title: Multilayered molecular profiling supported the monoclonal origin of metastatic renal cell carcinoma.
abstract: 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.
authors: Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, China; National-Regional Key Technology Engineering Laboratory for Clinical Application of Cancer Genomics, Shenzhen Key Laboratory of Genitourinary Tumor, Shenzhen, China.
authors: Yi
authors: Y
authors: Huang
authors: Shengjie
authors: S
authors: Gao
authors: Song
authors: S
authors: Wu
authors: Pengfei
authors: P
authors: Song
authors: Xiaojuan
authors: X
authors: Sun
authors: Xueda
authors: X
authors: Hu
authors: Shiqiang
authors: S
authors: Zhang
authors: Yuan
authors: Y
authors: Yu
authors: Jialou
authors: J
authors: Zhu
authors: Cailing
authors: C
authors: Li
authors: Zike
authors: Z
authors: Qin
authors: Liangfu
authors: L
authors: Xie
authors: Qiong
authors: Q
authors: Yao
authors: Aifa
authors: A
authors: Tang
authors: Zesong
authors: Z
authors: Li
authors: Guangwu
authors: G
authors: Guo
authors: Shengqing
authors: S
authors: Wan
authors: Pei
authors: P
authors: Dong
authors: Liang
authors: L
authors: Sun
authors: Weiping
authors: W
authors: Li
authors: Daping
authors: D
authors: Wang
authors: Yaoting
authors: Y
authors: Gui
authors: Huanming
authors: H
authors: Yang
authors: Fangjian
authors: F
authors: Zhou
authors: Xiuqing
authors: X
authors: Zhang
authors: Zhiming
authors: Z
authors: Cai
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000556:secondary; D063646:Carcinogenesis / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D059472:Exome / Q000235:genetics; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009362:Neoplasm Metastasis / Q000235:genetics*; D009360:Neoplastic Cells, Circulating
keywords: metastasis; renal cancer; tumor evolution