Sex specific associations in genome wide association analysis of renal cell carcinoma

Abstract

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10−8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90–1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10−8 compared with ORfemale = 0.93 [95% CI = 0.82–1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3

Data availability

Genome-wide summary statistics are made available through the NHGRI-EBI GWAS Catalog https://www.ebi.ac.uk/gwas/downloads/summary-statistics. Data from the first IARC GWAS scan included in the study are available from Paul Brennan upon reasonable request. The data from second IARC scan are accessible on dbGaP: (phs001271.v1.p1). The first and second NCI scans are accessible on dbGaP (phs000351.v1.p1 and phs001736.v1.p1 respectively). Data from the MDA scan is available from Xifeng Wu upon reasonable request.

References

  1. 1.

    Znaor A, Lortet-Tieulent J, Laversanne M, Jemal A, Bray F. International variations and trends in renal cell carcinoma incidence and mortality. Eur Urol. 2015;67:519–30.

  2. 2.

    Lopez-Beltran A, Scarpelli M, Montironi R, Kirkali Z. 2004 WHO classification of the renal tumors of the adults. Eur Urol. 2006;49:798–805.

  3. 3.

    Scelo G, Li P, Chanudet E, Muller DC. Variability of sex disparities in cancer incidence over 30 years: the striking case of kidney cancer. Eur Urol Focus. 2018;4:586–90.

  4. 4.

    Bray FCM, Mery L, Piñeros M, Znaor A, Zanetti R and Ferlay J, editors. Cancer Incidence in Five Continents, 2017, Vol. XI (electronic version).

  5. 5.

    Clocchiatti A, Cora E, Zhang Y, Dotto GP. Sexual dimorphism in cancer. Nat Rev Cancer. 2016;16:330–9.

  6. 6.

    Yuan Y, Liu L, Chen H, Wang Y, Xu Y, Mao H, et al. Comprehensive characterization of molecular differences in cancer between male and female patients. Cancer Cell. 2016;29:711–22.

  7. 7.

    Haas NB, Nathanson KL. Hereditary kidney cancer syndromes. Adv Chronic Kidney Dis. 2014;21:81–90.

  8. 8.

    Purdue MP, Johansson M, Zelenika D, Toro JR, Scelo G, Moore LE, et al. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3. Nat Genet. 2011;43:60–65.

  9. 9.

    Wu X, Scelo G, Purdue MP, Rothman N, Johansson M, Ye Y, et al. A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23. Hum Mol Genet. 2012;21:456–62.

  10. 10.

    Henrion M, Frampton M, Scelo G, Purdue M, Ye Y, Broderick P, et al. Common variation at 2q22.3 (ZEB2) influences the risk of renal cancer. Hum Mol Genet. 2013;22:825–31.

  11. 11.

    Henrion MY, Purdue MP, Scelo G, Broderick P, Frampton M, Ritchie A, et al. Common variation at 1q24.1 (ALDH9A1) is a potential risk factor for renal cancer. PLoS ONE. 2015;10:e0122589.

  12. 12.

    Scelo G, Purdue MP, Brown KM, Johansson M, Wang Z, Eckel-Passow JE, et al. Genome-wide association study identifies multiple risk loci for renal cell carcinoma. Nat Commun. 2017;8:15724.

  13. 13.

    Gudmundsson J, Sulem P, Gudbjartsson DF, Masson G, Petursdottir V, Hardarson S, et al. A common variant at 8q24.21 is associated with renal cell cancer. Nat Commun. 2013;4:2776.

  14. 14.

    Winkler TW, Justice AE, Graff M, Barata L, Feitosa MF, Chu S, et al. Correction: The influence of age and sex on genetic associations with adult body size and shape: a large-scale genome-wide interaction study. PLoS Genet. 2016;12:e1006166.

  15. 15.

    Zhuang JJ, Morris AP. Assessment of sex-specific effects in a genome-wide association study of rheumatoid arthritis. BMC Proc. 2009;3 (Suppl 7):S90.

  16. 16.

    Randall JC, Winkler TW, Kutalik Z, Berndt SI, Jackson AU, Monda KL, et al. Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. PLoS Genet. 2013;9:e1003500.

  17. 17.

    Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–9.

  18. 18.

    Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336–7.

  19. 19.

    Magi R, Morris AP. GWAMA: software for genome-wide association meta-analysis. BMC Bioinf. 2010;11:288.

  20. 20.

    Hormozdiari F, van de Bunt M, Segre AV, Li X, Joo JWJ, Bilow M, et al. Colocalization of GWAS and eQTL signals detects target genes. Am J Hum Genet. 2016;99:1245–60.

  21. 21.

