Homologous Recombination Deficiency in Skin Cancers: Prevalence and Clinical Implications of This Distinct Patient Cohort
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Authors
Nassief G.
Adeyelu T.
Elliott A.
Phillipps J.
Morecroft R.
Zhou A.Y.
Szlosarek P.W.
Robert C.
Abdulla F.
Vanderwalde A.
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2026
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Article
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PURPOSE: Homologous recombination deficiency (HRD) results in DNA instability in tumor cells and contributes to tumor pathogenesis. Although HRD-directed therapies are established in other cancers, their role in skin cancers remains unclear. Given the poor response to standard therapies in skin cancer subtypes like acral and mucosal melanoma, we aimed to characterize the prevalence of HRD across skin cancer subtypes, evaluate its correlation with immune checkpoint inhibitor (ICI) response biomarkers, and assess its prognostic relevance in patients treated with immunotherapy (IO). METHOD(S): A total of 2,508 patients with skin cancer underwent molecular profiling including whole-exome sequencing, whole-transcriptome sequencing, and immunohistochemistry. HRD status was defined by a high loss of heterozygosity (LOH-high) or mutations in homologous recombination repair (HRR) genes. Associations between HRD and established ICI biomarkers (tumor mutational burden, PD-L1, deficient mismatch repair/microsatellite instability-high, immune cell fractions, and transcriptomic signatures) were assessed. Survival outcomes on ICI therapy were assessed in cutaneous melanoma using insurance claims data. RESULT(S): Overall, among the melanoma subtypes, mucosal and acral melanoma had a greater prevalence of LOH-high than cutaneous (30.9% v 13.1% v 8.3%, P < .001). Generally, LOH-high in skin cancer did not correlate with mutations in HRR genes. Additionally, there was no significant association in ICI response biomarkers and HRD among patients with skin cancers. Furthermore, HRD was not associated with a prognostic advantage following IO (hazard ratio, 0.981 CI, 0.80 to 1.20]; P = .854). CONCLUSION(S): HRD defines a biologically distinct subset of skin cancers and is not predictive of ICI response or improved outcomes. The high prevalence of HRD in acral and mucosal melanoma highlights the need to investigate HRD-directed therapies strategies in this distinct cohort, such as poly (ADP-ribose) polymerase inhibitors or platinum-based therapies.
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JCO precision oncology
Volume
10