From Springer Nature via Jisc Publications RouterHistory: received 2021-02-05, rev-recd 2021-02-26, accepted 2021-03-02, registration 2021-03-04, pub-electronic 2021-04-06, online 2021-04-06, pub-print 2021-08-17Publication status: PublishedFunder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289; Grant(s): A27412 and A22902Summary: In 1967, Sandy Posey pronounced that sunglasses are essential beachwear (https://www.youtube.com/watch?v=4HVBEb-GA1Y). Now, whole-genome sequencing reveals that ultraviolet radiation (UVR) can contribute to melanomas in the iris and conjunctiva, data that provide a molecular explanation for why it is important to protect our eyes from exposure to UVR

Dhomen, Nathalie

Marais, Richard

Mundra, Piyushkumar A.

ChesterRep

COMMENTSunglasses to hide behind may also prevent melanomaof the eyesNathalie Dhomen1, Piyushkumar A. Mundra1 and Richard Marais 1In 1967, Sandy Posey pronounced that sunglasses are essential beachwear (https://www.youtube.com/watch?v=4HVBEb-GA1Y).Now, whole-genome sequencing reveals that ultraviolet radiation (UVR) can contribute to melanomas in the iris and conjunctiva,data that provide a molecular explanation for why it is important to protect our eyes from exposure to UVR.British Journal of Cancer (2021) 125:470–472; https://doi.org/10.1038/s41416-021-01343-8MAINThe American Joint Committee on Cancer (AJCC) staging systememphasises body site as important for melanoma diagnosis,1because site predicts broad clinical characteristics and therefromtherapeutic options. Common cutaneous melanomas (~90% ofcases) arise in the skin. More rarely, melanomas arise in themucosa (~1–2% of cases) of, for example, the gastrointestinal andgenitourinary tracts, and in the eyes (~5% of cases), either withinthe uveal tract (choroid, iris and ciliary body) or in the conjunctiva(the mucosa covering the sclera and lining the insides of theeyelids) (see Fig. 1). Of particular concern, these rare melanomasubtypes have limited treatment options.Many epidemiological and experimental studies link commoncutaneous melanoma of non-glabrous skin to exposure to ultravioletradiation (UVR) and their genomes consequently show evidence ofdirect UVR-induced DNA damage, presenting with high tumourmutation burdens (TMBs), large numbers of C>T transitions andpredominance of a mutational process known as single basesubstitution signature 7 (SBS7).2 Rare melanomas by contrastgenerally have low TMB and low proportions of C>T transitionsand SBS7, but instead have large numbers of genome structuralvariations (SVs) with characteristic chromosomal gains and losses.The different melanoma subtypes are also driven by distinctoncogenes. Cutaneous melanomas are typically driven by BRAF,NRAS and NF1, with secondary mutations in hTERT and TP53. Mucosalmelanomas are driven by BRAF and NRAS but at a lower frequencythan cutaneous melanoma, and KIT is also a frequent driver in thisdisease. Lastly, uveal melanomas are driven by GNAQ, GNA11 andCYSLTR2, with secondary mutations in BAP1, SF3B1 and EIF1AX.3–6Thus, different melanoma subtypes have distinct aetiologies,but recent genomic evidence suggests that these distinctions arenot so clear-cut. In 2018, we reported that ~15% of commoncutaneous melanomas do not appear to be UVR-driven,2 causingus to question by analogy if UVR is involved in some raremelanomas. In this context, the eye is particularly intriguing,because although the uveal tract is largely sun-protected, the irisis sun-exposed, and the conjunctiva is unusual because it is apartially sun-exposed mucosal membrane (Fig. 1). Sun exposurecauses conditions such as photokeratitis, pinguecula, pterygium,cataracts and macular degeneration, and three recent papers nowestablish that it also contributes to melanoma of the eye.The first paper, from Nicholas Hayward and colleagues7reported whole-genome sequencing (WGS) of 103 uveal melano-mas. As expected, these melanomas generally presented lowTMBs, but eight were from the iris and they all presented highTMB and SBS7 predominance. Intriguingly, despite this clearevidence of UVR-induced DNA damage, the iris melanomas werestill driven by mutant GNAQ, GNA11 or CYSLTR2, and six samplesalso had