Tumour Antigen-Specific Antibody Signatures as Diagnostic Biomarkers for Melanoma

Early detection of melanoma remains challenging, and minimally invasive diagnostic tools are needed to complement imaging and histopathology. Circulating tumour antigen-specific antibodies (Abs) are promising biomarkers, but their diagnostic value across melanoma stages is not fully established. Circulating IgG and IgM Abs were profiled in plasma from two independent melanoma cohorts, early-stage (n = 65) and advanced-stage (n = 77), alongside healthy controls (n = 86) and individuals with prior cancer in remission (n = 37). A protein microarray containing 263 tumour antigens, predominantly cancer-testis (CT) antigens, was used to measure plasma antibody (Ab) reactivity. Univariate and multivariate ROC analyses identified candidate diagnostic biomarker signatures. Early-stage melanoma was best distinguished by an IgM signature comprising AURKA, BAGE3, BAGE4, CDK7, CEP290, MYBL2, PIAS2, RAD51 and SPANXB1 (AUC = 0.939). An IgG signature including ANKRD45, BCL2L14, CDK2, MAGEA4v3, MAPK3 and RBM46 achieved AUC = 0.827. Advanced-stage melanoma exhibited broader Ab repertoires, including an IgG signature (CTAG1A, DKKL1, PIWIL2, SPANXN1, TSGA10, TSPY1; AUC = 0.865) and an IgM signature (CPXCR1, CSAG2, FMR1NB, FOXR2, LIPI, MAGEA5, TSGA10; AUC = 0.889). Individuals in cancer remission displayed persistent Ab signatures distinct from early melanoma and healthy controls. Overlap between IgG and IgM repertoires was minimal, highlighting complementary discriminatory value. Circulating IgG and IgM Abs against tumour antigens reveal stage-specific signatures that distinguish melanoma from healthy individuals and those in cancer remission, identifying candidate discovery-stage diagnostic biomarker signatures warranting independent validation in larger prospective cohorts to determine clinical utility.