BRCA Gene Mutations and Prostate Cancer

Abstract

Prostate cancer remains the second most common cancer in men, with diverse courses from indolent cases to aggressive diseases. Among the key factors implicated in its pathogenesis are genomic alterations such as the TMPRSS2-ERG and related fusion oncogenes, loss of tumor suppressor PTEN, p53 or NKX3.1, inflammation, enhanced DNA damage, and chromosomal instability. Men with prostate cancer who carry BRCA1/2 mutations are at more risk of worse disease and poor prognosis. Cancer cells with mutant BRCA1 or BRCA2 repair genes with defects in homologous recombination are vulnerable to PARP inhibitors that target the genetic phenomenon known as synthetic lethality to exploit faulty DNA repair mechanisms. With relevance to prostate cancer, other features of cancer cells may also sensitize to PARP inhibitors, including aberrant transcription due to the androgen-driven fusion oncogene TMPRSS2-ERG or PTEN loss. Several models of synthetic lethality and potential biomarkers suggested up to date are also discussed. The chapter also highlights the importance of genetic screening of men with BRCA and shows diagnostic utility of plasma-derived circulating tumor DNA.

1. Introduction

Prostate cancer is one of the most common malignancies in men and a significant cause of cancer-related deaths [1]. Its incidence varies between less to highly developed countries with highlights of the implication of diagnostic practices, mainly PSA screening and lifestyle and environmental risk factors [2]. A family history of the disease is also a well-stated risk factor for prostate cancer. The risk for first-degree relatives of men with prostate cancer is about twice that for men in the general population [3]. Like all cancers, prostate cancer is a genetic disease driven by the activation of oncogenes as well as the depression of tumor suppressors [2]. The cross talk between multiple genes and environmental factors results in complex molecular pathogenesis in the development of prostate cancer (PCa), and these genetic and epigenetic changes can develop at various stages. Prostate cancer has multiple genetic alterations, including somatic copy number or chromosomal number changes, point mutations, and various structural modifications [4]. Somatic copy number alterations may be found in around 90% of PCa cases. Primary PCa often shows deletions on different chromosome numbers such as 6q, 8p, 10q, and 13q. In metastatic castration-resistant prostate cancer (mCRPC), the augmentation of chromosomes x, 7, 8q, and 9q has been identified [5]. Genes related to prostate cancer development and their chromosomal localization are summarized in a review by Kral and colleagues [6]. Hereditary prostate cancer (HPCa) has the highest heritability of any cancer in men. The proportion of PCa attributable to hereditary factors has been estimated at 5–15%. To date, the genes more consistently associated with HPCa susceptibility include mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and homologous recombination genes (e.g., BRCA1 and BRCA2, ATM, PALB2, or CHEK2). Additional genes should be integrated into specific research, including HOXB13, BRP1, and NSB1 [7, 8, 9]. BRCA1 and BRCA2, together with PALB2 or BARD1, are critical mediators of the HRR process, and their loss results in functional impairment of the HRR pathway [10].

2. Current challenges in prostate cancer research and treatment

Significant advances have been made in understanding prostate cancer’s molecular makeup, diagnosis, and treatment, e.g., approval of novel drugs that improve survival in men with advanced prostate cancer. Nonetheless, several areas of unmet need remain, for example, adjuvant therapies to increase cure rates in higher-risk locally advanced diseases or treatment of metastatic cancer [3]. Novel therapeutic strategies tailored to biologically defined prostate cancer subsets are being developed thanks to clinical trial benefits, new drugs, the use of NGS, advanced functional imaging, and the better use of existing therapies in early-stage disease [3]. PCa initiation and progression are driven by androgen receptor (AR) signaling. PCa is uniquely dependent on androgens for growth and progression, and androgen deprivation therapy (ADT) is an effective treatment for patients with advanced disease. However, when a castration-resistant state develops, the patient has more chance of dying of PCa than other causes. Alterations in AR signaling in metastatic castration-resistant PCa (mCRPC) include persistent AR activation, which leads to AR amplification, AR splice variants, and intratumoral androgen biosynthesis. Enzalutamide, an AR antagonist, blocks AR translocation function, and Abiraterone inhibits androgen biosynthesis [7]. Recently, mCRPC patients with germline defects in DNA damage repair showed a decreased response to AR-targeted therapy. At the same time, other authors reported an improved response to second-generation ADT with the administration of drugs, including Abiraterone or Enzalutamide, in men with BRCA or ATM mutations [7].

