Prevalence of UV Mutational Signatures Among Cutaneous Primary Tumors

UV radiation exposure causes a characteristic genomic mutational pattern associated with elevated tumor mutational burden (TMB) via the formation of pyrimidine-pyrimidine photodimers (COSMIC signature 7).¹ This signature is highly specific to UV-mediated mutagenesis, suggests cutaneous origin in cancers of uncertain primary site, and may also flag potential misdiagnoses by conventional histopathological examination. This principle has been used to support cutaneous origin for what had previously been termed primary pulmonary melanoma,² but broader pan-cancer analyses are limited. Here, we examined the frequency of UV signatures in a pan-cancer next-generation sequencing (NGS) database.

Approval for this cross-sectional study, including a waiver of informed consent and Health Insurance Portability and Accountability Act waiver of authorization, was obtained from the Western Institutional Review Board. This study is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

We retrospectively analyzed all solid tumors submitted to Foundation Medicine for comprehensive genomic profiling between December 2013 and June 2021. NGS was performed using hybrid-capture as previously described.³ Mutational signature calling was performed using the decomposition method of Zehir et al⁴ using the 96-feature single-base substitution COSMIC reference signatures (version 2, March 2015) generated by Alexandrov et al,⁵ in which signature 7 is considered the UV signature, to yield coefficient weights representing the contributions of the signatures in each sample.^4-6 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.

Among 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.

This 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.

Accepted for Publication: January 30, 2022.

Published: March 23, 2022. doi:10.1001/jamanetworkopen.2022.3833

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2022 Mata DA et al. JAMA Network Open.

Corresponding Author: Douglas A. Mata, MD, MPH, Foundation Medicine, 150 Second St, Cambridge, MA 02141 (douglas.a.mata@gmail.com).

Author Contributions: Dr Mata had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Mata, Tse, Decker.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Mata, Williams, Sokol, Fleischmann, Tse, Decker.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Mata, Sokol, Fleischmann, Decker.

Supervision: Mata.

Conflict of Interest Disclosures: All authors reported being employed by Foundation Medicine, and receive part of their compensation in equity from Roche Holding, the parent company of Foundation Medicine. Dr Mata reported receiving personal fees from Astellas outside the submitted work. Dr Decker reported owning stock in Vaccitech outside the submitted work.

Funding/Support: This work was supported by Foundation Medicine.

Role of the Funder/Sponsor: All authors are employees of Foundation Medicine and had roles in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Douglas I. Lin, Matthew Hiemenz, Donna Ferguson, Tyler Janovitz, Jonathan Killian, Iain A. Speece, Matthew L. Margolis, Mirna Lechpammer, Vamsi Parimi, Garrett M. Frampton, Richard S. P. Huang, Jeffrey S. Ross, Mia A. Levy, Geoffrey R. Oxnard, Shakti Ramkissoon, Jo-Anne Vergilio, and Julia Elvin provided feedback on the manuscript. None were compensated for their contributions.