Multilayered molecular profiling supported the monoclonal origin of metastatic renal cell carcinoma

Primary renal cell carcinomas (pRCCs) have a high degree of intratumoral heterogeneity and are composed of multiple distinct subclones. However, it remains largely unknown that whether metastatic renal cell carcinomas (mRCCs) also have startling intratumoral heterogeneity or whether development of m...

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Bibliographic Details
Published in:International journal of cancer 2014-07, Vol.135 (1), p.78-87
Main Authors: Huang, Yi, Gao, Shengjie, Wu, Song, Song, Pengfei, Sun, Xiaojuan, Hu, Xueda, Zhang, Shiqiang, Yu, Yuan, Zhu, Jialou, Li, Cailing, Qin, Zike, Xie, Liangfu, Yao, Qiong, Tang, Aifa, Li, Zesong, Guo, Guangwu, Wan, Shengqing, Dong, Pei, Sun, Liang, Li, Weiping, Wang, Daping, Gui, Yaoting, Yang, Huanming, Zhou, Fangjian, Zhang, Xiuqing, Cai, Zhiming
Format: Article
Language:English
Subjects:
Biological and medical sciences
Brain Neoplasms - genetics
Brain Neoplasms - secondary
Cancer
Carcinogenesis - genetics
Carcinoma, Renal Cell - genetics
Carcinoma, Renal Cell - metabolism
DNA fingerprinting
DNA sequencing
Exome - genetics
Gene Expression Profiling
Genetic distance
Genetic Heterogeneity
Genome, Human
Genomes
High-Throughput Nucleotide Sequencing
Humans
Kidney cancer
Kidneys
Medical research
Medical sciences
Metastases
Metastasis
Molecular biology
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Neoplasm Metastasis - genetics
Neoplastic Cells, Circulating
Nephrology. Urinary tract diseases
Oncology
renal cancer
Renal cell carcinoma
Rodents
Transcriptomes
Tumor cells
tumor evolution
Tumors
Tumors of the urinary system
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Summary:Primary renal cell carcinomas (pRCCs) have a high degree of intratumoral heterogeneity and are composed of multiple distinct subclones. However, it remains largely unknown that whether metastatic renal cell carcinomas (mRCCs) also have startling intratumoral heterogeneity or whether development of mRCCs is due to early dissemination or late diagnosis. To decipher the evolution of mRCC, we analyzed the multilayered molecular profiles of pRCC, local invasion of the vena cava (IVC), and distant metastasis to the brain (MB) from the same patient using whole‐genome sequencing, whole‐exome sequencing, DNA methylome profiling, and transcriptome sequencing. We found that mRCC had a lower degree of heterogeneity than pRCC and was likely to result from recent clonal expansion of a rare, advantageous subclone. Consequently, some key pathways that are targeted by clinically available drugs showed distinct expression patterns between pRCC and mRCC. From the genetic distances between different tumor subclones, we estimated that the progeny subclone giving rise to distant metastasis took over half a decade to acquire the full potential of metastasis since the birth of the subclone that evolved into IVC. Our evidence supported that mRCC was monoclonal and distant metastasis occurred late during renal cancer progression. Thus, there was a broad window for early detection of circulating tumor cells and future targeted treatments for patients with mRCCs should rely on the molecular profiles of metastases. What's new? While much is known about the intratumoral heterogeneity of primary renal cell carcinomas, the clonal composition of metastatic tumors remains unclear. To explore whether metastatic renal cell carcinomas stem from early dissemination or late diagnosis, the authors characterized the genetic, epigenetic and transcriptional profiles of multiple metastatic tumors from the same patient. They show that the metastatic tumor itself has a low degree of intratumoral heterogeneity, but likely results from the recent clonal expansion of a rare, advantageous subclone arising late within the primary tumor. This study highlights the therapeutic potential of early detection and molecular profiling of metastatic kidney tumors.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.28654