Advances in Experimental Medicine and Biology 1268 Jörg Reichrath  Editor Sunlight, Vitamin D and Skin Cancer Third Edition Advances in Experimental Medicine and Biology SeriesEditors WimE.Crusio,InstitutdeNeurosciencesCognitivesetIntégratives d’Aquitaine,CNRSandUniversityofBordeaux,Pessac,Cedex,France HaidongDong,DepartmentsofUrologyandImmunology,MayoClinic, Rochester,MN,USA HeinfriedH.Radeke,Instituteof Pharmacology&Toxicology,Clinicofthe GoetheUniversityFrankfurtMain,FrankfurtamMain,Hessen,Germany NimaRezaei,ResearchCenterforImmunodeficiencies,Children’sMedical Center,TehranUniversityofMedicalSciences,Tehran,Iran Advances in Experimental Medicine and Biology provides a platform for scientific contributions in the main disciplines of the biomedicine and the life sciences. This series publishes thematic volumes on contemporary researchintheareasofmicrobiology,immunology,neurosciences,biochem- istry, biomedical engineering, genetics, physiology, and cancer research. Covering emerging topics and techniques in basic and clinical science, it bringstogethercliniciansandresearchersfromvariousfields. Advances in Experimental Medicine and Biology has been publishing exceptionalworksinthefieldforover40years,andisindexedinSCOPUS, Medline (PubMed), Journal Citation Reports/Science Edition, Science Cita- tion Index Expanded (SciSearch, Web of Science), EMBASE, BIOSIS, Reaxys, EMBiology, the Chemical Abstracts Service (CAS), and Pathway Studio. 2019ImpactFactor:2.4505YearImpactFactor:2.324 Moreinformationaboutthisseriesathttp://www.springer.com/series/5584 Jörg Reichrath Editor Sunlight, Vitamin D and Skin Cancer Third Edition Editor JörgReichrath CenterforClinicalandExperimentalPhotodermatology andDepartmentofDermatology SaarlandUniversityMedicalCenter Homburg,Germany ISSN0065-2598 ISSN2214-8019 (electronic) AdvancesinExperimentalMedicineandBiology ISBN978-3-030-46226-0 ISBN978-3-030-46227-7 (eBook) https://doi.org/10.1007/978-3-030-46227-7 #SpringerNatureSwitzerlandAG2008,2014,2020 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeor part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,recitation,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway, andtransmissionorinformationstorageandretrieval,electronicadaptation,computersoftware,or bysimilarordissimilarmethodologynowknownorhereafterdeveloped. Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthis publication does not imply, even in the absence of a specific statement, that such names are exemptfromtherelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. Thepublisher,theauthors,andtheeditorsaresafetoassumethattheadviceandinformationin thisbookarebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernor the authors or the editors give a warranty, expressed or implied, with respect to the material containedhereinorforanyerrorsoromissionsthatmayhavebeenmade.Thepublisherremains neutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations. ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSwitzerlandAG Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland Preface Thepowerfulraysofthesunrepresentaconditiosinequanonforlifeonearth in its present form and a major driver for human evolution. However, solar radiation exerts both positive and negative effects on human health. As a resultofthisdilemma,thereisanongoingcontroversyandintensediscussion in scientific communities and the general population to answer this funda- mentalquestionofenvironmentalmedicine:howmuchsunisgoodforhuman health? The first two editions of “Sunlight, Vitamin D and Skin Cancer,” designed and organized to be up-to-date reviews, were widely recognized benchmarks on the subject when published in 2008 and 2014, respectively. This new and extended volume continues to include extensive, in-depth chapters covering the most important aspects of the ongoing debate on how much sun is good/optimal for human health and how to balance between positiveandnegativeeffectsofsolarandartificialUVradiation.Asaresultof a mountain of new information about the health benefits caused by the UV- induced cutaneous synthesis of vitamin D, this book has been expanded substantially to include many new topics. It is generally accepted that UV exposure represents the most important risk factor for the development of non-melanoma skin cancer. Additionally, assessment of sun exposure parameters has consistently shown an association between the development of malignant melanoma and short-term intense UV exposure, particularly burns acquired in childhood. As a consequence, protection of the skin from UV radiation is an integral part of skin cancer prevention campaigns. How- ever,morechronicless-intenseUVexposurehasnotbeenfoundtobearisk factor for melanoma and in fact has been found in some studies to be protective.Moreover,besidesmanyotherphotoproducts,90%ofallrequisite vitaminDisformedwithintheskinthroughtheactionofthesun–aserious problem, for a connection between vitamin D deficiency and many severe diseases, including various types of cancer (e.g., colon, prostate, and breast cancer), has been demonstrated in a large number