RT Journal Article
SR Electronic
T1 Autoimmune Alleles at the Major Histocompatibility Locus Modify Melanoma Susceptibility
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.12.456166
DO 10.1101/2021.08.12.456166
A1 James Talwar
A1 David Laub
A1 Meghana Pagadala
A1 Andrea Castro
A1 McKenna Lewis
A1 Georg E. Luebeck
A1 Gerald P. Morris
A1 Rany M. Salem
A1 Wesley K. Thompson
A1 Kit Curtius
A1 Maurizio Zanetti
A1 Hannah Carter
YR 2021
UL http://biorxiv.org/content/early/2021/08/13/2021.08.12.456166.abstract
AB 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 cohort (N = 586), MHC-I autoimmune allele carriers are significantly associated with a later age of melanoma diagnosis. MHC-I autoimmune allele contributions to melanoma risk are not captured by current polygenic risk scores (PRS) and incorporation of autoimmune MHC allele presence can improve relative risk stratification. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles (population frequency ≥ 1%). However, autoimmune alleles showed a marked affinity relative to common alleles for particular windows of melanocyte conserved antigens suggesting a potential relationship between antigen processing, binding, and cell-surface presentation. Overall, this study presents evidence that MHC-I autoimmune risk alleles modulate melanoma risk currently unaccounted for by current PRS.Competing Interest StatementThe authors have declared no competing interest.