3. BRCA1 and BRCA2 importance in prostate cancer

BRCA1 and BRCA2 genes are inherited in an autosomal dominant manner. Men and women have an equal chance of inheriting either of these genes and passing them to their descendants. There are numerous studies investigating the cancer risks and outcomes of female carriers, while studies of the cancer characteristics in male carriers are still lacking [11]. Men with germline BRCA1 and BRCA2 mutations are less investigated than female peers [11]. The risk of breast cancer in BRCA1 carrier men at age 70 is 1.2%, while for BRCA2 carriers is 6.8%. Besides breast cancer, male germline mutation carriers also have an increased lifetime risk for prostate cancer with a cumulative lifetime risk of 29% (95% CI = 17–45%) for BRCA1-mutation carriers and 60% (95% CI = 43–78%) for BRCA2-mutation carriers compared with a lifetime risk of 16% of the general population [12, 13]. Familial aggregation of mutations is also well documented in Laitinen et al. [14]. Men with a family history of prostate cancer in first-degree relatives bear an increased risk of the disease, as shown in a long-term follow-up study among Nordic twins [15]. The Prostate Cancer database Sweden (PCBaSE) study also confirmed a 14.9% risk of developing prostate cancer in men of age 65, compared with 4.8% for men who did not have a brother with prostate cancer. At age 75, the risk of developing prostate cancer was 30.3% for patients having a brother with the disease vs. 12.9% for patients without a brother with PCa [16].

The clinical impact of the role of DNA damage repair genes is still evolving in PCa, although it likely mirrors the path of hereditary breast and ovarian cancer [8]. Transformations in BRCA1 and BRCA2 have recognized the factor for the progression of poor-risk PCa. Besides BRCA1 and BRCA2, cancer cells with mutant BRCA1 or BRCA2 repair genes with defects in homologous recombination are vulnerable to poly (ADP-ribose) polymerase (PARP) inhibitors that target the genetic phenomenon known as synthetic lethality to exploit faulty DNA repair mechanisms.

The notion of synthetic lethality stems from genetic studies on the fruit fly Drosophila Melanogaster [17]. It describes the example of the co-occurrence of different gene mutations resulting in cell death where an individual, single genetic event is still compatible with life [18]. Unlike conventional targeted drugs, synthetic lethal therapy promotes indirect mutation targeting by identifying an alternative synthetic lethal target that may include oncogenes, tumor suppressors, DNA repair machinery, cancer metabolism agents, etc. [19]. Synthetic lethal relationships can potentially broaden the strategies of novel anticancer treatments. Identification and validation of potential synthetic lethal partner genes represent the challenge of current research. Clinical studies on breast cancer BRCA carriers described the auspicious synthetic lethal effect of BRCA/PARP [20]. Later, several mechanisms of resistance to PARP inhibitors were suggested. These are secondary mutations of BRCA1 and BRCA2, as well as upregulation of the gene encoding P-glycoprotein pump or loss of TP53BP1 protein [20].

4. Prognostic role of BRCA mutations in prostate cancer

The largest comprehensive study of clinicopathologic, therapeutic, and survival data of 2181 prostate cancer patients was processed to evaluate the evidence for the independent prognostic value of BRCA1/2 mutation status on PCa cause-specific survival (CSS). Patients cohorts included in study were from United Kingdom Genetic Prostate Cancer study (UKGPCS) and Epidemiological Study of BRCA1/2 Mutation Carriers (EMBRACE). The Study showed that node involvement and distant metastasis are more common in patients with PCa who have BRCA1/2 mutations and those carriers with local disease develop metastasis earlier [21]. Further, poor outcome was mostly dependent on BRCA2, whereas the contribution of BRCA1 mutations remained unclear [21]. Taken together, BRCA1/2 mutations are associated with a more aggressive disease/lethal prostate cancer and the proportion of germline mutations in localized disease is 4.6% while 11.8–16.2% is observed in metastatic cases [22]. Presence of such a mutations, however, also identifies individuals who could benefit from PARP inhibitors [23]. Moreover, presence of BRCA mutations can predict response to drugs based on platinum salts [24]. Other HRR mutations are also frequent, but their prognostic/predictive importance for prostate cancer patients remains elusive. Moreover, a proportion of these mutations are associated with inherited germline defects and are relevant to the patients’ risk of second malignancies and their relatives’ risk of cancer [10].

