Nagpal Chitrakshi, Divakar Mohit Kumar, Baskarane Hemavathi, Tansir Ghazal, Jain Rishabh, Sharma Aparna, Sahoo Ranjit Kumar, Bakhshi Sameer, Gupta Ishaan, Minocha Shilpi, Kumar Saran, Tanwar Pranay, Nayak Brusabhanu, Nayyar Rishi, P Sridhar, Kaushal Seema, Ojha Sanjay, Nangla Parnika, Haresh Kunhi Parambath, Seth Amlesh, Batra Atul
Department of Medical Oncology, Dr B.R.A. IRCH, AIIMS, New Delhi, India.
Department of Medical Oncology, National Cancer Institute, AIIMS, Jhajjar, India.
JCO Glob Oncol. 2025 Jul;11:e2500137. doi: 10.1200/GO-25-00137. Epub 2025 Jul 11.
Genetic predisposition plays an important role in the pathogenesis of renal cell carcinoma. The prevalence of pathogenic/likely pathogenic (P/LP) in patients with renal cell cancer (RCC) is highly variable, and close to 40% of these can be missed with the current testing guidelines.
This is a prospective study of all patients with metastatic RCC unselected for high-risk features, registered at our center between September 2023 and August 2024. Baseline clinicopathologic details were collected, and germline whole-exome sequencing was done on blood samples. Our aim was to determine the frequency of germline mutations in an unselected cohort of patients with metastatic RCC. Germline P/LP variants were visualized using cBioPortal, and chi-square and Mann-Whitney tests were used to identify differences in patients with/without these variants.
Out of 140 participants, P/LP variants in cancer-predisposition genes were detected in 20%, and 4.2% were in RCC-associated genes. was the most common RCC-associated variant (2.8%), while , , and (1.4% each) were the commonest non-RCC-associated variants. RCC-associated genes were more frequent in non-clear cell histology ( = .02); there was no difference in cancer predisposition genes on the basis of age, histology, or sex.
Patients with advanced RCC have a high prevalence of germline variants in both RCC-associated and non-RCC cancer-specific genes irrespective of the high-risk genetic features, signifying the importance of a baseline genetic evaluation in all patients with advanced RCC as it has implications for family screening and, in future, selection of therapy.
遗传易感性在肾细胞癌的发病机制中起重要作用。肾细胞癌（RCC）患者中致病性/可能致病性（P/LP）变异的发生率差异很大，按照当前检测指南，近40%的此类变异可能会被漏检。
这是一项对所有未因高危特征而被筛选的转移性RCC患者的前瞻性研究，这些患者于2023年9月至2024年8月在我们中心登记。收集了基线临床病理细节，并对血样进行了种系全外显子测序。我们的目的是确定未筛选的转移性RCC患者队列中种系突变的频率。使用cBioPortal可视化种系P/LP变异，并使用卡方检验和曼-惠特尼检验来识别有/无这些变异的患者之间的差异。
在140名参与者中，20%的患者在癌症易感基因中检测到P/LP变异，4.2%的患者在RCC相关基因中检测到变异。 是最常见的RCC相关变异（2.8%），而 、 、 和 （各1.4%）是最常见的非RCC相关变异。RCC相关基因在非透明细胞组织学类型中更常见（ = .02）；在年龄、组织学类型或性别方面，癌症易感基因没有差异。
晚期RCC患者无论有无高危遗传特征，在RCC相关和非RCC癌症特异性基因中种系变异的发生率都很高，这表明对所有晚期RCC患者进行基线基因评估很重要，因为这对家族筛查以及未来的治疗选择都有影响。
