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Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Clear Cell Type A and B Molecular Subtypes in Metastatic Clear Cell Renal Cell Carcinoma: Tumor Heterogeneity and
Daniel J Serie1, Richard W Joseph2, John C Cheville3
1Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
Background:
Intratumor molecular heterogeneity has been reported for primary clear cell renal cell carcinoma (ccRCC) tumors; however, heterogeneity in metastatic ccRCC tumors has not been explored.
Objective:
To evaluate intra- and intertumor molecular heterogeneity in resected metastatic ccRCC tumors.
Design, Setting, And Participants:
We identified 111 patients who had tissue available from their primary tumor and at least one metastasis. ClearCode34 genes were analyzed for all tumors.
Outcome Measurements And Statistical Analysis:
Primary and metastatic tumors were classified as clear cell type A (ccA) or B (ccB) subtypes. Logistic and Cox regression were used to evaluate associations with pathologic features and survival.
Results And Limitations:
Intratumor heterogeneity of ccA/ccB subtypes was observed in 22% (95% confidence interval [CI] 3-60%) of metastatic tumors. Subtype differed across longitudinal metastatic tumors from the same patient in 23% (95% CI 10-42%) of patients and across patient-matched primary and metastatic tumors in 43% (95% CI 32-55%) of patients. Association of subtype with survival was validated in primary ccRCC tumors. The ccA/ccB subtype in metastatic tumors was significantly associated with metastatic tumor location, metastatic tumor grade, and presence of tumor necrosis. A limitation of this study is that we only analyzed patients who had both a nephrectomy and metastasectomy.
Conclusions:
Approximately one quarter of metastatic tumors displayed intratumor heterogeneity; a similar rate of heterogeneity was observed across longitudinal metastatic tumors. Thus, for biomarker studies it is likely adequate to analyze a single sample per metastatic tumor provided that pathologic review is incorporated into the study design. Subtypes across patient-matched primary and metastatic tumors differed 43% of the time, suggesting that the primary tumor is not a good surrogate for the metastatic tumor.
Patient Summary:
Primary and secondary/metastatic cancers of the kidney differed in nearly one half of ccRCC patients. The pattern of this relationship may affect tumor growth and the most suitable treatment.
Insights
Metastatic clear cell renal cell carcinoma (ccRCC) tumors show significant molecular heterogeneity, with nearly half differing from primary tumors. This suggests primary tumor analysis is insufficient for guiding metastatic ccRCC treatment.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Intratumor molecular heterogeneity is established in primary clear cell renal cell carcinoma (ccRCC).
- Heterogeneity within metastatic ccRCC tumors remains largely unexplored.
- Understanding this heterogeneity is crucial for effective cancer treatment strategies.
Purpose of the Study:
- To investigate intra- and intertumor molecular heterogeneity in resected metastatic ccRCC.
- To compare molecular subtypes (ccA/ccB) between primary and metastatic ccRCC tumors.
- To assess the clinical implications of molecular heterogeneity in ccRCC metastasis.
Main Methods:
- Analysis of 111 patients with matched primary tumor and metastasis tissue samples.
- Classification of primary and metastatic tumors into clear cell type A (ccA) or B (ccB) subtypes.
- Statistical analysis using logistic and Cox regression to correlate subtypes with clinical features and survival.
Main Results:
- Intratumor heterogeneity of ccA/ccB subtypes was found in 22% of metastatic tumors.
- Subtype differences were observed in 23% of longitudinal metastatic tumors and 43% of patient-matched primary and metastatic tumors.
- ccA/ccB subtype in metastases correlated significantly with tumor location, grade, and necrosis.
Conclusions:
- Approximately one quarter of metastatic ccRCC tumors exhibit intratumor heterogeneity.
- The primary tumor is not a reliable surrogate for the metastatic tumor due to frequent subtype differences.
- Single-sample analysis of metastatic tumors may suffice for biomarker studies if pathological review is included.
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