    Hoyal CR, Kammerer S, Roth RB, Reneland R, Marnellos G, Kiechle M, et al. Genetic polymorphisms in DPF3 associated with risk of breast cancer and lymph node metastases. J Carcinog. 2005;4:13.

  22. 22.

    Ricketts CJ, Linehan WM. Gender specific mutation incidence and survival associations in clear cell renal cell carcinoma (CCRCC). PLoS ONE. 2015;10:e0140257.

  23. 23.

    Cancer Genome Atlas Research N. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499:43–49.

  24. 24.

    Kapur P, Pena-Llopis S, Christie A, Zhrebker L, Pavía-Jiménez A, Rathmell WK, et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol. 2013;14:159–67.

  25. 25.

    Kwekel JC, Desai VG, Moland CL, Vijay V, Fuscoe JC. Sex differences in kidney gene expression during the life cycle of F344 rats. Biol Sex Differ. 2013;4:14.

  26. 26.

    Brannon AR, Haake SM, Hacker KE, Pruthi RS, Wallen EM, Nielsen ME, et al. Meta-analysis of clear cell renal cell carcinoma gene expression defines a variant subgroup and identifies gender influences on tumor biology. Eur Urol. 2012;61:258–68.

  27. 27.

    Huby RD, Glaves P, Jackson R. The incidence of sexually dimorphic gene expression varies greatly between tissues in the rat. PLoS ONE. 2014;9:e115792.

  28. 28.

    Putra AC, Eguchi H, Lee KL, Yamane Y, Gustine E, Isobe T, et al. The A Allele at rs13419896 of EPAS1 is associated with enhanced expression and poor prognosis for non-small cell lung cancer. PLoS ONE. 2015;10:e0134496.

  29. 29.

    Iwamoto S, Tanimoto K, Nishio Y, Putra AC, Fuchita H, Ohe M, et al. Association of EPAS1 gene rs4953354 polymorphism with susceptibility to lung adenocarcinoma in female Japanese non-smokers. J Thorac Oncol. 2014;9:1709–13.

  30. 30.

    Riazalhosseini Y, Lathrop M. Precision medicine from the renal cancer genome. Nat Rev Nephrol. 2016;12:655–66.

  31. 31.

    Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer. 2015;15:55–64.

  32. 32.

    Fuady JH, Gutsche K, Santambrogio S, Varga Z, Hoogewijs D, Wenger RH. Correction: Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2alpha in invasive breast cancer cells. Oncotarget. 2017;8:20516.

  33. 33.

    Grampp S, Platt JL, Lauer V, Salama R, Kranz F, Neumann VK, et al. Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer. Nat Commun. 2016;7:13183.

  34. 34.

    Schodel J, Bardella C, Sciesielski LK, Brown JM, Pugh CW, Buckle V, et al. Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression. Nat Genet. 2012;44:420–5. S421-422

  35. 35.

    Yagai T, Matsui S, Harada K, Inagaki FF, Saijou E, Miura Y, et al. Expression and localization of sterile alpha motif domain containing 5 is associated with cell type and malignancy of biliary tree. PLoS ONE. 2017;12:e0175355.

  36. 36.

    Hwang SJ, Yang Q, Meigs JB, Pearce EN, Fox CS. A genome-wide association for kidney function and endocrine-related traits in the NHLBI’s Framingham Heart Study. BMC Med Genet. 2007;8(Suppl 1):S10.

  37. 37.

    Iyengar SK, Sedor JR, Freedman BI, Kao WH, Kretzler M, Keller BJ, et al. Genome-wide association and trans-ethnic meta-analysis for advanced diabetic kidney disease: family investigation of nephropathy and diabetes (FIND). PLoS Genet. 2015;11:e1005352.

Download references

Acknowledgements

We thank all of the participants who took part in this research and the funders and support staff who made this study possible. Funding for the genome-wide genotyping was provided by the US National Institutes of Health (NIH), National Cancer Institute (U01CA155309) for those studies coordinated by IARC, and by the intramural research program of the National Cancer Institute, US NIH, for those studies coordinated by the NCI. MD Anderson GWAS was supported by NIH (grant R01 CA170298) and the Center for Translational and Public Health Genomics, Duncan Family Institute for Cancer Prevention and Risk Assessment, The University of Texas MD Anderson Cancer Center. Funding for the IARC gene expression and eQTL study was provided by the US National Institutes of Health (NIH), National Cancer Institute (U01CA155309). RSL received IARC Postdoctoral fellowship from the IARC, partially supported by EC FP7 Marie Curie Actions – People – Co- Funding of regional, national and international programmes (COFUND). DCM is supported by a Cancer Research UK Population Research Fellowship. MMCI- supported by MH CZ - DRO (MMCI, 00209805).

Author information

Correspondence to Ghislaine Scelo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary figures

Supplementary tables

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark