Skip to main content

Advertisement

SpringerLink
Log in

Genetic variants in the HLA class II region associated with risk of cutaneous squamous cell carcinoma

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

The immune system has been implicated in the pathophysiology of cutaneous squamous cell carcinoma (cSCC) as evidenced by the substantially increased risk of cSCC in immunosuppressed individuals. Associations between cSCC risk and single nucleotide polymorphisms (SNPs) in the HLA region have been identified by genome-wide association studies (GWAS). The translation of the associated HLA SNPs to structural amino acids changes in HLA molecules has not been previously elucidated.

Methods

Using data from a GWAS that included 7238 cSCC cases and 56,961 controls of non-Hispanic white ancestry, we imputed classical alleles and corresponding amino acid changes in HLA genes. Logistic regression models were used to examine associations between cSCC risk and genotyped or imputed SNPs, classical HLA alleles, and amino acid changes.

Results

Among the genotyped SNPs, cSCC risk was associated with rs28535317 (OR = 1.20, p = 9.88 × 10− 11) corresponding to an amino-acid change from phenylalanine to leucine at codon 26 of HLA-DRB1 (OR = 1.17, p = 2.48 × 10− 10). An additional independent association was observed for a threonine to isoleucine change at codon 107 of HLA-DQA1 (OR = 1.14, p = 2.34 × 10− 9). Among the classical HLA alleles, cSCC was associated with DRB1*01 (OR = 1.18, p = 5.86 × 10− 10). Conditional analyses revealed additional independent cSCC associations with DQA1*05:01 and DQA1*05:05. Extended haplotype analysis was used to complement the imputed haplotypes, which identified three extended haplotypes in the HLA-DR and HLA-DQ regions.

Conclusions

Associations with specific HLA-DR and -DQ alleles are likely to explain previously observed GWAS signals in the HLA region associated with cSCC risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

cSCC:

Cutaneous squamous cell carcinoma

GERA:

Genetic Epidemiology Research in Adult Health and Aging

GWAS:

Genome-wide association study

HLA:

Human leukocyte antigen

KPNC:

Kaiser Permanente Northern California

LD:

Linkage disequilibrium

MAF:

Minor allele frequency

OR:

Odds ratio

SNP:

Single nucleotide polymorphism

References

  1. Jennings L, Schmults CD (2010) Management of high-risk cutaneous squamous cell carcinoma. J Clin Aesthet Dermatol 3(4):39–48

    PubMed  PubMed Central  Google Scholar 

  2. Lindström LS, Yip B, Lichtenstein P et al (2007) Etiology of familial aggregation in melanoma and squamous cell carcinoma of the skin. Cancer Epidemiol Biomarkers Prev 16(8):1639–1643

    Article  PubMed  CAS  Google Scholar 

  3. Trakatelli M, Ulrich C, del Marmol V et al (2007) Epidemiology of nonmelanoma skin cancer (NMSC) in Europe: accurate and comparable data are needed for effective public health monitoring and interventions. Br J Dermatol 156(Suppl 3):1–7

    Article  PubMed  Google Scholar 

  4. Euvrard S, Kanitakis J, Claudy A (2003) Skin cancers after organ transplantation. N Engl J Med 348(17):1681–1691

    Article  PubMed  Google Scholar 

  5. Silverberg MJ, Leyden W, Warton EM et al (2013) HIV infection status, immunodeficiency, and the incidence of non-melanoma skin cancer. J Natl Cancer Inst 105(5):350 – 60

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Asgari MM, Wang W, Ioannidis NM et al (2016) Identification of susceptibility loci for cutaneous squamous cell carcinoma. J Invest Dermatol 136(5):930–937

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Chahal HS, Lin Y, Ransohoff KJ et al (2016) Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma. Nat Commun 7:12048

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Jia X, Han B, Onengut-Gumuscu S et al (2013) Imputing amino acid polymorphisms in human leukocyte antigens. PLoS One 8(6):e64683

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Hoffmann TJ, Zhan Y, Kvale MN et al (2011) Design and coverage of high throughput genotyping arrays optimized for individuals of East Asian, African American, and Latino race/ethnicity using imputation and a novel hybrid SNP selection algorithm. Genomics 98(6):422–430

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Hoffmann TJ, Kvale MN, Hesselson SE et al (2011) Next generation genome-wide association tool: design and coverage of a high-throughput European-optimized SNP array. Genomics 98(2):79–89

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Patterson N, Price AL, Reich D (2006) Population structure and eigenanalysis. PLoS Genet 2(12):e190

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Jorgenson E, Melles RB, Hoffmann TJ et al (2016) Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration. Eur J Hum Genet 24(7):1049–1055

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Chang CC, Chow CC, Tellier LC et al (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4:7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Ollila HM, Ravel JM, Han F et al (2015) HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am J Hum Genet 96(1):136–46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Raj P, Rai E, Song R et al. Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity. Elife 2016;5:e12089, (PMCID: PMC4811771)

