Autoimmune alleles at the major histocompatibility locus modify melanoma susceptibility

James V Talwar; David Laub; Meghana S Pagadala; Andrea Castro; McKenna Lewis; Georg E Luebeck; Bryan R Gorman; Cuiping Pan; Frederick N Dong; Kyriacos Markianos; Craig C Teerlink; Julie Lynch; Richard Hauger; Saiju Pyarajan; Philip S Tsao; Gerald P Morris; Rany M Salem; Wesley K Thompson; Kit Curtius; Maurizio Zanetti; Hannah Carter

doi:10.1016/j.ajhg.2023.05.013

Autoimmune alleles at the major histocompatibility locus modify melanoma susceptibility

Am J Hum Genet. 2023 Jul 6;110(7):1138-1161. doi: 10.1016/j.ajhg.2023.05.013. Epub 2023 Jun 19.

Authors

James V Talwar¹, David Laub¹, Meghana S Pagadala², Andrea Castro¹, McKenna Lewis³, Georg E Luebeck⁴, Bryan R Gorman⁵, Cuiping Pan⁶, Frederick N Dong⁵, Kyriacos Markianos⁷, Craig C Teerlink⁸, Julie Lynch⁸, Richard Hauger⁹, Saiju Pyarajan¹⁰, Philip S Tsao¹¹, Gerald P Morris¹², Rany M Salem¹³, Wesley K Thompson¹⁴, Kit Curtius¹⁵, Maurizio Zanetti¹⁶, Hannah Carter¹⁷

Affiliations

¹ Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA 92093, USA.
² Biomedical Science Program, University of California San Diego, La Jolla, CA 92093, USA.
³ Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA 92093, USA.
⁴ Public Health Sciences Division, Herbold Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁵ Center for Data and Computational Sciences (C-DACS), VA Boston Healthcare System, Boston, MA 02130, USA; Booz Allen Hamilton, Inc., McLean, VA 22102, USA.
⁶ Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto, CA, USA.
⁷ Center for Data and Computational Sciences (C-DACS), VA Boston Healthcare System, Boston, MA 02130, USA; Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02115, USA.
⁸ Department of Veterans Affairs Informatics and Computing Infrastructure (VINCI), VA Salt Lake City Healthcare System, Salt Lake City, UT, USA; Department of Internal Medicine, Division of Epidemiology, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁹ VA San Diego Healthcare System, La Jolla, CA, USA; Center for Behavioral Genetics of Aging, University of California San Diego, La Jolla, CA, USA; Center of Excellence for Stress and Mental Health (CESAMH), VA San Diego Healthcare System, San Diego, CA, USA.
¹⁰ Center for Data and Computational Sciences (C-DACS), VA Boston Healthcare System, Boston, MA 02130, USA; Department of Medicine, Brigham Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹¹ Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹² Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA.
¹³ Division of Epidemiology, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA 92093, USA.
¹⁴ Center for Population Neuroscience and Genetics, Laureate Institute for Brain Research, Tulsa, OK 74136, USA.
¹⁵ Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
¹⁶ Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; The Laboratory of Immunology, University of California San Diego, La Jolla, CA 92093, USA; Department of Medicine, Division of Hematology and Oncology, University of California San Diego, La Jolla, CA 92093, USA.
¹⁷ Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: hkcarter@health.ucsd.edu.

Abstract

Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8⁺ T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8⁺ T cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo- and psoriasis-predisposing MHC-I alleles conferred a melanoma-protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (n = 451) and an independent validation set (n = 586), MHC-I autoimmune-allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune-allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veteran Program (OR = 0.962, p = 0.024). Existing melanoma polygenic risk scores (PRSs) did not predict autoimmune-allele carrier status, suggesting these alleles provide orthogonal risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles. However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte-conserved antigens and loss of heterozygosity of autoimmune alleles caused the greatest reduction in presentation for several conserved antigens across individuals with loss of HLA alleles. Overall, this study presents evidence that MHC-I autoimmune-risk alleles modulate melanoma risk unaccounted for by current PRSs.

Keywords: autoimmunity; major histocompatibility complex; melanoma; polygenic risk scores.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alleles
CD8-Positive T-Lymphocytes / metabolism
Histocompatibility
Histocompatibility Antigens Class I / genetics
Humans
Melanoma* / genetics
Melanoma* / metabolism
Skin Neoplasms* / genetics

Substances

Histocompatibility Antigens Class I

Abstract

Publication types

MeSH terms

Substances

Grants and funding