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Published on: December 28, 2015
Differential VHL Mutation Patterns in Bilateral Clear Cell RCC Distinguishes Between Independent Primary Tumors and
Cathy D Vocke1, Christopher J Ricketts1, Adam R Metwalli1
1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Objective:
To evaluate whether bilateral, multifocal clear cell renal cell carcinoma (ccRCC) patients can be differentiated by VHL mutation analysis into cases that represent either multiple independently arising primary tumors, or a single primary tumor which has spread ipsilaterally as well as to the contralateral kidney. The nature of kidney cancer multifocality outside of known hereditary syndromes is as yet poorly understood.
Materials And Methods:
DNA from multiple tumors per patient were evaluated for somatic VHL gene mutation and hypermethylation. A subset of tumors with shared VHL mutations were analyzed with targeted, next-generation sequencing assays.
Results:
This cohort contained 5 patients with multiple tumors that demonstrated a shared somatic VHL mutation consistent with metastatic spread including to the contralateral kidney. In several cases this was substantiated by additional shared somatic mutations in ccRCC-associated genes. In contrast, the remaining 14 patients with multiple tumors demonstrated unique, unshared VHL alterations in every analyzed tumor, consistent with independently arising kidney tumors. None of these latter patients showed any evidence of local spread or distant metastasis.
Conclusion:
The spectrum of VHL alterations within evaluated bilateral, multifocal ccRCC tumors from a single patient can distinguish between multiple independent tumor growth and metastasis. This can be performed using currently available clinical genetic tests and will improve the accuracy of patient diagnosis and prognosis, as well as informing appropriate management.
Insights
VHL gene mutation analysis can distinguish between independent kidney tumors and metastasis in clear cell renal cell carcinoma (ccRCC) patients. This genetic testing improves diagnosis and management for multifocal ccRCC.
Area of Science:
- Oncology
- Genetics
- Nephrology
Background:
- The origin of multifocal clear cell renal cell carcinoma (ccRCC) is often unclear, especially outside of hereditary syndromes.
- Distinguishing between independent primary tumors and metastatic spread is crucial for patient management.
Purpose of the Study:
- To determine if VHL gene mutation analysis can differentiate bilateral, multifocal ccRCC into independent primaries versus metastatic disease.
- To assess the utility of genetic testing in understanding ccRCC multifocality.
Main Methods:
- Somatic VHL gene mutation and hypermethylation analysis were performed on multiple tumors from ccRCC patients.
- Targeted next-generation sequencing was used for tumors with shared VHL mutations.
Main Results:
- Five patients showed shared VHL mutations, indicating metastatic spread, often confirmed by additional shared mutations.
- Fourteen patients had unique VHL alterations in each tumor, consistent with independent primary tumors and no evidence of spread.
Conclusions:
- VHL gene alterations can reliably distinguish between metastatic ccRCC and independently arising multifocal tumors.
- This genetic analysis, using standard clinical tests, enhances diagnostic accuracy, prognosis, and treatment strategies for ccRCC.
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