5. Importance of genetic screening of men with BRCA

The character of available information on BRCA1/2-related cancers is directed mainly at women, reflecting a gendered approach that may lead men to underestimate their risk of carrying BRCA mutations [25]. The determinants of men’s motivations to engage in genetic screening for BRCA1 and BRCA2 were explored in a very recent study by Annoni and Longhini [26] through the lens of the Health Action Process Approach. One-hundred and twenty-five men with a mean age of 58.53 ± 10.37 participated in an online survey. The intention to undergo genetic screening for BRCA1/2 mutations in men was significantly and positively associated with self-efficacy and risk perception. Moreover, having offspring positively affected intention as well. Petrylak et al. [27] highlighted the importance of genomic screening as part of a comprehensive assessment of prostate cancer prognosis and treatment options and suggested plasma as the best material to select patients with mCRPC for treatment with a PARP inhibitor [27]. The authors noted that the analysis of plasma and archival biopsy samples obtained before the patient started Rucaparib treatment detected the same alterations. However, BRCA2 homozygous loss (whole gene, 26 of 26 exons) and several other alterations were also detected, but in plasma only. Authors hypothesize that the response of the patient’s tumor to Rucaparib was likely driven by DNA damage repair deficiency caused by homozygous loss of all BRCA2 exons [27]. A similar approach was suggested by Chi and colleagues [28], when evaluating the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying BRCA1, BRCA2, and ATM alterations in patients with mCRPC from the phase III PROfound study. They showed that 81% of ctDNA samples yielded an NGS result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement when tissue was a reference. The concordance was high for nonsense (93%), splice (87%), and frameshift (86%) mutations but lower for large rearrangements (63%) and homozygous deletions (27%) [28].

6. Therapeutic targeting of men with BRCA1 and BRCA2 mutations

The mutation status of genes involved in PCa may impact therapeutic strategies. PARP inhibitors such as Olaparib, Rucaparib, Niraparib, and Telazoparib, effectively kill tumors defective in the BRCA1 or BRCA2 genes through the concept of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines [29]. According to one suggested model, PARP inhibitors cause an increase in DNA single-strand breaks (SSBs), which, during replication, are converted to irreparable toxic DNA double-strand breaks (DSBs) in BRCA1/2 defective cells. Alternative models suggested by Helleday [29] are not mutually exclusive. One of the models proposes that PARP inhibition causes PARP-1 to be trapped onto DNA repair intermediates during base excision repair. This may, in turn, obstruct replication forks, which require BRCA-dependent homologous recombination to be resolved [29]. According to another model, PARP is directly involved in catalyzing replication repair in a distinct pathway from homologous recombination. Targeting DNA repair defects by PARP1 inhibitors requires suitable predictive biomarkers. The third phase of the clinical trial was conducted on two groups of men having alterations in genes involved in homologous recombination repair with progressing metastatic castration-resistant prostate cancer while receiving Enzalutamide or Abiraterone: Cohort A with at least one alteration in BRCA1, BRCA2, or ATM, and cohort B with alterations in any of 12 other prespecified genes. Olaparib was associated with more prolonged progression-free survival and better response measures and patient-reported endpoints than either enzalutamide or Abiraterone [30]. Kurfurstova et al. [31] performed an immunohistochemical analysis of multiple markers of DNA damage signaling, oxidative stress, DNA repair, and cell cycle control pathways in human prostate benign hyperplasia, intraepithelial neoplasia, and PCa and observed that the DNA damage checkpoint barrier (γH2AX, pATM, p53) mechanism was activated during PCa tumorigenesis. The authors observed that oxidative stress (8-Oxoguanine lesions) and NQO1 increased during disease progression.

Interestingly, TMPRSS2-ERG rearrangement and PTEN loss are events sensitizing to PARPi, frequently occurring along with heterogeneous loss of DNA repair factors 53BP1, JMJD1C, and Rev7. Their defects may cause resistance to PARPi [31]. Oplustilova et al. [32] evaluate several other biomarkers, such as spontaneous PARsylation and Rad51 foci formation, as surrogate markers for PARP activity and HR, respectively, supporting their candidacy for biomarkers of PARP-1i responses [32]. Altmeyer [33], in its comment on the research article by Oplustilova et al. [32], mentions that the use of single biomarkers could indeed be misleading and that a combination of markers to assess which cancer cells are likely “addicted to PAR” might be more reliable [33].

7. Concluding remarks and perspectives

BRCA1 and BRCA2 tumor suppressors gained higher clinical significance with regard to metastatic and lethal prostate cancer. BRCA2 was demonstrated as a strong predictor of response to PARP inhibitors. Molecular characterization of mCRPC patients should be integrated into routine clinical testing to select potential responders to treatment. This chapter contributes to the role of BRCA1 and BRCA2 gene alterations in prostate cancer. A more detailed understanding of the complex DNA damage repair network in prostate cancer with an unstable genome will give deeper insights into the diverse functions of PARPs and potential contributors of synthetic lethality.