NEW YORK (GenomeWeb News) – A new study in the British Journal of Cancer suggests it could be possible to preemptively find men at risk of developing aggressive prostate cancer.
An Institute of Cancer Research-led team did targeted sequencing on 22 tumor suppressor genes in blood samples from nearly 200 men belonging to prostate cancer-prone families, identifying loss-of-function mutation in eight genes that were especially frequent amongst prostate cancer patients who developed aggressive, invasive, and/or metastatic forms of the disease. The findings are prompting optimism about finding a prognostic germline gene set.
"Although ours was a small, first-stage study, we proved that testing for known cancer mutations can pick out men who are destined to have a more aggressive form of prostate cancer," co-senior author Ros Eeles, an oncogenetics researcher affiliated with the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, said in a statement.
"We already have the technical capabilities to assess men for multiple mutations at once, so all that remains is for us to do further work to prove that picking up dangerous mutations early can save lives," Eeles added. "If so then in the future, genetic testing may be needed as part of the prostate cancer care pathway."
For their analysis, she and her colleagues focused on men with prostate cancer enrolled through the UK Genetic Prostate Cancer study who came from families with higher-than-usual prostate cancer risk and had two or more relatives with the disease.
After isolating germline, genomic DNA from blood samples for 191 such men, the researchers used an Agilent SureSelect bait library to nab 22 known tumor suppressor genes from each individual. They subsequently sequenced the gene sets to average depths of 20-fold coverage or higher over 80 percent of the targeted regions using Illumina cBOT and HiSeq 2000 instruments.
Sifting through the sequence data, the team narrowed in on 14 suspicious loss-of-function mutations — mutations subsequently verified by Sanger sequencing.
One of the mutations was ultimately deemed pathogenic. The remaining 13 loss-of-function mutations clustered in eight genes — a set that included the breast and ovarian cancer players BRCA1 and BRCA2 — and were detected in 14 of the familial prostate cancer patients.
While individuals with prostate cancer who carried such loss-of-function mutations were typically diagnosed with the disease at around the same age as those who did not, the researchers reported, the features of their cases tended to be quite different.
In particular, individuals who had one or more of the loss-of-function mutations in their germline DNA were more apt to have advanced prostate cancers, characterized nodal involvement, high-grade tumors, and/or tumor metastasis to other parts of the body.
The affected individuals also tended to have poor outcomes overall, the study authors noted, suggesting that the gene set may serve as the foundation for a future genetic test that can flag some individuals at risk of developing life-threatening forms of the disease early on.
"[M]utations to at least eight genes — and probably many more — greatly increase the risk of aggressive prostate cancer," co-senior author Zsofia Kote-Jarai, with the Institute of Cancer Research, said in a statement.
"Any future screening program would need to assess as many of these genes as possible — more than we currently look for in women at risk of breast cancer, for example."