Clinical, Pathologic, and Genetic Correlates of Nuclear Grade in von Hippel-Lindau-associated Renal Cell Carcinoma - Beyond the Abstract
VHL-associated Renal Cell Carcinoma (RCC) nuclear grade is well known to correlate with risk of metastasis, though no previous analyses have been done on risk factors for higher pathologic grade in VHL-associated RCC. In this study, we sought to identify clinical, pathologic, and genetic correlates of high-grade disease in VHL-associated RCC. We found that older patient age, larger tumors, ipsilateral partial nephrectomy history, and frameshift germline VHL variant were all associated with higher pathologic grade. On the other hand, germline partial deletion and splice variants were negatively associated with pathologic grade.
Regarding prior partial nephrectomy, some previous literature suggests that remnant cancer cells from past operations may result in the accumulation of oncogenic factors, increasing the risk for high-grade pathology. A study on sporadic bilateral multifocal RCC patients identified contralateral metastatic versus independent renal tumors via NGS of each tumor for repeated vs unique genetic variants. Future studies may consider a similar analysis of recurrent ipsilateral RCC post-partial nephrectomy (PN) to better understand if tumors occurring post-PN are independent occurrences or remnant continuations.
While frameshift mutations were associated with high-grade disease, nonsense variants, which are generally similarly deleterious, are not. This difference may be the result of differences in the location of the variant within the VHL gene, or that nonsense variants may produce versions of the VHL protein that are removed by nonsense-mediated decay, while frameshift variants could produce inactive chimeric or abnormal proteins that generate more cellular stress than other variant types. Additionally, partial deletion germline VHL variants, which we found to be associated with lower-grade pathology, have been found in other studies to correlate with older age of RCC onset, suggesting that patients with partial deletion VHL variants may experience both clinically and pathologically less aggressive disease.
Written by: Mark W. Ball, MD FACS, Associate Research Physician (Associate Professor), NCI Liason to Surgical Administrative Committee/SAC Co-Chair, Associate Program Director, Urologic Oncology Fellowship, Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD
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