Autoimmune alleles at the major histocompatibility locus modify melanoma susceptibility.

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.

SEPIA: simulation-based evaluation of prioritization algorithms.

BACKGROUND: The ability to prioritize people living with HIV (PLWH) by risk of future transmissions could aid public health officials in optimizing epidemiological intervention. While methods exist to perform such prioritization based on molecular data, their effectiveness and accuracy are poorly understood, and it is unclear how one can directly compare the accuracy of different methods. We introduce SEPIA (Simulation-based Evaluation of PrIoritization Algorithms), a novel simulation-based framework for determining the effectiveness of prioritization algorithms. SEPIA expands upon prior related work by defining novel metrics of effectiveness with which to compare prioritization techniques, as well as by creating a simulation-based tool with which to perform such effectiveness comparisons. Under several metrics of effectiveness that we propose, we compare two existing prioritization approaches: one phylogenetic (ProACT) and one distance-based (growth of HIV-TRACE transmission clusters). RESULTS: Using all proposed metrics, ProACT consistently slightly outperformed the transmission cluster growth approach. However, both methods consistently performed just marginally better than random, suggesting that there is significant room for improvement in prioritization tools. CONCLUSION: We hope that, by providing ways to quantify the effectiveness of prioritization methods in simulation, SEPIA will aid researchers in developing novel risk prioritization tools for PLWH.