Abstract
Clear-cell renal cell carcinoma (ccRCC) is the most common and lethal subtype of kidney cancer. VHL and PBRM1 are the top two significantly mutated genes in ccRCC specimens, while the genetic mechanism of the VHL/PBRM1-negative ccRCC remains to be elucidated. Here we carried out a comprehensive analysis of single-cell genomic copy number variations (CNVs) in VHL/PBRM1-negative ccRCC. Genomic CNVs were identified at the single-cell level, and the tumor cells showed widespread amplification and deletion across the whole genome. Functional enrichment analysis indicated that the amplified genes are significantly enriched in cancer-related signaling transduction pathways. Besides, receptor protein tyrosine kinase (RTK) genes also showed widespread copy number variations in cancer cells. Our studies indicated that the genomic CNVs in RTK genes and downstream signaling transduction pathways may be involved in VHL/PBRM1-negative ccRCC pathogenesis and progression, and highlighted the role of the comprehensive investigation of genomic CNVs at the single-cell level in both clarifying pathogenic mechanism and identifying potential therapeutic targets in cancers.
Highlights
Renal cell carcinoma (RCC) is one kind of kidney cancer, accounting for nearly 300,000 new cancer cases per year worldwide (Hakimi et al, 2013)
The genomic copy number variations (CNVs) were called by using Control-FREEC (Boeva et al, 2012)
Some deleted loci were found both in normal and cancer cells, which may be caused by multiple displacement amplification (MDA) amplification (Yilmaz and Singh, 2012) or exome capture during DNA library preparation
Summary
Renal cell carcinoma (RCC) is one kind of kidney cancer, accounting for nearly 300,000 new cancer cases per year worldwide (Hakimi et al, 2013). RCC includes several histological subtypes, among which clear cell renal cell carcinoma (ccRCC) is the most common and lethal one (Hakimi et al, 2016). VHL and PBRM1, located within the chromosome 3p25 and 3p21 segments, are the top two significantly mutated genes in ccRCC (Sato et al, 2013). 90% of ccRCCs undertake the deletion on chromosome 3p, leading to a very high frequency of VHL inactivation (Gnarra et al, 1994). VHL and PBRM1 are mutated in about 50 and 41% of sporadic ccRCC, respectively (Kaelin, 2004; Varela et al, 2011). Little is known about the genetic mechanisms in VHL/PBRM1negative ccRCC
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