Clear Cell Type A and B Molecular Subtypes in Metastatic Clear Cell Renal Cell Carcinoma: Tumor Heterogeneity and Aggressiveness.
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.
['Serie|Daniel J|DJ|', 'Joseph|Richard W|RW|', 'Cheville|John C|JC|', 'Ho|Thai H|TH|', 'Parasramka|Mansi|M|', 'Hilton|Tracy|T|', 'Thompson|R Houston|RH|', 'Leibovich|Bradley C|BC|', 'Parker|Alexander S|AS|', 'Eckel-Passow|Jeanette E|JE|']
D000368:Aged D014408:Biomarkers, Tumor D002292:Carcinoma, Renal Cell D005260:Female D020869:Gene Expression Profiling D018740:Genetic Heterogeneity D020022:Genetic Predisposition to Disease D006801:Humans D053208:Kaplan-Meier Estimate D007680:Kidney Neoplasms D016015:Logistic Models D008297:Male D059146:Metastasectomy D008875:Middle Aged D009336:Necrosis D060787:Neoplasm Grading D009361:Neoplasm Invasiveness D009367:Neoplasm Staging D009392:Nephrectomy D010641:Phenotype D011237:Predictive Value of Tests D016016:Proportional Hazards Models D012307:Risk Factors D059467:Transcriptome D016896:Treatment Outcome
Subtype ClearCode34 Biomarker Kidney Formalin-fixed paraffin-embedded tissue