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, Kote-Jarai Z, Giles GG, Olama AA, Guy M, Jugurnauth SK, Mulholland S, Leongamornlert DA, Edwards SM, Morrison J, Field HI, Southey MC, Severi G, Donovan JL, Hamdy FC, Dearnaley DP, Muir KR, Smith C, Bagnato M, Ardern-Jones AT, Hall AL, O’Brien LT, Gehr-Swain BN, Wilkinson RA, Cox A, Lewis S, Brown PM, Jhavar SG, Tymrakiewicz M, Lophatananon A, Bryant SL, UK Genetic Prostate Cancer Study Collaborators, British Association of Urological Surgeons’ Section of Oncology, UK ProtecT Study Collaborators, Horwich A, Huddart RA, Khoo VS, Parker CC, Woodhouse CJ, Thompson A, Christmas T, Ogden C, Fisher C, Jamieson C, Cooper CS, English DR, Hopper JL, Neal DE, & Easton DF (2008). Multiple newly identified loci associated with prostate cancer susceptibility. Nature genetics, 40 (3), 316-21 PMID: 18264097
- Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, Harper KT, Brinkhuizen T, Menko FH, Davies DM, Land SC, Pause A, Baar K, van Steensel MA, & Tee AR (2011). Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene, 30 (10), 1159-73 PMID: 21057536
- Purdue MP, Johansson M, Zelenika D, Toro JR, Scelo G, Moore LE, Prokhortchouk E, Wu X, Kiemeney LA, Gaborieau V, Jacobs KB, Chow WH, Zaridze D, Matveev V, Lubinski J, Trubicka J, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Bucur A, Bencko V, Foretova L, Janout V, Boffetta P, Colt JS, Davis FG, Schwartz KL, Banks RE, Selby PJ, Harnden P, Berg CD, Hsing AW, Grubb RL 3rd, Boeing H, Vineis P, Clavel-Chapelon F, Palli D, Tumino R, Krogh V, Panico S, Duell EJ, Quirós JR, Sanchez MJ, Navarro C, Ardanaz E, Dorronsoro M, Khaw KT, Allen NE, Bueno-de-Mesquita HB, Peeters PH, Trichopoulos D, Linseisen J, Ljungberg B, Overvad K, Tjønneland A, Romieu I, Riboli E, Mukeria A, Shangina O, Stevens VL, Thun MJ, Diver WR, Gapstur SM, Pharoah PD, Easton DF, Albanes D, Weinstein SJ, Virtamo J, Vatten L, Hveem K, Njølstad I, Tell GS, Stoltenberg C, Kumar R, Koppova K, Cussenot O, Benhamou S, Oosterwijk E, Vermeulen SH, Aben KK, van der Marel SL, Ye Y, Wood CG, Pu X, Mazur AM, Boulygina ES, Chekanov NN, Foglio M, Lechner D, Gut I, Heath S, Blanche H, Hutchinson A, Thomas G, Wang Z, Yeager M, Fraumeni JF Jr, Skryabin KG, McKay JD, Rothman N, Chanock SJ, Lathrop M, & Brennan P (2011). Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3. Nature genetics, 43 (1), 60-5 PMID: 21131975
- Thomas G, Jacobs KB, Yeager M, Kraft P, Wacholder S, Orr N, Yu K, Chatterjee N, Welch R, Hutchinson A, Crenshaw A, Cancel-Tassin G, Staats BJ, Wang Z, Gonzalez-Bosquet J, Fang J, Deng X, Berndt SI, Calle EE, Feigelson HS, Thun MJ, Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Giovannucci E, Willett WC, Cussenot O, Valeri A, Andriole GL, Crawford ED, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover R, Hayes RB, Hunter DJ, & Chanock SJ (2008). Multiple loci identified in a genome-wide association study of prostate cancer. Nature genetics, 40 (3), 310-5 PMID: 18264096
- Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M, Seal S, Ghoussaini M, Hines S, Healey CS, Hughes D, Warren-Perry M, Tapper W, Eccles D, Evans DG, Breast Cancer Susceptibility Collaboration (UK), Hooning M, Schutte M, van den Ouweland A, Houlston R, Ross G, Langford C, Pharoah PD, Stratton MR, Dunning AM, Rahman N, & Easton DF (2010). Genome-wide association study identifies five new breast cancer susceptibility loci. Nature genetics, 42 (6), 504-7 PMID: 20453838