Good and surprising news finds germline mutations are rare in low-risk prostate cancer

From the Nelson Lab, part of the Human Biology and Public Health Sciences Divisions

Genetic mutations can be acquired throughout our lives or we can be born with them – the latter are known as germline mutations. Germline mutations in some genes, such as DNA repair pathway genes, can predispose people to certain cancers including prostate cancer. Unsurprisingly, these pathogenic germline mutations “have been documented as being present at significantly higher rates in metastatic prostate cancer when compared to localized prostate cancer which suggests an association with aggressive disease,” explains Dr. Lauren Brady, a postdoctoral researcher in Dr. Peter Nelson’s Lab, part of the divisions of Human Biology, Clinical Research, and Public Health Sciences, and head of the Prostate Cancer Research Program at Fred Hutch. Dr. Brady goes on to say that “identifying men with these heritable mutations has implications for their family members, and also potentially for how aggressively their prostate cancer may behave.” For men diagnosed with low-risk prostate cancer, or small, slow-growing cancer that is contained within the prostate when diagnosed, it doesn’t always make sense to begin “immediate treatments such as surgery or radiation- which can have substantial side-effects towards quality of life,” Dr. Brady notes. Instead, these patients have the option of enrolling in a treatment management strategy called Active Surveillance. This strategy entails routine monitoring and clinical tests, including blood tests and repeat biopsies, as a way to keep a close eye on the cancer and begin treatments only when or if necessary. Dr. Brady wanted to understand “what role, if any, germline mutations might play for this subset of patients” which could help “better stratify patients who might benefit from a different treatment plan at diagnosis.” Together with Dr. Lisa Newcomb, Deputy Director of the Canary Prostate Active Surveillance Study (PASS), and Dr. Dan Lin, Director of Urologic Oncology at the University of Washington and a member of the Public Health Sciences Division, Dr. Brady and researchers from the Nelson Lab asked whether patients with low-risk prostate cancer harboring germline mutations show greater risk of developing more aggressive, advanced stage prostate cancer. Their results were recently published in Cancer Medicine.

Frequency of germline cancer predisposition mutations in men on Active Surveillance who developed adverse characteristics and those who did not.
Frequency of germline cancer predisposition mutations in men on Active Surveillance who developed adverse characteristics and those who did not. Image provided by Lauren Brady.

The authors hypothesized that there would be an association between pathogenic germline mutations and adverse outcomes among those men participating in Active Surveillance. In total, the study investigated the disease progression of 437 PASS participants who were followed up for an average of just over seven years. During that time, 169 men developed adverse characteristics, defined by metastasis (n=10 participants), recurrence of cancer after treatment without metastasis (n=42), or adverse pathology at radical prostatectomy (surgery to remove the prostate) with no evidence of recurrence (n=117). The researchers then asked which men, of those who developed adverse outcomes and those who did not, had germline mutations. In total, Brady et al. detected 148 mutations in 22 genes of 123 participants. Of these, 32 mutations in 8 genes found in 29 participants were considered pathogenic, which included 19 participants harboring mutations in DNA damage repair processes such as ATM, BRCA1 and BRCA2. The investigators did not observe an association between having these mutations and characteristics associated with advanced or adverse prostate cancer.

Prostate cancers can be slow growing, taking up to 15-20 years to develop adverse characteristics and the Canary PASS participants will continue to be followed to see if additional men develop more advanced stage cancers. However, Dr. Nelson explains that the participants not being followed for long enough is likely not the reason they did not detect an association between germline mutations and adverse characteristics. Instead, he mentions that “these penetrant germline mutations are rare in the population. They are clearly enriched in patients with more aggressive prostate cancer [at diagnosis] – but as our cohort was specifically those men with low risk disease, these mutations were detected in a very small fraction of participants”. Dr. Brady and Dr. Newcomb add, “many patients with these mutations may have already been screened and deemed ineligible for Active Surveillance, for example those with a family history of the disease or who may have presented with more aggressive disease at diagnosis,” making it less surprising that such a low number of participants were seen to have pathogenic mutations. In line with this, other studies estimate that germline DNA repair pathway mutations could be as high as 12% in metastatic prostate cancers but found in less than 1% of non-aggressive cancers, similar to the rates that the authors observed and suggesting different genetic drivers of metastatic vs. low-risk prostate cancers.

Although the Nelson group did not observe an association between pathogenic germline mutations and characteristics associated with more advanced disease, “future studies will focus on histopathology review of patient biopsies and tumor specimens”, including “genomic profiling of tumor specimens collected during radical prostatectomy which will provide further insight into the presence and biology of germline and somatic mutations in DNA damage repair genes,” emphasizes Dr. Brady.

This work was supported by the Canary Foundation, the National Institutes of Health, and the Department of Defense.

UW/Fred Hutch Cancer Consortium members Dr. Peter Nelson, Dr. Daniel Lin, Dr. William J Ellis, Dr. Yingye Zheng, and Dr. Colin Pritchard contributed to this research.

Brady L, Newcomb LF, Zhu K, Zheng Y, Boyer H, Sarkar N, McKenney JK, Brooks JD, Carroll PR, Dash A, Ellis WJ, Filson CP, Gleave ME, Liss MA, Martin F, Morgan TM, Thompson IM, Wagner AA, Pritchard CC, Lin DW, Nelson PS. Germline mutations in penetrant cancer predisposition genes are rare in men with prostate cancer selecting active surveillance. Cancer Med. 2022 Apr 25. doi: 10.1002/cam4.4778. Epub ahead of print. PMID: 35467778.