Kurian Allison W, Gornstein Erica, Heppler Lisa, Dougherty Kali Chatham, Keller-Evans Rachel B
Stanford University School Of Medicine, Stanford, California.
Foundation Medicine, Inc., Cambridge, Massachusetts.
Cancer Res Commun. 2025 Aug 1;5(8):1282-1287. doi: 10.1158/2767-9764.CRC-25-0038.
Although recommended for a high percentage of patients with cancer, germline genetic testing is widely underutilized. Classification of pathogenic variants of potential germline origin (potential pathogenic germline variants; PPGV) from tumor comprehensive genomic profiling enables identification of patients and families with high cancer risk via an alternative pathway to clinical germline evaluation. Foundation Medicine utilizes evidence in the ClinVar database to classify PPGVs. We investigated the impact of ClinVar database evolution over a 2-year period on the classification of PPGVs across solid tumors. Substantial growth in the database (a 52.2% increase in classified variants across 24 cancer susceptibility genes) yielded a modest increase in PPGV prevalence (+0.5% across tissue and liquid biopsies combined). Whereas filtering of PPGVs because of insufficient evidence for pathogenic classification decreased across all ancestry groups, disproportionate filtering of variants in patients of South Asian (40.0%), admixed American (36.5%), and African (36.3%) versus European genomic ancestry (33.8%, P ≤ 0.01 for all comparisons) was still observed. Continuing improvements to genetic testing access and data sharing are needed to mitigate disparities.
Whereas efforts to improve data sharing have led to the growth of public genomic databases (e.g., ClinVar) over time, underutilization of genetic testing and persistent racial and ethnic disparities are limitations that continue to affect these important resources.
尽管种系基因检测被推荐用于高比例的癌症患者，但该检测的使用仍普遍不足。通过肿瘤综合基因组分析对潜在种系起源的致病变异（潜在致病种系变异；PPGV）进行分类，能够通过临床种系评估的替代途径，识别出具有高癌症风险的患者和家族。Foundation Medicine利用ClinVar数据库中的证据对PPGV进行分类。我们研究了ClinVar数据库在两年内的演变对实体瘤中PPGV分类的影响。数据库的大幅增长（24个癌症易感基因的分类变异增加了52.2%）使PPGV的患病率略有上升（组织活检和液体活检综合起来增加了0.5%）。虽然由于致病分类证据不足而对PPGV进行过滤的情况在所有祖先群体中都有所减少，但仍观察到南亚（40.0%）、美国混血（36.5%）和非洲（36.3%）基因组祖先的患者与欧洲基因组祖先的患者相比，变异过滤比例不成比例（33.8%，所有比较的P≤0.01）。需要持续改善基因检测的可及性和数据共享，以减少差异。
虽然随着时间的推移，改善数据共享的努力促使公共基因组数据库（如ClinVar）不断发展，但基因检测利用不足以及持续存在的种族和族裔差异仍然是影响这些重要资源的限制因素。
