DNA repair gene (DRG) alterations have been established as an emerging class of biomarkers and targets for cancer therapies. Although mutations interfering with specific DNA repair pathways have been characterized and exploited mainly in breast and ovarian cancers, the recent identification of a fraction of primary and metastatic prostate cancer (PCa) patients harboring similar defects has opened up for testing DRG mutation-induced vulnerabilities also for this disease (1,2). Enthusiasm was especially triggered by seminal work by Mateo et al., which highlighted the clinical efficacy of exploiting DRG alterations by reporting preferential positive response to PARP inhibition in metastatic castration resistant prostate cancer (mCRPC) patients (3). Altogether this suggested a novel class of biomarkers to molecularly stratify mCRPC patients and increased the interest in the identification of additional DRG alterations in PCa patients.
PCa represents a common and clinically heterogeneous disease entity, one of the most heritable of human cancers and a leading cause of cancer-related death in males worldwide (4,5). Nearly all PCa patients are diagnosed with adenocarcinomas that show a broad range of clinical behaviours, from relatively indolent to metastatic progression and lethality. Even though most of PCa patients are successfully treated with surgery or radiation therapy, a fraction of men relapses and progresses to an incurable metastatic stage.
The identification of markers to distinguish indolent from aggressive disease at time of diagnosis together with the characterization of markers for treatment stratification at time of androgen deprivation therapy resistance are among the biggest challenges in the setting of PCa translational research.
Given the strong hereditary component of PCa (4), the identification of genetic markers for disease development and progression have been studied over the last two decades. The recent advances in high-throughput, genome-wide profiling technologies have further enabled the discovery and characterization of genetic variants associated with PCa predisposition, including inherited mutations in several genes involved in DNA damage repair. Accordingly, early studies associated germline mutations of BRCA2 with the development of an aggressive form of PCa and with poor survival (6,7). In 2016 Pritchard and colleagues reported an increase in the prevalence of germline DRG mutations (in a panel of 20 DRGs) in mCRPC patients (11.8%) compared to localized PCa patients (4.6%), arguing that germline DRG variants are associated with a more aggressive disease (8). Supporting this association, further studies comparing aggressive and indolent PCa patients provided evidence that germline variants within a restricted list of DRGs (involved mainly in the homologous recombination repair pathway) contribute to metastatic PCa predisposition (9,10). However, following data of mCRPC patients from a prospective study suggested that only BRCA2 germline mutations are prognostic factors and that there is no significant association between other DRG germline variants and patients outcome (11). Nevertheless, the debate concerning the association between other DRG mutations and PCa is still ongoing.
In this scenario, Leongamornlert et al. recently reported the results of a screening of 167 genes involved in 8 DNA damage response and repair pathways within a UK-based cohort of 1,281 young-onset PCa cases and 1,160 controls selected for either no family history for the disease or low PSA level (12,13). By performing targeted sequencing of exonic regions of a total of 175 genes using healthy cells DNA (final target regions consisted of about 1.5 Mbp), the study identified a total of 233 protein truncating variants, including frameshift indels, stop gain, and splice variants. Of those, 80 are part of the BROCA panel of cancer predisposition genes (http://web.labmed.washington.edu/tests/genetics/BROCA_VERSIONS) (14). Among the identified inherited variants, 6 variants in the XPC gene (Xeroderma pigmentosum, complementation group C) were associated with aggressive phenotype (defined as Gleason score ≥8) and a single nucleotide variant in NBN (Nibrin) was established in the gene-level case-control analysis as associated with PCa predisposition, together with marginally associated variants in HOXB13 and in POLL. The gene-set-level analysis performed with adaptive combination of P values (ADA) led to the definition of two gene-sets: one predisposition panel (Predis18: RNASEL, BRCA2, POLE, POLM, CHEK2_1100del, RECQL4, MSH5, ATM, CHEK2_non1100del, BLM, ERCC3, GEN1, NHEJ1, PARP2, POLD1, CDC25C, MSH2, NEIL2, TDP1, LIG4 and BRCA1) with significant enrichment among PCa cases compared to controls, and one aggressive panel (Agg4: BRCA2, MSH2, ERCC2, CHEK2_non1100del), whose carriers showed significant association with clinical variables denoting aggressive disease (higher PSA, Gleason score ≥8, higher tumor stage, and nodal spread). When testing association with overall survival and disease-specific survival, carriers of the Agg4 panel demonstrated significantly worse clinical behaviour.
The study of Leongamornlert et al. confirmed previous results related to an enrichment for ATM, BRCA1, BRCA2, CHEK2, and GEN1 variants [genes already identified by Pritchard et al. (8)] in PCa cases compared to controls and, additionally, provided an extended list of DRGs that could be potential candidates for clinical screening and risk profiling.
