Prevalence of UV Mutational Signatures Among Cutaneous Primary Tumors
Authors: Douglas A. Mata, Erik A. Williams, Ethan Sokol, Geoffrey R. Oxnard, Zoe Fleischmann, Julie Y. Tse, Brennan Decker
Journal: JAMA Network Open (2022)

5][6] At least 10 variants were required for signature analysis, which included all predicted somatic point variants with unknown functional status.TMB, quantified in mutations per megabase (mt/Mb), was determined on up to 1.1 Mb of DNA.Statistical tests were 2-sided and used a significance threshold of P < .05. ResultsAmong 343 589 tumors, each from a different patient, 73 944 (21.5%) had sufficient mutations for signature analysis, of which 8143 tumors (11.0%) exhibited UV signatures (median [IQR] TMB, 31.3 [15.0-61.3]mt/Mb).Among the full cohort, the median (IQR) patient age was 63.0 (54.0-71.0)years, and 189 139 patients (55.0%) were women.Of 8143 tumors with UV mutational signatures, 4181 (51.3%) were submitted as tumors of primary cutaneous origin (3229 melanomas, 584 squamous cell carcinomas [SCCs], 191 basal cell carcinomas, 148 Merkel cell carcinomas, 82 angiosarcomas, 38 adnexal carcinomas, and 31 other mesenchymal neoplasms).Therefore, detection of a UV signature supported the diagnosis.In addition, 2765 tumors (34.0%) were submitted as tumors without a specified primary site (2150 melanomas, 228 SCCs, 147 carcinomas not otherwise specified, 64 neuroendocrine carcinomas, 33 adenocarcinomas, 7 sarcomas, and 136 other neoplasms).Detection of a UV signature in these tumors raised the possibility of cutaneous origin and a more precise tumor classification.Most interestingly, 1075 tumors (13.2%) were submitted as tumors of extracutaneous origin; thus, detection of a UV signature raised the possibility of an occult cutaneous primary and suggested the potential for reclassification on further clinicopathologic evaluation (Figure 1).Potentially misclassified tumors included 314 lung cancers, 168 sarcomas (including 28 malignant peripheral nerve sheath tumors and 3 clear cell sarcomas), 126 salivary gland cancers, 121 nonsalivary head and neck cancers, 54 breast cancers, 14 urothelial cancers, and 278 other neoplasms.Detection of a UV signature, regardless of a clinical diagnosis of cutaneous, unspecified, or extracutaneous origin, was associated with genomic alterations typical of cancers occurring on sun-exposed skin, including nonacral cutaneous melanoma (BRAF, NF1, NRAS), squamous cell carcinoma (NOTCH1/2/3, PTEN, PIK3CA), and basal cell carcinoma (PTCH1, SMO, SUFU) (Figure 2).Alterations in TERT, TP53, CDKN2A, and RB1 were frequent throughout the cohort. DiscussionThis retrospective cross-sectional study of 343 589 patients with solid tumors represents the largest pan-cancer genomic survey of UV mutational signatures conducted to our knowledge.Among 73 944 tumors suitable for mutational signature analysis, identification of a UV signature served as a useful biomarker for identifying cancers of potential cutaneous origin with important implications for clinical management.Although associated clinical data were not always available for direct review, in many cases, reclassification would be expected to affect pathologic and clinical stage, including primary vs metastatic status, as well as therapy selection.Limitations of this study include its retrospective nature, a lack of follow-up data, and the requirement for at least 10 mutations for signature analysis.Nevertheless, this study provides compelling evidence that NGS-based UV mutational signature analysis could refine the primary site in cancers of uncertain origin and suggest alternative diagnoses in tumors initially classified as extracutaneous.Therefore, this method provides a complementary tool to the standard histological and immunohistochemical workup, with important implications for clinical management.