Somatic mutations in DCC are associated with genomic instability and favourable outcomes in melanoma patients treated with immune checkpoint inhibitors.

Abstract

Deleted in colorectal cancer (DCC) encodes a transmembrane dependence receptor and is frequently mutated in melanoma. The associations of DCC mutation with chromosomal instability and immunotherapeutic efficacy in melanoma are largely uncharacterised. We performed an integrated study based on biological experiments and multi-dimensional data types, including genomic, transcriptomic and clinical immune checkpoint blockade (ICB)-treated melanoma cohorts from public databases. DCC mutation was significantly correlated with the tumour mutational burden (TMB) in The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and ICB-treated melanoma cohorts. DCC expression levels were correlated with DNA damage response and repair (DDR) pathways responsive to irradiation (IR) in the Malme-3M and SK-MEL-2 cell lines. In the TCGA cohort, DCC-mutated samples presented more neoantigens, higher proportions of infiltrating antitumour immunocytes and lower proportions of infiltrating pro-tumour immunocytes than DCC wild-type samples. DCC-mutated samples were significantly enriched in activated immune response and DDR pathways. Furthermore, patients harbouring mutated DCC treated with ICB showed remarkable clinical benefits in terms of the response rate and overall survival. Somatic mutations in DCC are associated with improved clinical outcomes in ICB-treated melanoma patients. Once further validated, the DCC mutational status can improve patient selection for clinical practice and future study enrolment.