Abstract
BackgroundRenal cell carcinoma (RCC) is a disease of genomic alterations, of which the complete panorama helps in facilitating molecular-guided therapy. Germline mutation profiles and associated somatic and clinical characteristics remains unexplored in Chinese RCC patients.MethodsWe retrospectively profiled the germline and somatic mutations of 322 unselected RCC patients using a panel consisting of 808 cancer-related genes. We categorized patients into three groups based on germline mutation status and compared the somatic mutation spectrum among different groups.ResultsApproximately one out of ten (9.9%) RCC patients were identified to carry pathogenic/likely pathogenic (P/LP) germline variants (PGVs), of which 3.7% were variants in syndromic RCC-associated genes and 6.2% were other cancer-predisposition genes. The most common PGV was found in VHL (2.2%), followed by FH, TSC2, ATM, BRCA1, NBN, and BLM (0.6% each). Young patients (≤46 years) were more likely to harbor PGVs. Variants in syndromic RCC-associated genes were predominant identified in young patients, while variants in other cancer-predisposition genes were found in patients >46 years more frequently. Furthermore, 39.3% (11/28) of patients carrying PGVs were detected to have somatic “second hit” events. Germline and somatic sequencing, including microsatellite instability (MSI) status analysis, provided potentially actionable therapeutic targets in 17.1% of patients in the whole cohort.ConclusionsOur results revealed that approximately 10% of RCC patients carried clinically significant germline mutations. Current guidelines recommendation for genetic testing seemed not sensitive enough to identify patients with hereditary RCC susceptibility. It is rational to promote genetic testing in RCC population.
Highlights
Renal cell carcinoma (RCC) is one of the most common malignancies worldwide, which is estimated to cause over 13000 and 25600 deaths per year in the United States and China respectively [1, 2]
In a multi-ethnic large cohort study, pathogenic/likely pathogenic (P/LP) variants were found in 17% of 1829 patients and FH variants were found to be significantly enriched in patients of African ancestry [9]
The present study evaluated germline mutations of cancerassociated genes in Chinese RCC patients unselected for inherited syndrome risk factors, including age of onset, presence of multifocal lesions, or family history et al We used nextgeneration sequencing (NGS) to identify the frequency of pathogenic/likely pathogenic germline variants (PGVs) in cancer-associated genes
Summary
Renal cell carcinoma (RCC) is one of the most common malignancies worldwide, which is estimated to cause over 13000 and 25600 deaths per year in the United States and China respectively [1, 2]. 3-17% of RCC is considered to have hereditary susceptibility [5,6,7,8,9], the reported germline mutation frequency in RCC patients can be affected by different ethnicities, pathological subtypes, clinical stages of the disease and selection criteria for study population. Deleterious germline mutations were detected in 9.5% of Chinese patients with early-onset RCC [11]. The prevalence of hereditary susceptibility in the Chinese kidney cancer population needs to be carefully clarified in detail. Identification of germline susceptibility is crucial for risk assessment, early detection and treatment decisions for RCC patients and their close relatives. Germline mutation profiles and associated somatic and clinical characteristics remains unexplored in Chinese RCC patients
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