Prostate Cancer - Drivers of Genetic Mutations & Their Role in Disease Progression
Prostate cancer is one of the most common forms of cancer that affects the prostate gland in the male urogenital tract. Most prostate cancers are slow growing and are usually detected in individuals older than age 50. Although environmental factors contribute to the development of prostate cancer, risk is significantly associated with incidence among first-degree relatives. In recent years, several inherited and spontaneously mutated genes have been linked to prostate cancer. Here we highlight these findings and how they provide insight into the development of targeted prostate cancer therapies.
Prostate cancer tumors are typically characterized by a wide range of genomic aberrations including somatic copy number alterations (SCNAs), structural rearrangements, and point mutations. Metastatic prostate tumors may have hundreds of these aberrations throughout the genome, but recent studies of primary prostate tumors have been critical to defining mutations associated with tumor development. Most primary prostate tumors have SCNAs, typically in the form of deletions that target a small area of the genome1. Deletions are often seen in the tumor suppressor genes BRCA2, NKX3.1, PTEN, and RB12.
Structural rearrangements are another source of genomic variation observed in primary prostate tumors, for which the TMPRSS2:ERG rearrangement is most common and causes the androgen-responsive TMPRSS2 serine protease to drive expression of the ERG oncogene3. Other rearrangements have been linked to prostate cancer, including TMPRSS2 fusions with other ETS family members beyond ERG (ETV1 and ETV4)4. Some studies have suggested a link between ERG rearrangements and SCNA incidence, although it is not yet clear if rearrangements lead to destabilization of the genome and increased occurrence of SCNAs1.
Somatic mutations occur on relatively high frequency primary prostate tumors, and this has been linked to mutations DNA mismatch repair proteins, tumor suppressors and oncogenes. The tumor suppressor TP53 is consistently identified as mutated in prostate tumors5. Mutations in the tumor suppressor genes BRCA1 and BRCA2 are well known for their association with breast and ovarian cancer but have also been linked to prostate cancer, and recent studies have shown that certain BRCA2 pathogenic sequence variants are associated with an elevated risk for aggressive prostate cancer6,7. PALB2 is a protein that interacts with BRCA2, and a recent study indicated that individuals who have certain PALB2 variants are more predisposed to aggressive forms of prostate cancer8. In addition, mutations in genes associated with DNA mismatch repair (MMR), such as MSH2, MSH6, and MLH1, are associated with greater prostate cancer risk9, and individuals with Lynch syndrome, which is caused by a germline mutation in one of these MMR genes, are also at greater risk of developing an aggressive form of prostate cancer10.
One of the most important genes involved in prostate cancer progress is the gene expressing the androgen receptor (AR). Dozens of somatic mutations have been identified in the AR, and many of these mutations target the ligand binding domain11. Some prostate cancers can be treated successfully with drugs that inhibit AR signaling, such as enzalutamide, but resistance frequently occurs and is associated with worse outcomes. AR promotes prostate cancer cell survival by regulating several cellular programs. Although AR activity inhibition through androgen deprivation therapy (ADT) results in the suppression of AR-related pathways and durable clinical remission12, the disease may recur as castration-resistant prostate cancer (CRPC), typically with reactivated AR signaling. In this case, patients are treated with second-generation AR pathway inhibitors such as enzalutamide and abiraterone. Unfortunately, durable complete responses under these treatments are rare, and a substantial number of CRPC tumors progress under treatment despite loss of AR signaling. CRPC with AR-null phenotype are classified as tumors with diffuse small cell or neuroendocrine (NE) characteristics (SCNPC) or as double-negative (DNPC) phenotype that lacks both NE and AR activity13. A recently described genome-wide CRISPR-Cas9 screen was used to identify kinases that could be inhibited in the presence of enzalutamide. BRAF or downstream MAPK signaling molecules were identified as targets that could be co-inhibited with enzalutamide to improve overall therapeutic effects of these drugs14.
Genomic alterations in prostate cancer are highly variable and can impact many critical cellular processes. By understanding which genes drive disease progression, potential therapeutic targets can be identified, and disease outcomes under different treatment regimens can be better predicted.
 Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010 Jul 13;18(1):11-22.
 Wallis CJ, Nam RK. Prostate Cancer Genetics: A Review. EJIFCC. 2015 Mar 10;26(2):79-91.
 Tomlins SA, Rhodes DR, Perner S et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005 Oct 28;310(5748):644-8.
 Rubin MA, Maher CA, Chinnaiyan AM. Common gene rearrangements in prostate cancer. J. Clin. Oncol. 2011 Sep 20;29(27):3659-68.
 Ecke TH, Schlechte HH, Schiemenz K et al. TP53 gene mutations in prostate cancer progression. Anticancer Res. 2010 May 1;30(5):1579-86.
 Patel VL, Busch EL, Friebel TM, et al. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness. Cancer Res. 2020 Feb 1;80(3):624-638.
 Oh M, Alkhushaym N, Fallatah S, et al. The association of BRCA1 and BRCA2 mutations with prostate cancer risk, frequency, and mortality: A meta-analysis. Prostate. 2019 Jun;79(8):880-895.
 Wokołorczyk D, Kluźniak W, Stempa K, Rusak B, Huzarski T, Gronwald J, Gliniewicz K, Kashyap A, Morawska S, Dębniak T, Jakubowska A. PALB2 mutations and prostate cancer risk and survival. Br. J. Cancer. 2021 May 18:1-7.
 Ritch E, Fu SY, Herberts C, Wang G, et al. Identification of hypermutation and defective mismatch repair in ctDNA from metastatic prostate cancer. Clin. Cancer Res. 2020 Mar 1;26(5):1114-25.
 Haraldsdottir S, Hampel H, Wei L, et al. Prostate cancer incidence in males with Lynch syndrome. Genet. Med. 2014 Jul;16(7):553-7.
 Ferraldeschi R, Welti J, Luo J, Attard G, de Bono JS. Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects. Oncogene. 2015 Apr 2;34(14):1745-57.
 Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25(2):276–308.
 Bluemn EG, Coleman IM, Lucas JM et al. Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell. 2017;32(4):474–489.
 Palit SAL, van Dorp J, Vis D, Lieftink C, Linder S, Beijersbergen R, Bergman AM, Zwart W, van der Heijden MS. A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer. Sci. Rep. 2021 Jul 1;11(1):13683.