A type of mutation in a single nucleotide called rs11672691 plays a role in the development of aggressive prostate cancer by increasing the levels of two genes, PCAT19 and CEACAM21, a study has found.
The study, “Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus,” was published in the journal Cell.
Genome-wide association studies have implicated more than 100 single nucleotide polymorphisms (SNPs) — a type of mutation that changes a single DNA building block — in prostate cancer development.
In particular, recent studies have identified the presence of the SNP rs11672691 in several cases of aggressive prostate cancer. This SNP is located within a gene called PCAT19, which creates a type of RNA molecule called a long non-coding RNA that plays a role in regulating the expression of other genes.
However, the biological basis for the association between rs11672691 and prostate cancer development is not known.
In this study, researchers at the University of Oulu in Finland set out to further investigate the association between rs11672691 and the development of prostate cancer in a group of 2,738 men diagnosed with prostate cancer.
As shown previously, they observed a significant association between the presence of rs11672691 and the aggressiveness of prostate cancer, demonstrated by high tumor stage, high levels of prostate-specific antigen (PSA) — a marker of prostate cancer — and the development of castration-resistant prostate cancer.
The researchers went on to identify the mechanisms by which rs11672691 was promoting cancer aggressiveness. Using nearly 1,000 prostate tissue samples from three independent groups, they found that rs11672691 was associated with the high expression of two previously unknown prostate cancer genes, PCAT19 and CEACAM21.
Using the CRISPR-Cas9 genome editing technique, researchers then determined that rs11672691 plays a role in directly increasing the expression of PCAT19 and CEACAM21.
“Landmark analysis using CRISPR-Cas9 genome editing tool reveals that rs11672691 genotype can directly influence the expression of PCAT19 and CEACAM21, and the phenotype of prostate cancer cells,” Ping Gao, PhD, and Ji-Han Xia, two co-first authors of the study, said in a press release.
Furthermore, researchers showed that the presence of a guanine (one of the four bases that comprise DNA sequences) at rs11672691 was associated with increased binding of HOXA2 — a transcription factor that binds to genes and regulates their expression.
As rs11672691 is present in the PCAT19 gene, binding of HOXA2 to the rs11672691 region led to an increase in levels of PCAT19, which, in turn, plays a role in increasing expression of the CEACAM21 gene. This means the guanine allele of rs11672691 led to an increase in expression of CEACAM21 via increased expression of PCAT19.
“In particular, we find that the risk G, guanine allele of rs11672691 is associated with elevated expression of PCAT19 and CEACAM21, as well as poor prognosis in prostate cancer patients,” said senior author Gong-Hong Wei, PhD. “Rs11672691 G allele enhances chromatin binding of HOXA2, a novel oncogenic transcription factor with prognostic potential in prostate cancer, and a transcriptional regulator of CEACAM21 and PCAT19. The latter is a long noncoding RNA gene.”
Researchers also determined that the presence of rs11672691, as well as the expression of PCAT19 and CEACAM21, have a synergistic effect on predicting the relapse of prostate cancer and survival.
This highlights the potential clinical utility of this SNP as a risk stratification marker for the management of prostate cancer patients.
“This work shows that combined analyses of rs11672691 genotype and PCAT19 or CEACAM21 expression improve prediction of prostate cancer prognosis and progression, which may in particular prove useful,” Wei said.