Clear Cell Type A and B Molecular Subtypes in Metastatic Clear Cell Renal Cell Carcinoma: Tumor Heterogeneity and Aggressiveness

Abstract

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.

Loss of GLS2 function is essential for obtaining oncogenic functions and promotes the progression of clear cell renal cell carcinoma.

“…expression. Previous studies confirmed that the E2F pathway controlled tumor cell growth [33,34] Substantial heterogeneity was detected in ccRCC tissues in previous studies, and single biomarkers or biomarkers for predicting prognosis concluded from studies with fewer samples usually cannot meet the standard of efficacy and lead to treatment failure [37,38]. RNA-seq data from three studies were included in this study to overcome the heterogeneity, as identifying DEGs between primary and metastatic tissues would represent the prognosis better than target sequencing of single tissue.…”

Patient-specific molecular alterations are associated with metastatic clear cell renal cell cancer progressing under tyrosine kinase inhibitor therapy

“…This can be achieved with the ultra-high DNA sequencing. However, apart from large catalogues of somatic mutations in cancer including ccRCC [ 14 , 15 ] provided by international sequencing projects like TCGA and ICGC, multiregional sequencing also revealed remarkable intra-tumor heterogeneity [ 16 – 18 , 20 ] Here, we provide evidence for considerable temporal molecular heterogeneity between therapy-naïve primary tumors and metastases developing under TKI. The mutational profiles provide insights into clonal evolution occuring during tumor progression under therapy: Molecular profiling revealed recurrent genomic alterations in genes frequently altered in ccRCC [ 14 ], including VHL , SETD2 , and BAP1.…”

“…On the molecular level, ccRCC is a heterogeneous tumor displaying a broad spectrum of genetic alterations [ 14 , 15 ]. Multiregion sequencing revealed intra-tumor heterogeneity of mRCC with wide subclonal diversity [ 16 – 18 ]. Here, we report the results of a pilot study (MORE, Molecular Renal Cancer Evolution) using whole-exome sequencing (WES) of primary and biopsy tissue samples from treatment-naïve patients at baseline and after TKI treatment respectively.…”

Identification of the Role of GLS2 in the Development and Progression of Clear Cell Renal Cell Carcinoma.

“…Substantial heterogeneity was detected in ccRCC tissues in previous studies, and single prognostic biomarker or the biomarkers concluded from studies with fewer samples usually cannot meet the standard of e cacy and lead to treatment failure [35,36]. RNA-seq data from three studies were included in this study to overcome the heterogeneity, as identifying DEGs between paired primary and metastatic tissues would represent the prognosis better than target sequencing on single tissue.…”