Three billion base pairs in the human genome are nearly identical between any two individuals. Nevertheless, genome sequence variation such as single nucleotide polymorphisms (SNP) does occur in the population and may have profound effects on an individual's risk of developing various diseases, including prostate cancer (lat. Carcinoma). However, researchers at the University of Oulu (UniOulu) in Finland in collaboration with the University of Turku, Medical College of Wisconsin and other institutes, have discovered novel genes and mechanisms that can explain how a genomic variant influences prostate cancer aggressiveness. Their findings also suggest ways to improve risk stratification and clinical treatment for advanced prostate cancer.
Professor Gong-Hong Wei emphasized that how human genomic variants cause disease and its progression is in general one of the most compelling puzzles and questions in medicine. The rs11672691 SNP at the region of chromosome 19q13 has been found in association with aggressive prostate cancer, but how this genomic variant accounts for this association had not yet been uncovered.
Using genetic, genomic, molecular and computational tools, Gong-Hong Wei and his multinational collaborators confirmed the association in a large cohort of patients with prostate cancer, and discovered an oncogenic regulatory circuit among several novel genes, HOXA2, CEACAM21 and PCAT19 that may have the potential to cause prostate cancer progression to an incurable stage.
Dr Wei said, in particular, the team found that the risk G, guanine allele of rs11672691 is associated with increased expression of PCAT19 and CEACAM21, as well as poor prognosis in prostate cancer patients. 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.
Ping Gao and Ji-Han Xia, two co-first authors of the study, noted that 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. Prostate cancer is the second most common cancer and the fifth leading cause of cancer-related death in men, with more than 1,100,000 new cases diagnosed and 300,000 deaths annually worldwide. In Finland, nearly 5,000 new cases were diagnosed every year. Because of this, an important public health goal would be to improve treatment for the right patient at right time.
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.
Dr Wei said researchers think the findings may be repurposed to stratify prostate cancer patients for personalized treatment and care. Novel genes and mechanisms uncovered also open the door to developing precision medicine for advanced prostate cancer. But how this gene regulatory circuit accounts for pathogenesis and progression of prostate cancer warrants further investigation.