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Multilayered molecular profiling supported the monoclonal origin of metastatic renal cell carcinoma
Author(s) -
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
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28654
Subject(s) - metastasis , renal cell carcinoma , exome sequencing , tumour heterogeneity , transcriptome , exome , cancer research , biology , genetic heterogeneity , circulating tumor cell , somatic evolution in cancer , targeted therapy , dna sequencing , gene expression profiling , cancer , medicine , pathology , gene , mutation , genetics , gene expression , phenotype
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.