK3-PSA profiles.

Eeles et al. (2008) replied to the comments by Ahn et al. (2008) with a report of an analysis of rs2735839 in 13 further case-control studies as part of the PRACTICAL Consortium. The estimated per allele OR for prostate cancer associated with rs2735839 was 0.89 (95% CI = 0.83-0.95; p = 0.0007), very close to their original estimate. Eeles et al. (2008) also noted that when data from the 5 CGEMS studies were combined, the per allele OR was also remarkably similar (per allele OR = 0.90, 95% CI = 0.83-0.90, p = 0.01), although this was not formally significant using the 4-degree-of-freedom test given by Ahn et al. (2008). If the combined results from stage 2 of their initial study (Eeles et al., 2008), PRACTICAL, and CGEMS are combined, the overall evidence of association reached genomewide levels of significance (p less than 10(-8)).

Hua et al. (2018) confirmed that homozygosity for the G allele of rs11672691 within the gene for the long noncoding RNA (lncRNA) PCAT19 (618192) on chromosome 19q13 was associated with poor prognosis after prostate cancer diagnosis. The authors determined that the promoter region of the PCAT19-short variant, which is in intron 3 of the PCAT-long variant, contains rs11672691. The SNP regulated expression of the 2 PCAT19 isoforms in a reciprocal manner, with the G risk allele associated with decreased abundance of PCAT19-short and increased abundance of PCAT19-long. The transcription factors NKX3.1 (602041) and YY1 (600013) preferentially bound the A nonrisk allele of rs11672691 of the PCAT19-short promoter region and promoted expression of PCAT19-short. In contrast, the G risk allele of rs11672691 decreased binding of NKX3.1 and YY1, resulting in weaker promoter activity but stronger enhancer activity that subsequently activated PCAT19-long. In vitro and in vivo analyses revealed that PCAT19-long increased cell proliferation and promoted prostate cancer progression. RNA pull-down assays showed that PCAT19-long interacted with the RNA-binding protein HNRNPAB (602688) to activate a subset of cell-cycle genes that promoted aggressive prostate cancer. Hua et al. (2018) concluded that the G risk allele of rs11672691 mediates a promoter-enhancer switching mechanism underlying both initiation and progression of aggressive prostate cancer.

Gao et al. (2018) confirmed that the G risk allele of the intronic SNP rs11672691 within PCAT19 was associated with aggressive prostate cancer. Moreover, the G risk allele was associated with higher expression levels of PCAT19 and CEACAM21 (618191), and upregulation of PCAT19 and CEACAM21 correlated with prostate cancer development. The authors determined that the transcription factor HOXA2 (604685) directly bound an enhancer element encompassing rs11672691 and showed a preference for the G risk allele. Knockdown of PCAT19 led to reduced mRNA levels of CEACAM21, indicating that PCAT19 contributes to CEACAM21 regulation. Variation at rs11672691 also altered CEACAM21 promoter activity directly and contributed to HOXA2-mediated regulation of CEACAM21 expression. CRISPR/Cas9-mediated single-nucleotide editing in prostate cancer cells revealed direct effects of the G risk allele of rs11672691 on enhanced expression of PCAT19 and CEACAM21 and on prostate cancer proliferation and severity.