NEW YORK – Due to the lack of diversity in genetics research, commercially available germline genetic tests used to gauge inherited cancer risk and inform care may not be applicable for Black South African men with advanced prostate cancer, a new study in the Journal of the National Comprehensive Cancer Network suggests.
The findings, which demonstrate how currently used tests may not be gauging pathogenic variants specific to patients with sub-Saharan ancestry, are especially concerning given the prostate cancer mortality rates in this patient population. In sub-Saharan Africa, prostate cancer death rates in 2020 were 2.5 times higher than those observed in the US population, according to one estimate. For available tests to accurately assess sub-Saharan African prostate cancer patients' inherited genetic risk for the disease and inform prognosis and personalized treatment options, they must detect germline variants associated with prostate cancer in this population. As the new research shows, this currently is not the case.
Researchers from the University of Sydney and University of Pretoria in South Africa, led by Kazzem Gheybi and Vanessa Hayes, sought to determine whether men with African ancestry from the sub-Saharan region of the continent might benefit from wider or ancestry-specific germline testing recommendations.
"Although men of African ancestry have the highest incidence rates for aggressive prostate cancer and associated death globally, due to lack of available data, no tailored testing criteria have been established for such populations at increased risk," Gheybi, a postdoctoral researcher at the University of Sydney and the lead author of the JNCCN study, said in a statement.
Gheybi's team genetically tested 113 Black South African patients with advanced prostate cancer, deeply sequencing 20 genes most commonly included in germline testing panels. Most of these patients would be considered to have prostate cancers at high risk of progression or recurrence according to international scoring standards, prostate-specific antigen (PSA) levels, or their family cancer histories.
Researchers used Illumina's HiSeq X Ten or NovaSeq tests to sequence patients' blood samples, which detected 21,899 single-nucleotide variants, 4,626 small insertions and deletions, and 73 structural variants across these 20 genes. After removing the common variants, researchers initially flagged 38 predicted deleterious variants. Further annotation with the help of the public variant database ClinVar, guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, and a computational tool called Cancer Genome Interpreter, Gheybi and colleagues settled on 17 variants — four pathogenic variants in ATM, BRCA2, CHEK2, and TP53, and 13 potentially oncogenic variants — in 12 genes.
Of the 17.7 percent of the prostate cancer patients in the study with known or potentially deleterious variants, the vast majority — 75 percent or 90 percent depending on the clinical scoring system used — presented with advanced disease. Five patients had a known pathogenic variant, CHEK2 p.Arg95Ter, but other pathogenic variants had never been seen before.
"Noting that 10.2 percent of the predicted deleterious variants/structural variants were novel, we find that the bias toward variants of uncertain pathogenic significance, together with the identification of a single known prostate cancer pathogenic variant, CHEK2 p.Arg95Ter, further emphasizes the need for further African-specific investigation to establish tailored prostate cancer screening panels," wrote Gheybi and colleagues in their paper.
Importantly, researchers found rare cancer-causing variants in 5.6 percent of the study population. This "was significantly lower than the established rate of 11.8 percent [rare cancer-causing variants] for non-African patients with confirmed metastatic prostate cancer," the authors wrote in a statement, noting that this suggests "decreased sensitivity of current gene panels for risk assessment in this patient population."
Samuel Washington, assistant professor of urology, epidemiology, and biostatistics at the University of California, San Francisco, added in a statement that this paper highlights the "poor clinical utility" of the most widely used germline panels, largely because test developers didn't include Black South African patients when developing these assays. (Washington wasn't involved in the study.)
Hayes, who co-led the study with Gheybi, suggested test developers establish a research arm specifically focused on improving inclusion of African patients in research studies that support development of their assays. "We need to move away from the one-size-fits-all model for prostate cancer care," Hayes said. "African solutions should address African-relevant disparities in prostate cancer outcomes."