Integrative Analysis of Germline Rare Variants in Clear and Non-clear Cell Renal Cell Carcinoma.
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Abstract | BACKGROUND AND OBJECTIVE: Previous germline studies on renal cell carcinoma (RCC) have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification, which might have led to an inaccurate estimation of genetic risk. Here, we aim to analyze the major germline drivers of RCC risk and clinically relevant but underexplored germline variant types.METHODS: We first characterized germline pathogenic variants (PVs), cryptic splice variants, and copy number variants (CNVs) in 1436 unselected RCC patients. To evaluate the enrichment of PVs in RCC, we conducted a case-control study of 1356 RCC patients ancestry matched with 16 512 cancer-free controls using approaches accounting for population stratification and histological subtypes, followed by characterization of secondary somatic events.KEY FINDINGS AND LIMITATIONS: Clear cell RCC patients ( = 976) exhibited a significant burden of PVs in compared with controls (odds ratio [OR]: 39.1, = 4.95e-05). Non-clear cell RCC patients ( = 380) carried enrichment of PVs in (OR: 77.9, = 1.55e-08) and (OR: 1.98e11, = 2.07e-05). In a -focused analysis with European participants, clear cell RCC ( = 906) harbored nominal enrichment of low-penetrance variants-p.Ile157Thr (OR: 1.84, = 0.049) and p.Ser428Phe (OR: 5.20, = 0.045), while non-clear cell RCC ( = 295) exhibited nominal enrichment of loss of function PVs (OR: 3.51, = 0.033). Patients with germline PVs in exhibited significantly earlier age of cancer onset than patients without germline PVs (mean: 46.0 vs 60.2 yr, < 0.0001), and more than half had secondary somatic events affecting the same gene ( = 10/15, 66.7%). Conversely, PV carriers exhibited a similar age of onset to patients without germline PVs (mean: 60.1 vs 60.2 yr, = 0.99), and only 30.4% carried somatic events in ( = 7/23). Finally, pathogenic germline cryptic splice variants were identified in and and pathogenic germline CNVs were found in 18 patients, including CNVs in , , and .CONCLUSIONS AND CLINICAL IMPLICATIONS: This analysis supports the existing link between several RCC risk genes and RCC risk manifesting in earlier age of onset. It calls for caution when assessing the role of due to the burden of founder variants with varying population frequency. It also broadens the definition of the RCC germline landscape of pathogenicity to incorporate previously understudied types of germline variants.PATIENT SUMMARY: In this study, we carefully compared the frequency of rare inherited mutations with a focus on patients' genetic ancestry. We discovered that subtle variations in genetic background may confound a case-control analysis, especially in evaluating the cancer risk associated with specific genes, such as . We also identified previously less explored forms of rare inherited mutations, which could potentially increase the risk of kidney cancer. |
Year of Publication | 2024
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Journal | European urology open science
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Volume | 62
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Pages | 107-122
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Date Published | 04/2024
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ISSN | 2666-1683
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DOI | 10.1016/j.euros.2024.02.006
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PubMed ID | 38496821
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