Advertisement

Digestive Diseases and Sciences

, Volume 59, Issue 5, pp 986–991 | Cite as

Molecular Evolution of Genetic Susceptibility to Hepatocellular Carcinoma

  • Saowanee Ngamruengphong
  • Tushar PatelEmail author
Original Article

Abstract

Background

Hepatocellular carcinoma (HCC) is a leading cancer-related cause of death worldwide. There are widespread global differences in HCC risk. Although the impact of geographic prevalence of specific causes of chronic liver disease on HCC is recognized, the contribution of the underlying genetic architecture to the risk of HCC remains undefined. Our aim was to characterize evolutionary trends in genetic susceptibility to HCC.

Methods

We examined the genetic risk associated with HCC risk alleles identified from genome-wide association studies and correlated these with geographic location and temporal and spatial patterns of human migration.

Results

A moderate increase in differentiation was noted for rs2596542 (F st = 0.106) and rs17401966 (F st = 0.116), single nucleotide polymorphisms (SNPs) associated with an increased risk of HCC in patients with chronic HCV and HBV, respectively. Both of these SNPs show a recent increase in allelic frequency with the most recent human migrations into East Asia, Oceania and the Americas. In contrast another SNP associated with an increased risk of HCC, rs9275572, showed a lack of differentiation (F st = 0.09) with stable allelic expression across populations. The genetic risk score for HCC, based on the allelic frequency and risk odds ratio of five SNPs associated with increased risk of HCC, was greatest in populations from Africa and decreased with subsequent migration into Europe and Asia. However, a major increase was noted with the most recent migrations into Oceania and the Americas.

Conclusions

There are differences in directional differentiation of HCC risk alleles across human populations that can contribute to population-based differences in HCC prevalence.

Keywords

Single nucleotide polymorphisms Risk alleles Liver cancer Migration Population genetics 

Abbreviations

GWAS

Genome-wide association studies

HCC

Hepatocellular carcinoma

SNP

Single nucleotide polymorphism

Notes

Conflict of interest

None.

References

  1. 1.
    Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127:S5–S16.PubMedCrossRefGoogle Scholar
  2. 2.
    Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, et al. Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology. 2011;54:463–471.PubMedCrossRefGoogle Scholar
  3. 3.
    El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–1273. e1261.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Villanueva A, Newell P, Hoshida Y. Inherited hepatocellular carcinoma. Best Pract Res Clin Gastroenterol. 2010;24:725–734.PubMedCrossRefGoogle Scholar
  5. 5.
    Zhang H, Zhai Y, Hu Z, Wu C, Qian J, et al. Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers. Nat Genet. 2010;42:755–758.PubMedCrossRefGoogle Scholar
  6. 6.
    Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet. 2011;43:455–458.PubMedCrossRefGoogle Scholar
  7. 7.
    Barreiro LB, Laval G, Quach H, Patin E, Quintana-Murci L. Natural selection has driven population differentiation in modern humans. Nat Genet. 2008;40:340–345.PubMedCrossRefGoogle Scholar
  8. 8.
    Cavalli-Sforza LL. The Human Genome Diversity Project: past, present and future. Nat Rev Genet. 2005;6:333–340.PubMedGoogle Scholar
  9. 9.
    Li JZ, Absher DM, Tang H, Southwick AM, Casto AM, et al. Worldwide human relationships inferred from genome-wide patterns of variation. Science. 2008;319:1100–1104.PubMedCrossRefGoogle Scholar
  10. 10.
    The Human Genome Diversity Project database. ftp://ftp.cephb.fr/hgdp_supp1. Accessed August 1, 2012.
  11. 11.
    Rajeevan H, Soundararajan U, Kidd JR, Pakstis AJ, Kidd KK. ALFRED: an allele frequency resource for research and teaching. Nucleic Acids Res. 2012;40:D1010–D1015.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Rajeevan H, Cheung KH, Gadagkar R, Stein S, Soundararajan U, et al. ALFRED: an allele frequency database for microevolutionary studies. Evol Bioinform Online. 2005;1:1–10.PubMedCentralGoogle Scholar
  13. 13.
    Allele Frequency Database. http://alfred.med.yale.edu/. Accessed August 1, 2012.
  14. 14.
    Zhivotovsky LA, Rosenberg NA, Feldman MW. Features of evolution and expansion of modern humans, inferred from genomewide microsatellite markers. Am J Hum Genet. 2003;72:1171–1186.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, et al. Genetic signatures of strong recent positive selection at the lactase gene. Am J Hum Genet. 2004;74:1111–1120.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Myles S, Somel M, Tang K, Kelso J, Stoneking M. Identifying genes underlying skin pigmentation differences among human populations. Hum Genet. 2007;120:613–621.PubMedCrossRefGoogle Scholar
  17. 17.
    Myles S, Tang K, Somel M, Green RE, Kelso J, et al. Identification and analysis of genomic regions with large between-population differentiation in humans. Ann Hum Genet. 2008;72:99–110.PubMedGoogle Scholar
  18. 18.
    Jin F, Qu LS, Shen XZ. Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis. J Exp Clin Cancer Res. 2010;29:18.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Gu X, Qi P, Zhou F, Ji Q, Wang H, et al. An intronic polymorphism in the corticotropin-releasing hormone receptor 2 gene increases susceptibility to HBV-related hepatocellular carcinoma in Chinese population. Hum Genet. 2010;127:75–81.PubMedCrossRefGoogle Scholar
  20. 20.
    Easton DF, Eeles RA. Genome-wide association studies in cancer. Hum Mol Genet. 2008;17:R109–R115.PubMedCrossRefGoogle Scholar
  21. 21.
    Wacholder S, Hartge P, Prentice R, Garcia-Closas M, Feigelson HS, et al. Performance of common genetic variants in breast-cancer risk models. N Engl J Med. 2010;362:986–993.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Zheng SL, Sun J, Wiklund F, Smith S, Stattin P, et al. Cumulative association of five genetic variants with prostate cancer. N Engl J Med. 2008;358:910–919.PubMedCrossRefGoogle Scholar
  23. 23.
    Nahon P, Zucman-Rossi J. Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis. J Hepatol. 2012;57:663–674.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Gastroenterology and HepatologyMayo ClinicJacksonvilleUSA
  2. 2.Departments of Transplantation and Cancer BiologyMayo ClinicJacksonvilleUSA

Personalised recommendations