A common variant at 8q24.21 is associated with renal cell cancer

Guðmundsson, Jūlı́us; Sulem, Patrick; Guðbjartsson, Daníel F.; Másson, Gísli; Pétursdóttir, Vigdís; Hardarson, Sverrir; Gudjonsson, Sigurjon A.; Johannsdottir, Hrefna; Helgadottir, Hafdís T.; Stacey, Simon; Magnússon, Ólafur Þ.; Helgason, Hannes; Panadero, Angeles; Zanden, Loes F. van der; Aben, Katja K.H.; Vermeulen, Sita H.; Oosterwijk, Egbert; Kong, Augustine; Mayordomo, J. I.; Sverrisdóttir, Ásgerður; Jónsson, Eiríkur; Guðbjartsson, Tómas; Einarsson, Guðmundur; Kiemeney, Lambertus A.; Þorsteinsdóttir, Unnur; Rafnar, Thorunn; Stefánsson, Kári

doi:10.1038/ncomms3776

Cited by 56 publications

(45 citation statements)

References 40 publications

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“…rs35252396 was not genotyped in this cohort, but we identified SNPs in the TCGA cohort (rs10111989, rs4733579 and rs17775239) that were genotyped and are in LD with rs35252396 (ref. 9). Analysis of genotype expression correlations revealed that the risk allele of SNP rs10111989 (pairwise LD with rs35252396: r 2 =0.33, D′=0.98 (ref.…”

Section: Resultsmentioning

confidence: 99%

“…Though the reasons for the marked tissue restriction of VHL-associated cancer are unclear, genetic and epigenetic factors can influence RCC development4567. In this context, genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) that are specifically associated with renal cancer susceptibility8910. So far, two genetic regions with ccRCC-related SNPs may have an impact on the VHL–HIF signalling axis.…”

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confidence: 99%

“…Recently, a novel variant rs35252396, a two base pair substitution AC>CG, has been detected on chromosome 8q24.21 (ref. 9). rs35252396 is strongly associated with renal cancer risk in Icelandic and other populations of European descent (odds ratio 1.27, P -value 5.4 × 10 −11 , minor allele frequency 0.46 in the combined analysis)9.…”

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confidence: 99%

“…9). rs35252396 is strongly associated with renal cancer risk in Icelandic and other populations of European descent (odds ratio 1.27, P -value 5.4 × 10 −11 , minor allele frequency 0.46 in the combined analysis)9. The index polymorphism is located in an intergenic and putative regulatory region interposed between the major oncogenic driver MYC (136 kb upstream) and the oncogenic long non-coding RNA PVT1 (14 kb downstream).…”

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confidence: 99%

“…However, the renal cancer-associated variant rs35252396 observed in the Icelandic population is not in linkage with any other disease-associated SNP in the 8q24.21 region ( r 2 <0.02) (ref. 9), suggesting the involvement of renal cancer-specific mechanisms in generating the predisposition.…”

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confidence: 99%

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Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer

et al. 2016

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Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel-Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins. Moreover, we demonstrate that the risk-associated polymorphisms increase chromatin accessibility and activity as well as HIF binding to the enhancer. These findings provide further evidence that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL-HIF axis and provide a functional explanation for the disease-associated effects of SNPs in ccRCC.

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Section: Resultsmentioning

confidence: 99%