mutations in BAP1, EIF1AX or SF3B1.The other two papers reported the genomic landscapes ofconjunctival melanomas. Following a brief earlier report,8 CarloRivolta and colleagues9 have now analysed WGS on twoconjunctival melanomas and whole-exome sequencing on afurther 12. They reported high proportions of copy numbervariants, but also high TMBs and high proportions of C>Ttransitions. BRAF, NRAS, HRAS or NF1 were mutated in 12 lesions,hTERT was mutated in nine, and TP53 was also mutated in nine.Notably, SBS7 was predominant, but the association betweenSBS7 and presumed sun exposure was weak.In the third paper, we reported WGS of ten conjunctivalmelanomas compared with eight other mucosal melanomas and54 cutaneous melanomas.10 The conjunctival melanomas hadgenome SVs that were similar to the other mucosal melanomas,but nine also had high TMBs, high proportions of C>T transitionsand SBS7 predominance. Six of the nine had BRAF, NRAS and NF1mutations, four had hTERT mutations, two had TP53 mutation, andeight had mutations in 1 to 11 genes recurrently mutated incommon cutaneous melanoma. Notably, five of the SBS7-dominant lesions were from the sun-exposed bulbar conjunctivaand the non-SBS7 lesion was from the largely sun-protectedfornix, but one SBS7-dominant lesion spanned sun-exposed andsun-protected sites and three were from the largely sun-protectedtarsal conjunctiva (Fig. 1). In our validation cohort, UVR involve-ment was evident in some lip and gingiva mucosal melanomas,which can be sun-exposed, but also in the nasal cavity andoropharynx mucosal melanomas, which are sun-protected. Thus,our data also showed a weak association between UVR signaturesand presumed sun exposure sites.www.nature.com/bjcReceived: 5 February 2021 Revised: 26 February 2021 Accepted: 2 March 2021Published online: 6 April 20211Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, UKCorrespondence: Richard Marais (richard.marais@cruk.manchester.ac.uk)© The Author(s) 2021 Published by Springer Nature on behalf of Cancer Research UKThere is interesting biology to explore, but these data show thatUVR plays a role in uveal melanomas in the iris, most conjunctivalmelanomas and some mucosal melanomas at other sun-exposedsites. Curiously, despite clear UVR signatures, the iris melanomaswere still driven by uveal melanoma oncogenes and theconjunctival melanomas still had the genomic SVs characteristicof mucosal melanoma. It is unclear what drives mutagenesis inuveal and mucosal melanomas, but the persistence of baselinegenomic features in the UVR-driven lesions suggests that they arepeculiar to the different microenvironments in which melanocytesreside, and we posit that UVR accelerates melanomagenesis atvarious sites by imposing additional events over the existing site-specific processes. That 15% of skin melanomas do not appear tobe UVR-driven2 suggests that the skin microenvironment also hasan underlying process that can be accelerated by UVR.These new findings have two important implications. First, theyshow that UVR can damage melanocytes in the eye to drivemelanomagenesis, emphasising the importance of public healthcampaigns advocating sunglasses to protect the eyes from UVR.This is especially important in strong sunlight, such as on thebeach or during activities including driving, boating and skiing.Second, the genomes of UVR-driven rare melanomas areremarkably similar to those of UVR-driven cutaneous melanomasfor which targeted therapies and immunotherapies are approved,and we advocate therefore that UVR-driven rare melanomasshould be considered for these therapies. Accepting the eye as animmune-privileged site, we nevertheless advocate immunothera-pies for UVR-driven iris melanoma, particularly in the metastaticsetting. For UVR-driven conjunctival and other mucosal melano-mas, we again advocate immunotherapies, or if tractable BRAFmutations are present, BRAF/MEK inhibitors. As described above,the site of a melanoma does not immediately implicate UVR.Therefore, to facilitate administration of these drugs, we propose asimple assay based on targeted sequencing of only ten genes(LRP1B, GPR98, XIRP2, PKHD1L1, USH2A, DNAH9, PCDH15, DNAH10,TP53 and PCDHAC1) that can