以下内容原文发布于AACR官网的NEWSROOM , 中文内容仅做参考。
4月8日-13日举行的2022年AACR年会上展示的数据表明，将可导致前列腺特异性抗原（PSA）水平正常变化但与癌症无关的遗传因素纳入分析可提高PSA筛查的准确性。
“PSA水平是用于前列腺癌诊断的主要生物标志物。这一检测项目目前已得到广泛应用，但尚未纳入（前列腺癌）正式筛查计划中，”加州大学旧金山分校流行病学与生物统计学系博士后Linda Kachuri在她的演讲中介绍道，“由于PSA检测的敏感性和特异性较差，虽然其一般可用于检测潜在疾病，但可能在部分情况下遗漏侵袭性肿瘤病例。”
原文如下：
The accuracy of prostate-specific antigen (PSA) screening for prostate cancer could be improved by accounting for genetic factors that cause changes in PSA levels that are not associated with cancer, according to data presented during the AACR Annual Meeting 2022, held April 8-13.
“PSA levels represent the main diagnostic biomarker for prostate cancer. This test is widely used but not currently implemented as part of a formal screening program,” said presenter Linda Kachuri, MPH, PhD, a postdoctoral scholar in the Department of Epidemiology & Biostatistics at the University of California, San Francisco. “Because of its poor sensitivity and specificity, PSA testing can often lead to detecting latent disease or, in some cases, missing aggressive tumors.”
Kachuri and colleagues studied whether certain genetic factors could cause variations in the levels of PSA that are not attributable to cancer, and whether accounting for such normal variations could help improve the diagnostic potential of this biomarker. They conducted a large genome-wide association study of PSA in more than 95,000 men without diagnosed prostate cancer using data from five cohorts from the United States, United Kingdom, and Sweden.
The researchers identified 128 PSA-associated variants, including 82 new ones, which they used to build a polygenic score for PSA levels. The polygenic score provided a combined measure of each individual’s genetic predisposition to high PSA levels.
The authors validated the polygenic score by applying it to two cohorts of individuals enrolled in the PCPT and SELECT cancer prevention trials, involving 5,737 and 22,247 participants, respectively. The PSA polygenic score accounted for 7.3 percent and 8.7 percent of the variation in baseline PSA levels in the PCPT cohort and the SELECT cohort, respectively. Importantly, it was not associated with prostate cancer in either of the cohorts, confirming that it reflects benign PSA variation.
To examine whether the polygenic score could improve the detection of clinically significant disease and reduce overdiagnosis, the researchers applied the polygenic score correction factor to a real-world Kaiser Permanente cohort and estimated the effects of this adjustment on the PSA thresholds used for biopsy referrals.
“We adjusted each person’s PSA values based on his unique polygenic score,” explained Kachuri. “PSA values personalized in this way are more likely to reveal changes in PSA due to prostate cancer because they are corrected for the influence of inherited genetics.”
Applying a correction to the PSA levels appeared to improve the accuracy of the referral decisions, as it would have avoided 20 percent of negative biopsies in non-prostate cancer cases. It would have also resulted in 15.7 percent fewer biopsies in cases with low-grade disease, which accounted for 71 percent of all patients who would have avoided a biopsy. Furthermore, in both the PCPT and the SELECT cohorts, genetically adjusted PSA was more robustly associated with aggressive prostate cancer than unadjusted PSA levels.
“We showed that genetic correction of PSA levels has the potential to both reduce unnecessary biopsies and improve our ability to detect tumors with a more aggressive profile,” commented Kachuri. “We hope that our findings represent a step forward in developing informative screening guidelines and reducing the diagnostic gray area in PSA screening.”
While the study was very large, almost 90 percent of the participants were of predominantly European ancestry. According to Kachuri, this represents a key limitation because the composition of the study doesn’t reflect the patient population impacted by prostate cancer. “We hope to be able to share findings soon from our efforts to conduct larger and more diverse studies of PSA genetics,” she said.
This study was funded by the National Cancer Institute (R01CA241410). John S. Witte, PhD, principal investigator on the study, is a non-employee cofounder of Avail Bio and a consultant for Sanofi.
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