Association study between auto-immunity genetic markers, melanoma susceptibility and prognosis

Abstract

Auto-immunity has been shown to be associated with a better outcome and in interferon alpha-treated melanoma patients. In addition, polymorphism in NALP1 has recently been shown to be associated to vitiligo, a symptom often associated with an immune response in melanoma patients. Considerable progresses have been made in knowledge of genetic basis of auto-immunity. In this work, we performed for the first time an association study between numerous autoimmune genetic markers, melanoma susceptibility and prognosis. Thirteen SNPs belonging to 10 genes implicated in auto-immunity (FCRL3-rs7508684, NALP1-rs6502867, TLR5-rs5744168, TYK2-rs12720270, TYK2-rs2304256, PTPN22-rs2488457, PTPN22-rs2476601, PDCD1- rs11568821, PDCD1-rs2227981, SUMO4-rs237025, ZFP36-rs3746083, IFIH1-rs1990760, TNFRSF1Brs1061622) were genotyped in 700 melanoma patients (MelanCohort) and respectively 150 (TLR5, TYK2, PTPN22, PDCD1, SUMO4, ZFP36, IFIH1, TNFRSF1B), 465 (FCRL3), and 937 (NALP1) Caucasian controls. For each genetic variant, we first compared genotypes in patients and controls with a Fisher exact test according to the additive model. Stratified analyses were conducted to test for any genotype association with melanoma genetic subgroups (familial, multiple, associated to skin carcinoma), histological subtype, and tumor location. Tumor progression was investigated according to two parameters: Breslow index (analysis of variance) and sentinel lymph node invasion (positive versus negative).Two SNPs (IFIH1-rs1990760, FCRL3-rs7508684) had a protective effect on melanoma risk (P value= 0.027, OR= 0.76 (0.60-0.97), P value = 0.032, OR= 0.83 (0.70-0.98). In addition, NALP1 genotype was associated with Breslow index (P value= 0.008), and FCRL3. rs7508684 was moderately associated with lymph satellite node invasion (P value=0.03). Our result suggest that genetic variants in genes belonging to auto-immunity pathways may influence the occurrence of melanoma. In addition, some of these variants may also have an impact on melanoma progression and prognosis, independently of interferon therapy. Our data are comforted by previous observations: the appearance of clinical or biological autoimmunity signs (vitiligo, antibodies) during treatment with interferon alfa-2b is associate.