reveal UVR involvement withreasonable certainty, and which is more convenient and cost-effective than WGS.2,10AUTHOR CONTRIBUTIONSN.D., P.A.M. and R.M. jointly conceived and wrote the manuscript.ADDITIONAL INFORMATIONEthics approval and consent to participate Not applicable.Data availability Not applicable.Competing interests R.M. consultants for Pfizer, and as a former Institute of CancerResearch (London) employee, he may benefit from commercialised programmes. Theother authors declare no competing interests.Funding information We are grateful for funding from Cancer Research UK (A27412and A22902), the Wellcome Trust (100282/Z/12/Z), the European Research Council(ERC-ADG-2014 671262) and the European Commission under the Horizon 2020programme (U.M. Cure; project 667787).Publisher’s note Springer Nature remains neutral with regard to jurisdictional claimsin published maps and institutional affiliations.REFERENCES1. Amin, M. B., American Joint Committee on Cancer and American Cancer Society.in AJCC Cancer Staging Manual 8th edn (editor-in-chief Amin, M. B.; eds Stephen,B. E. and 16 others; Technical editor Donna, M. G.; Managing editor Laura, R. M.(American Joint Committee on Cancer, Springer, 2017).2. Trucco, L. D., Mundra, P. A., Hogan, K., Garcia-Martinez, P., Viros, A., Mandal, A. K.et al. Ultraviolet radiation-induced DNA damage is prognostic for outcome inmelanoma. Nat. Med. 25, 221–224 (2019).3. Hayward, N. K., Wilmott, J. S., Waddell, N., Johansson, P. A., Field, M. A., Nones, K.et al. Whole-genome landscapes of major melanoma subtypes. Nature 545,175–180 (2017).Choroid Bulbar conjunctiva (over sclera) Fornix Tarsal  conjunctiva Ciliary body Iris Fig. 1 Areas of the eye in which melanoma arises. Sagittal cross-section and frontal view of the eye indicating the location of thecomponents of the uveal tract (choroid, ciliary body and iris; red) and the conjunctiva (tarsal conjunctiva, fornix and bulbar conjunctiva; blue).The iris and bulbar conjunctiva are the sun-exposed areas of the uveal tract and conjunctiva respectively. Created with BioRender.com.Sunglasses to hide behind may also prevent melanoma of the eyesN Dhomen et al.4711234567890();,:4. Zhou, R., Shi, C., Tao, W., Li, J., Wu, J., Han, Y. et al. Analysis of mucosal melanomawhole-genome landscapes reveals clinically relevant genomic aberrations. Clin.Cancer Res. 25, 3548–3560 (2019).5. Robertson, A. G., Shih, J., Yau, C., Gibb, E. A., Oba, J., Mungall, K. L. et al. Integrativeanalysis identifies four molecular and clinical subsets in uveal melanoma. CancerCell 32, 204–220 e215 (2017).6. Newell, F., Kong, Y., Wilmott, J. S., Johansson, P. A., Ferguson, P. M., Cui, C. et al.Whole-genome landscape of mucosal melanoma reveals diverse drivers andtherapeutic targets. Nat. Commun. 10, 3163 (2019).7. Johansson, P. A., Brooks, K., Newell, F., Palmer, J. M., Wilmott, J. S., Pritchard, A. L.et al. Whole genome landscapes of uveal melanoma show an ultraviolet radiationsignature in iris tumours. Nat. Commun. 11, 2408 (2020).8. Rivolta, C., Royer-Bertrand, B., Rimoldi, D., Schalenbourg, A., Zografos, L., Leyvraz,S. et al. UV light signature in conjunctival melanoma; not only skin should beprotected from solar radiation. J. Hum. Genet. 61, 361–362 (2016).9. Cisarova, K., Folcher, M., El Zaoui, I., Pescini-Gobert, R., Peter, V. G., Royer-Bertran,B. et al. Genomic and transcriptomic landscape of conjunctival melanoma. PLoSGenet. 16, e1009201 (2020).10. Mundra, P. A., Dhomen, N., Rodrigues, M., Mikkelsen, L. H., Cassoux, N., Brooks, K.et al. Ultraviolet radiation drives mutations in a subset of mucosal melanomas.Nat. Commun. 12, 259 (2021).Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in anymedium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directlyfrom the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2021Sunglasses to hide behind may also prevent melanoma of the eyesN Dhomen et al.472

Sunglasses to hide behind may also prevent melanoma of the eyes

https://chesterrep.openrepository.com/bitstream/10034/625616/2/41416_2021_Article_1343.pdf

Sunglasses to hide behind may also prevent melanoma of the eyes

Abstract

Similar works

Full text

Available Versions

ChesterRep