Renal cell carcinoma susceptibility

A paper by Purdue et al. recently caught my eye, which highlights the power of collaboration within the scientific community, and also sheds more light on the factors affecting renal cell carcinoma (RCC) risk.

This large, international consortium conducted a genome-wide association study of RCC from the combined data-sets of thousands of individuals from both the United States and Europe. This meta-analysis identified two RCC susceptibility loci on chromosomes 2 and 11, as well as implicating another on chromosome 12.

The finding on chromosome 2 is notable because the candidate gene in this region, EPAS1, has previously been associated with RCC. EPAS1 encodes hypoxia-inducible factor 2α (HIF-2α), which is known to be aberrantly regulated in VHL syndrome, with recent work also linking it to BHD syndrome (Preston et al., 2010).

In contrast, the locus on chromosome 11 contains no characterised genes, but what is particularly interesting is that there are susceptibility loci for both breast and prostate cancer nearby (Eeles et al., 2008; Thomas et al., 2008; Turnbull et al., 2010). This finding suggests that this region is involved in cancer progression, and additional studies are certainly necessary in order to fully decipher its role.

The third locus on chromosome 12 also showed a genome-wide association, however, this result was not significant when the experiment was independently replicated. The candidate gene in this region is known as scavenger receptor class B, member 1 (SCARB1). This gene encodes a cell-surface receptor that binds to high-density lipoprotein cholesterol and mediates its uptake. The role of SCARB1 in cancer biology is not well defined, and further work will also help to delineate its role in RCC. Considering FLCN has now been linked to HIF signalling by Preston et al., could it also be involved in cholesterol metabolism somehow?

Lastly, Purdue et al. assessed the significance of age, gender, and risk factors, such as body mass index, smoking status and history of diagnosed hypertension, and saw that men had a slightly higher EPAS1-related risk of RCC. Additionally, the authors also observed that both former and current smokers carrying variants of EPAS1 seemed to be at greater risk of RCC than non-smokers, which further highlights the dangers of smoking.

In conclusion, the discovery of additional susceptibility loci is important as it should lead to further advances in the understanding of RCC. In addition, new links to FLCN could also be discovered, which could help to further unravel its role within BHD syndrome.

  • Eeles RA et al. (2008) Multiple newly identified loci associated with prostate cancer susceptibility. Nat. Genet. 40, 316–321.
  • Preston RS et al. (2010) Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene. Nov 8 (Epub ahead of print).
  • Purdue MP et al. (2010) Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3. Nat Genet. Dec 5 (Epub ahead of print).
  • Thomas G et al. (2008) Multiple loci identified in a genome-wide association study of prostate cancer. Nat. Genet. 40, 310–315.
  • Turnbull C et al. (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nat. Genet. 42, 504–507.

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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