There are several features empowering the findings of this work. First, the use of a large cohort including more than one thousand PCa cases and controls matched for genetic ancestry and with comparable age, and the selection of the control set with absence of PCa family history or low PSA levels (<0.5 ng/mL) significantly improve the statistical power of the study allowing for the detection of rare variants. Second, the selection of a young-onset (diagnosed at ≤60 yr) PCa patients’ cohort provides a great opportunity to identify novel variants associated with increased risk for this disease. Indeed, young men diagnosed with PCa have greater genetic risk compared to older patients (15). Furthermore, high-grade early-onset PCa patients showed worse prognosis compared to late-onset PCa (16,17). Third, compared to previous studies in which only highly selected genes were analysed, the work of Leongamornlert et al. includes a large panel of genes (167 genes) involved in several DNA repair pathways and in cell cycle regulation. Additionally, 8 PCa related genes and predisposition candidates (such as AR, HOXB13 and SPOP) were included in the analyses. Finally, the long follow up time of the patients represents an additional value of the study.
While the study from Leongamornlert et al. presents the most comprehensive design in the setting of DRG variants, additional work would augment its relevance and, more broadly, the understanding of the role of DRG mutations in PCa aggressiveness and in the response to different treatments. For instance, since the disease risk varies substantially based on ethnicity (18), DRG variants incidence should be evaluated across ancestries; germline and somatic variants should be jointly assessed to fully understand DRG role in aggressive disease, as the frequency of DRG alterations significantly increases when both components are considered (19-21). Additionally, the response of DRG mutation carriers to PCa specific treatments should be eventually investigated in large cohorts to clarify the role of DRG mutations as predictive biomarkers.
Studies as the one of Leongamornlert et al. represent a unique opportunity to identify rare genetic variants to be used for PCa screening and prognostication. On one side, these data can inform on PCa susceptibility and aggressiveness leading to earlier diagnosis and driving patient enrolment either in active surveillance or therapeutic intervention programs. On the other, they could contribute to the molecular stratification of PCa patients for personalized therapy and expose additional vulnerabilities expanding PCa therapeutic opportunities.
Funding: The authors like to acknowledge support from the Fondazione AIRC for the Investigator Grant 2016 19221, the MIUR Fare 2016 for R16Z7PSLHN (DNA repair genes vulnerability in prostate cancer) and the Fondazione Trentina per la Ricerca sui Tumori.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
- Cancer Genome Atlas Research Network. The Molecular Taxonomy of Primary Prostate Cancer. Cell 2015;163:1011-25. [Crossref] [PubMed]
- Robinson D, Van Allen EM, Wu YM, et al. Integrative Clinical Genomics of Advanced Prostate Cancer. Cell 2015;161:1215-28. [Crossref] [PubMed]
- Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015;373:1697-708. [Crossref] [PubMed]
- Mucci LA, Hjelmborg JB, Harris JR, et al. Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA 2016;315:68-76. [Crossref] [PubMed]
- Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108. [Crossref] [PubMed]
- 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;31:1748-57. [Crossref] [PubMed]
- Gallagher DJ, Gaudet MM, Pal P, et al. Germline BRCA Mutations Denote a Clinicopathologic Subset of Prostate Cancer. Clin Cancer Res 2010;16:2115. [Crossref] [PubMed]
- Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 2016;375:443-53. [Crossref] [PubMed]
- Mijuskovic M, Saunders EJ, Leongamornlert DA, et al. Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease. Br J Cancer 2018;119:96-104. [Crossref] [PubMed]
- Leongamornlert D, Saunders E, Dadaev T, et al. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br J Cancer 2014;110:1663-72. [Crossref] [PubMed]
- Castro E, Romero-Laorden N, del Pozo A, et al. PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 2019;37:490-503. [Crossref] [PubMed]
- Eeles RA, Ardern-Jones A, Shearer RJ, et al. Familial prostate cancer: the evidence and the Cancer Research Campaign/British Prostate Group (CRC/BPG) UK Familial Prostate Cancer Study. Br J Urol 1997;79:8-14. [Crossref] [PubMed]
- Leongamornlert DA, Saunders EJ, Wakerell S, et al. Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel. Eur Urol 2019. [Epub ahead of print]. [Crossref] [PubMed]
- Walsh T, Lee MK, Casadei S, et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci USA 2010;107:12629. [Crossref] [PubMed]
- Lange EM, Salinas CA, Zuhlke KA, et al. Early onset prostate cancer has a significant genetic component. Prostate 2012;72:147-56. [Crossref] [PubMed]
- Lin DW, Porter M, Montgomery B. Treatment and survival outcomes in young men diagnosed with prostate cancer. Cancer 2009;115:2863-71. [Crossref] [PubMed]
- Salinas CA, Tsodikov A, Ishak-Howard M, et al. Prostate cancer in young men: an important clinical entity. Nat Rev Urol 2014;11:317. [Crossref] [PubMed]
- Pernar CH, Ebot EM, Wilson KM, et al. The Epidemiology of Prostate Cancer. Cold Spring Harb Perspect Med 2018;8. [Crossref] [PubMed]
- Abida W, Cyrta J, Heller G, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci U S A 2019;116:11428-36. [Crossref] [PubMed]
- Abida W, Armenia J, Gopalan A, et al. Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making. JCO Precis Oncol 2017;2017. [Crossref] [PubMed]
- Armenia J, Wankowicz SAM, Liu D, et al. The long tail of oncogenic drivers in prostate cancer. Nat Genet 2018;50:645-51. [Crossref] [PubMed]