Heritable mutations have been linked to a number of cancers, well known examples being mutations to the RB gene in familial retinoblastoma and germline mutations of the BRCA genes in early onset breast cancer. In these classic examples, patients inherit a single, defective copy of a gene that predisposes them to developing specific cancers earlier in life. Knowledge that a patient has inherited one of these mutations serves at least two functions, the first being prognostic. Patients with these mutations are at higher risk and thus benefit from more regular screening and diagnostic efforts. The second function is to identify targeted agents that specifically benefit patients with these molecular signatures. With this in mind scientists have worked hard to identify such predictive germline mutations in familial cancers. Researchers at Fred Hutch and University of Washington took an open-minded approach when studying prostate cancer. Rather than focusing on mutations within a single gene, they analyzed the presence of mutations within an entire cellular pathway. The laboratory of Dr. Peter Nelson (Clinical Research Division) reports in the New England Journal of Medicine that mutations within a network of DNA-repair genes are highly prevalent in men with metastatic prostate cancer.
This study was a coordinated effort with research and medical centers all over the United States and United Kingdom. In total, samples from 692 patients with metastatic prostate cancer were analyzed for mutations in 20 DNA-repair genes that have previously been associated with cancer-predisposition syndromes. The genes interrogated included well-known players such as ATM, ATR, and BRCA1/2 but also studied less characterized genes such as PMS2, MRE11A, and RAD51C/D. For this analysis, non-tumor and tumor samples were sequenced allowing researchers to differentiate from inherited, germline mutations and somatic mutations within tumor tissue. Of the 20 genes analyzed, patients presented pathological mutations in 16. By studying these 16 DNA-repair genes together researchers found 11.8% of patients with metastatic disease had a pathogenic germline mutation within this pathway. This frequency of mutation to this pathway is significantly higher in patients with advanced cancer than in patients with localized prostate cancer (4.6% of patients) or patients without a known cancer diagnosis (2.7% of patients). The frequency of mutation to single genes was much less prevalent than analyzing the entire pathway, the mostly commonly mutated genes in these patients were BRCA2 (5.4%), CHEK2 (1.9%), and ATM (1.6%).
Heritable mutations associated with cancer are commonly associated with early onset of disease. This is particularly true for BRCA1/2 mutations in breast cancer patients. One explanation for earlier disease onset is that mutation of one copy of a DNA-repair gene in the germline facilitates somatic mutation of the remaining copy of the gene in tumors and/or other tumor suppressor genes. In fact this mutation pattern is commonly observed in BRCA1/2 mutated breast cancers. Similarly, researchers found when this network of DNA-repair enzymes were mutated in the germline, patients commonly lost the second allele in tumor samples (59% of patients). Despite these similarities to BRCA mutation in breast cancer, mutations of DNA-repair genes in prostate cancer patients are not associated with age of onset.
Another puzzling finding was that these germline mutations are only partially associated with a family history of cancer. These mutations did not associate with family history of prostate cancer as all patients (with or without mutations) reported a first-degree relative with prostate cancer. On the other hand, these mutations were associated with an increased familial incidence of non-prostate cancers. Familial incidence was high in both groups: 71% of patients with germline mutations and 50% without reported first-degree relatives with non-prostate cancers.
Overall this research provides two important lessons for clinicians and researchers. For researchers it suggests approaching cancer genetics in a global, systematic fashion may uncover previously unappreciated biology. In the case of this study, the association between metastatic disease and germline mutation was most evident by grouping at least four genes. In further study it will be interesting to understand why these mutations correlate more with metastatic disease and aggressiveness of disease rather than prostate cancer alone.
For clinicians understanding these deleterious mutations in DNA-repair genes can inform both treatment and family counseling. In the case of treatment, new studies have demonstrated that PARP1 is a successful treatment for metastatic prostate cancer containing genetic alterations to DNA-repair genes. Screening through this panel of common mutations will help decide the appropriate therapy for an individual. Identifying these germline mutations in patients may also improve early detection and diagnosis in family members. While this work does not evaluate the utility of these approaches, it does warrant further investigation.
Funding for this research was provided by the Stand Up To Cancer-Prostate Cancer Foundation, the National Institutes of Health, the Department of Defense, the Prostate Cancer Foundation, and others.
Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, Garofalo A, Gulati R, Carreira S, Eeles R, Elemento O, Rubin MA, Robinson D, Lonigro R, Hussain M, Chinnaiyan A, Vinson J, Filipenko J, Garraway L, Taplin ME, AlDubayan S, Han GC, Beightol M, Morrissey C, Nghiem B, Cheng HH, Montgomery B, Walsh T, Casadei S, Berger M, Zhang L, Zehir A, Vijai J, Scher HI, Sawyers C, Schultz N, Kantoff PW, Solit D, Robson M, Van Allen EM, Offit K, de Bono J, Nelson PS. 2016. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 375(5):443-53.