High-Specificity Detection of UV Mutational Signatures in Circulating Tumor DNA for Diagnostic Classification of Cutaneous and Unknown Primary Tumors Using FoundationOne Liquid CDx

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This study evaluated a UV mutational signature classifier applied to circulating tumor DNA (ctDNA) in cell-free DNA liquid biopsies, using the FoundationOne Liquid CDx platform. Among 73,790 samples, 12.9% (9527) met the variant threshold for signature analysis, with UV signatures detected in 3.8% (365) of cases. Of these, 51.5% (188) were initially submitted as cutaneous, 8.5% (31) as unspecified primary, and 40.0% (146) as extracutaneous tumors. The UV classifier demonstrated high specificity (99.7%) and variable sensitivity, reaching up to 37.5% and 67.6% in samples with elevated ctDNA levels and mutational loads, respectively. Molecular pathologist review confirmed that 74.0% (270/365) of UV calls were true positives and enabled resolution of false positives and ambiguous findings through integration of genomic and clinicopathologic features. This refined sensitivity estimates to 41.9% and 70.2% in cases with elevated ctDNA levels and mutational loads, respectively. Confirmed UV-positive tumors exhibited genomic alterations characteristic of sun-exposed skin cancers. In 175 matched liquid and tissue biopsy pairs, the positive percent agreement for UV signature detection was 38.7% overall, increasing to 87.5% and 90.6% in subsets with elevated ctDNA levels and mutational load, respectively. These results underline the utility of FoundationOne Liquid CDx, complemented by molecular pathologist oversight, in identifying cancers of cutaneous origin to refine diagnoses and guide treatment for patients with advanced cancers.

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