Researchers identify 11 genes linked to aggressive prostate cancer
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Key takeaways:
- Investigators identified DNA repair pathway gene variants associated with aggressive prostate cancer.
- Future studies should help determine if new genes should be included in testing panels.
An international group revealed a list of genetic alterations associated with aggressive types of prostate cancer, in what researchers are calling the largest ever study of its kind.
The results — published in JAMA Oncology — showed associations between aggressive prostate cancer in men who harbor deleterious genetic alterations in 11 DNA repair pathway and cancer susceptibility genes.
The findings have the potential to impact the future of genetic testing panels for men with prostate cancer, as the results revealed associations with genes not included on current panels while also identifying genes on current panels not associated with aggressive prostate cancer, according to Chris Haiman, ScD, co-leader of the cancer epidemiology research program at USC Norris Comprehensive Cancer Center and AFLAC chair in cancer research at Keck School of Medicine of USC.
“The design of the panels needs to be based on strong evidence — so men are not treated based on pathogenic variants that are not associated with prostate cancer,” Haiman told Healio.
“Germline gene panel testing in prostate cancer is currently limited to a small set of genes recommended for men with a family history of cancer or with high-risk or advanced disease,” he added. “[Our findings] provide support for the role of additional DNA repair genes in aggressive disease.”
Background and methodology
Current commercially available prostate cancer gene panels include a limited number of DNA repair pathway and cancer susceptibility genes, according to study investigators.
“Additional genes have been suggested for expanded gene panels, although most lack statistical evidence of an association with aggressive disease, as previous [prostate cancer] sequencing studies have been underpowered due to small sample sizes and the rarity of pathogenic variants,” Haiman and colleagues wrote.
In response to this issue, researchers conducted a two-stage exome-sequencing genetic association study to identify rare genetic variants associated with aggressive prostate cancer.
The analysis included 17,546 men of European ancestry, with data taken from 18 epidemiologic studies across the U.S., Australia and Europe. The study population included 9,185 men (mean age, 65.1 ± 9.2 years) with aggressive prostate cancer and 8,361 men (mean age, 63.7 ± 8 years) with nonaggressive disease.
Investigators defined aggressive prostate cancer as having category T4 disease or both category T3 and a Gleason score of 8 or more at initial diagnosis, having de novo or metachronous metastatic prostate cancer, or dying of prostate cancer. They defined nonaggressive prostate cancer as localized disease (category T1 or T2) and a Gleason score of 6 or less.
Investigators focused their study on 29 DNA repair pathway and cancer susceptibility genes previously linked with prostate cancer, in addition to a group of 167 genes thought to be related to DNA damage repair.
The statistical analysis evaluated for associations between deleterious genetic variants or variants of uncertain significance and aggressive vs. nonaggressive prostate cancer, with researchers establishing what they called a “modest” threshold for significance (unadjusted P<.05).
Key findings
Rare variants of known prostate cancer risk genes — including BRCA2 (OR = 4.29; 95% CI, 3.15-5.86), ATM (OR = 2.17; 95% CI, 1.58-2.99) and NBN (OR = 1.99; 95% CI, 0.98-4.05) — showed the strongest association with aggressive prostate cancer.
Researchers also noted “nominal evidence of association” that met the predefined significance threshold for variants of three other genes, including MSH2 (OR = 3.27; 95% CI, 1.29-8.31), XRCC2 (OR = 6.24; 95% CI, 1.24-31.4) and MRE11A (OR = 0.87; 95% CI, 0.37-2.06).
The analysis identified five additional genes with evidence of greater risk for aggressive prostate cancer, including TP53 (OR = 1.47; 95% CI, 0.57-3.81), RAD51D (OR = 1.67; 95% CI, 0.41-6.78), BARD1 (OR = 1.57; 95% CI, 0.7-3.53), GEN1 (OR = 0.72; 95% CI, 0.3-1.7) and SLX4 (OR = 1.39; 95% CI, 0.65-2.96).
In total, 2.3% of patients with nonaggressive, 5.6% with aggressive and 7% with metastatic prostate cancer harbored deleterious variants of the 11 genes identified in the study.
Noted study limitations included limited power (approximately80%) to detect exome-wide significant associations with single variants or genes with ORs less than 2 and carrier frequencies less than 0.6%.
Clinical implications
The results have the potential to impact clinical practice, especially if additional genes are validated in additional larger studies and subsequently added to gene panel tests, according to Haiman.
“The data also suggest that testing could be expanded to men without aggressive prostate cancer who are at risk for disease progression if they carry a pathogenic variant,” he told Healio.
The results provide evidence that will help formulate development of next-generation genetic tests for prostate cancer, according to Alexander W. Wyatt, BSc, DPhil, associate professor in the department of urologic sciences at University of British Columbia.
Wyatt did recognize that some of the associations in the study are “relatively weak” in their statistical significance.
“As Darst and colleagues acknowledged, the research community will likely need to study hundreds of thousands more prostate cancer cases to better define the associations with rarely altered genes, to explore genes with less than 0.6% variant carrier frequency, or to explore those with small effect sizes,” he wrote in an accompanying editorial. “A key lesson from [this] study ... is that we have neither fully elucidated high-penetrance germline variants in aggressive prostate cancer, nor have we optimized the design of gene panels for clinical genetic or somatic tests.”
References:
- Darst BF, et al. JAMA Oncol. 2023;doi:10.1001/jamaoncol.2023.3482.
- Wyatt AW. JAMA Oncol. 2023;doi:10.1001/jamaoncol.2023.3352.
For more information:
Christopher A. Haiman, ScD, can be reached at University of Southern California, Keck School of Medicine, Department of Population and Public Health Sciences, 1450 Biggy St., Room 1504, Los Angeles, CA 90033; email: haiman@usc.edu.
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