Prostate cancer is a complex and multifactorial disease with a strong genetic component. Genetic mutations and pathways are known to play a role in the development and progression of prostate cancer. In this article, we will discuss some of the specific examples of how genetics plays a role in prostate cancer and provide exact data references.
BRCA genes are a family of genes that play a critical role in DNA repair. Mutations in BRCA genes have been associated with an increased risk of several types of cancer, including prostate cancer. A study published in the Journal of Clinical Oncology found that men with BRCA2 mutations have a 20% lifetime risk of developing prostate cancer, compared to a 6% lifetime risk in the general population (1). Another study published in the same journal found that men with BRCA1 or BRCA2 mutations who developed prostate cancer had a worse prognosis than those without mutations (2).
HOXB13 is another gene that has been found to play a role in prostate cancer. A study published in the New England Journal of Medicine found that a rare mutation in the HOXB13 gene was associated with a 20-fold increased risk of developing prostate cancer (3).
Genetic mutations in the androgen receptor (AR) gene have also been implicated in the development of prostate cancer. A study published in the journal Cancer Research found that mutations in the AR gene were present in up to 60% of metastatic castration-resistant prostate cancers
(4). Other genetic pathways that have been implicated in the development and progression of prostate cancer include the phosphatidylinositol 3-kinase (PI3K) pathway and the tumor protein 53 (TP53) pathway. A study published in the journal European Urology found that mutations in the PI3K pathway were present in up to 40% of primary prostate cancers
(5). Another study published in the journal Nature found that mutations in the TP53 pathway were present in up to 10% of metastatic prostate cancers
(6).There are several genetic tests available for prostate cancer that can help identify inherited genetic mutations associated with an increased risk of developing the disease, as well as guide treatment decisions. In this article, we will discuss the different genetic tests available for prostate cancer and their indications.
BRCA1/2 testing: BRCA1/2 testing is recommended for men with a family history of breast, ovarian, or prostate cancer. Mutations in the BRCA1/2 genes have been associated with an increased risk of developing aggressive prostate cancer, and testing may help identify men who are at higher risk for the disease.HOXB13 testing: HOXB13 testing is recommended for men with a family history of prostate cancer, particularly those with a history of early-onset disease. A rare mutation in the HOXB13 gene has been associated with an increased risk of developing prostate cancer.Genetic testing for inherited cancer syndromes: Some inherited cancer syndromes, such as Lynch syndrome and Cowden syndrome, are associated with an increased risk of developing prostate cancer. Genetic testing for these syndromes may be recommended for men with a family history of multiple cancers.Prolaris testing: Prolaris is a genetic test that measures the activity of genes associated with prostate cancer cell growth. The test is used to predict the likelihood of cancer recurrence after treatment and may help guide treatment decisions.In conclusion, genetic mutations and pathways play an important role in the development and progression of prostate cancer. Most current therapies do not rely on genetic testing to drive clinical treatments however, testing can help ascertain which patients may be in higher subgroups and therefore warrant closer observation or earlier treatment.
For example, patients with early stage disease who have genetic predisposition may be better served with early therapy as opposed to active surveillance (watchful waiting). BRCA genes, HOXB13, androgen receptor gene, PI3K pathway, and TP53 pathway are specific examples of genetic alterations that have been implicated in the disease. Further research is needed to fully understand the role of genetics in prostate cancer and to develop effective therapies that can target these pathways.
References:
Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882. <P>Tryggvadottir L, Vidarsdottir L, Thorgeirsson T, et al. Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst. 2007;99(12):929-935. doi:10.1093/jnci/djm100.Ewing CM, Ray AM, Lange EM, et al. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med. 2012;366(2):141-149. doi:10.1056/NEJMoa1110000.Dehm SM, Schmidt LJ, Heemers HV, et al. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 2008;68(13):5469-5477. doi:10.1158/0008BRCA1/2 testing: National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 2.2021. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed on October 5, 2021.HOXB13 testing: Ewing CM, Ray AM, Lange EM, et al. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med. 2012;366(2):141-149. doi:10.1056/NEJMoa1110000. <P>Genetic testing for inherited cancer syndromes: National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2021.https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Accessed on October 5, 2021.Prolaris testing: Cuzick J, Swanson GP, Fisher G, et al. Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol. 2011;12(3):245-255. doi:10.1016/S1470-2045(10)70295-3.Decipher testing: Klein EA, Cooperberg MR, Magi-Galluzzi C, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol. 2014;66(3):550-560. doi:10.1016/j.eururo.2014.01.003.