    Article  PubMed  PubMed Central  Google Scholar 

  16. Glover MT, Bodmer J, Bodmer W et al (1993) HLA antigen frequencies in renal transplant recipients and non-immunosuppressed patients with non-melanoma skin cancer. Eur J Cancer 29A(4):520–524

    Article  PubMed  CAS  Google Scholar 

  17. Cerimele D, Contu L, Carcassi C et al (1988) HLA and multiple skin carcinomas. Dermatologica 176(4):176–81

    Article  PubMed  CAS  Google Scholar 

  18. Czarnecki DB, Lewis A, Nicholson I et al (1991) Multiple nonmelanoma skin cancer associated with HLA DR7 in southern Australia. Cancer 68(2):439–40

    Article  PubMed  CAS  Google Scholar 

  19. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570

    Article  PubMed  CAS  Google Scholar 

  20. Vinay DS, Ryan EP, Pawelec G et al (2015) Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol 35 S185-98

    Article  CAS  Google Scholar 

  21. Baecher-Allan C, Wolf E, Hafler DA (2006) MHC class II expression identifies functionally distinct human regulatory T cells. J Immunol 176(8):4622–4631

    Article  PubMed  CAS  Google Scholar 

  22. Hu JM, Li L, Chen YZ, et al. HLA-DRB1 and HLA-DQB1 methylation changes promote the occurrence and progression of Kazakh ESCC. Epigenetics 2014;9(10):1366–1373

  23. Jones EY, Fugger L, Strominger JL et al (2006) MHC class II proteins and disease: a structural perspective. Nat Rev Immunol 6(4):271 – 82

    Article  PubMed  CAS  Google Scholar 

  24. Raychaudhuri S, Sandor C, Stahl EA et al (2012) Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 44(3):291–296

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Feitsma AL, van der Helm-van Mil AH, Huizinga TW et al (2008) Protection against rheumatoid arthritis by HLA: nature and nurture. Ann Rheum Dis 67(Suppl 3):iii61-3

    Article  PubMed  Google Scholar 

  26. Fernandez CA, Smith C, Yang W et al (2014) HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. Blood 124(8):1266–1276

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Kvale MN, Hesselson S, Hoffmann TJ et al (2015) Genotyping Informatics and Quality Control for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA). Cohort Genetics 200(4):1051–1060

    Article  PubMed  CAS  Google Scholar 

  28. Pereyra F, Jia X, McLaren PJ et al (2010) The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330(6010):1551–1557

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Butler MO, Ansén S, Tanaka M et al (2010) A panel of human cell-based artificial APC enables the expansion of long-lived antigen-specific CD4 + T cells restricted by prevalent HLA-DR alleles. Int Immunol 22(11):863–73

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

This work was supported by a grant from the National Cancer Institute at the National Institutes of Health (Grant number R01CA166672).

Author information

Authors and Affiliations

  1. Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA

    Wei Wang, Alice S. Whittemore & Nilah M. Ioannidis

  2. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

    Hanna M. Ollila & Emmanuel Mignot

  3. Department of Dermatology, Massachusetts General Hospital, 50 Staniford Street, Suite 270, 02114, Boston, MA, USA

    Shadmehr Demehri & Maryam M. Asgari

  4. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA

    Eric Jorgenson

  5. Department of Population Medicine, Harvard Medical School, Boston, MA, USA

    Maryam M. Asgari

Authors
  1. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hanna M. Ollila
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alice S. Whittemore
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shadmehr Demehri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nilah M. Ioannidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eric Jorgenson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Emmanuel Mignot
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maryam M. Asgari
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WW: drafting and revisions to manuscript, acquisition of data, and/or analysis and interpretation of results. HMO: drafting and revisions to manuscript, acquisition of data, and/or analysis and interpretation of results. ASW: conception and design, revisions to manuscript. SD: interpretation of results and revisions to manuscript. NMI: revisions to manuscsript. EJ: interpretation of results and revisions to manuscript. EM: conception and design, data analysis, revisions to manuscript. MMA: conception, funding, data acquisition, revisions to manuscript.

Corresponding author

Correspondence to Maryam M. Asgari.

Ethics declarations

Conflict of interest

Dr. Asgari has received institutional research funding (role: Principal Investigator) from Valeant Pharmaceuticals for an unrelated topic (atopic dermatitis). All other authors declare that they have no conflict of interest.

Ethical approval and ethical standards

This study was approved by the Kaiser Permanente Northern California Institutional review board (approval number CN-12MAsga-03-H) and was conducted in accordance with the Helsinki declaration.

Informed consent

Informed consent was waived.

Additional information

Emmanuel Mignot and Maryam M. Asgari equally contributing as last author

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 128 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, W., Ollila, H.M., Whittemore, A.S. et al. Genetic variants in the HLA class II region associated with risk of cutaneous squamous cell carcinoma. Cancer Immunol Immunother 67, 1123–1133 (2018). https://doi.org/10.1007/s00262-018-2168-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-018-2168-2

Keywords

Search

Navigation