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.
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The datasets used in this study are available from the TCGA, ICGC and CCLE repositories. The ICB-treated melanoma datasets generated during the current study are available in six previous studies and their supplementary data files as described in the ‘Genomic and clinical data’ subsection. All data supporting the conclusions of this study have been included within the article and the Supplemental Data.
The computer codes used to generate results that support the paper’s conclusions are available from the corresponding author upon reasonable request.
All materials supporting the conclusions of this study have been included in the article and the Supplemental Data.
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The authors would like to thank all patients with melanoma who kindly donated samples for the TCGA and ICGC projects. The authors sincerely appreciated all of the data-sharing platforms, such as the TCGA, ICGC and CCLE. The authors would like to thank the colleagues from our department for their assistance.
This work was supported by the National Natural Science Foundation of China (81372429 to Lujun Zhao).
The authors declare no competing interests.
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Li, Y., Wang, Q., Chen, Y. et al. Somatic mutations in DCC are associated with genomic instability and favourable outcomes in melanoma patients treated with immune checkpoint inhibitors. Br J Cancer (2022). https://doi.org/10.1038/s41416-022-01921-4