of studies. Hence, the association between vitamin D deficiency and various diseases, including internal malignancies, has opened a debate among dermatologists and other clinicians on how to balance between positive and negative effects of solar and artificial UV exposure. The goal of this volume is to provide a compre- hensive highly readable, updated, and extended overview on our present knowledgeofpositive andnegativeeffectsofUVexposure,withafocuson vitamin D and skin cancer. Topics are discussed in depth by leading v vi Preface researchersandcliniciansrangingfromthenewestfindingsinendocrinology (including the relevance of non-classical vitamin D metabolites), epidemiol- ogy, histology, photobiology, immunology, cytogenetics, and molecular pathology to new concepts for disease prevention and treatment. Experts in thefieldaswellashealth-careprofessionalsnotintimately involvedinthese specialized areas have provided the most significant and timely information relatedtothesetopics.Itistheaimofthisthirdeditiontosummarizeessential up-to-date information for every clinician or scientist interested in how to balancebetweenpositiveandnegativeeffectsofUVexposuretominimizethe risks that are associated with insufficient (e.g., developing vitamin D defi- ciency)andexcessive(e.g.,skincancer)exposure.Again,allthechaptersare writtenbyauthorswhoareexpertsintheirrespectiveresearchareas,andIam grateful for their willingness to contribute to this book. I am convinced that this edition will be as successful as the previous ones. I would also like to express my thanks to Larissa Albright, Anthony Dunlap, Murugesan Tamilselvan,andalltheothermembersoftheSpringerNaturestafffortheir expertise,diligence,andpatienceinhelpingmecompletethiswork. Enjoythereading! Homburg/Saar,Germany JörgReichrath Contents PartI Introduction 1 LessonsLearnedfromPaleolithicModelsandEvolution forHumanHealth:ASnapShotonBeneficialEffects andRisksofSolarRadiation. . . . . . . . . . . . . . . . . . . . . . . . 3 JörgReichrath PartII UV-InducedCutaneousSynthesisofVitaminD andthePhysiologicConsequences(I) 2 Sunlight,UVRadiation,VitaminD,andSkinCancer: HowMuchSunlightDoWeNeed?. . . . . . . . . . . . . . . . . . . . 19 MichaelF.Holick PartIII SolarRadiation,VitaminDandHumanHealth 3 VitaminDStatusandCancerIncidence,Survival, andMortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 HanseulKimandEdwardGiovannucci 4 VitaminDReceptorPolymorphismsandCancer. . . . . . . . . 53 PatriziaGnagnarella,SaraRaimondi,ValentinaAristarco, HarrietAnnJohansson,FedericaBellerba,FedericaCorso, andSaraGandini 5 OntheRelationshipBetweenSunExposure andAll-CauseMortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 PelleG.Lindqvist 6 EpidemiologyofSkinCancer:Update2019. . . . . . . . . . . . . 123 UlrikeLeiter,UlrikeKeim,andClausGarbe PartIV EpidemiologyofSkinCancer 7 SolarUVExposureandMortalityfromSkinTumors: AnUpdate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 MarianneBerwickandAmyGarcia vii viii Contents 8 SolariumUseandRiskforMalignantMelanoma: ManyOpenQuestions,NottheTimetoClose theDebate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 BarbaraBurgardandJörgReichrath 9 MolecularBiologyofBasalandSquamous CellCarcinomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 LarsBoeckmann,MarieChristineMartens,andSteffenEmmert PartV PhotocarcinogenesisofSkinCancer 10 HumanPapillomavirusesandSkinCancer. . . . . . . . . . . . . 195 SigrunSmola 11 TheImmuneSystemandPathogenesisofMelanoma andNon-melanomaSkinCancer. . . . . . . . . . . . . . . . . . . . . 211 KoryP.Schrom,InYoungKim,andElmaD.Baron 12 ProtectionfromUltravioletDamageandPhotocarcinogenesis byVitaminDCompounds. . . . . . . . . . . . . . . . . . . . . . . . . . 227 WarusavithanaGunawardenaManoriDeSilva, MyriamAbboud,ChenYang,KatieM.Dixon, MarkS.Rybchyn,andRebeccaS.Mason PartVI TheRelevanceoftheVitaminDEndocrineSystem forSkinCancer 13 TheRoleofClassicalandNovelFormsofVitaminD inthePathogenesisandProgressionofNonmelanoma SkinCancers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 AndrzejT.Slominski,AnnaA.Brożyna,MichalA.Zmijewski, ZoricaJanjetovic,Tae-KangKim,RadomirM.Slominski, RobertC.Tuckey,RebeccaS.Mason,AntonM.Jetten, PurushothamGuroji,JörgReichrath,CraigElmets, andMohammadAthar 14 TheVitaminDReceptorasTumorSuppressor inSkin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 DanielD.Bikle 15 CrosstalkBetweenVitaminDandp53SignalinginCancer: AnUpdate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 JörgReichrath,SandraReichrath,ThomasVogt,andKlaus Römer 16 Sunlight,VitaminD,andXerodermaPigmentosum. . . . . . . 319 MarieChristineMartens,SteffenEmmert,andLarsBoeckmann PartVII PreventionandManagementofSkinCancer 17 Update:SolarUVRadiation,VitaminD,andSkinCancer SurveillanceinOrganTransplantRecipients(OTRs). . . . . . 335 RomanSaternus,ThomasVogt,andJörgReichrath Contents ix 18 SunscreensintheUnitedStates:CurrentStatus andFutureOutlook. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 KatherineS.GlaserandKennethJ.Tomecki 19 AHandfulofSunscreenforWhole-BodyApplication. . . . . 381 IdaM.Heerfordt,PeterA.Philipsen,andHansChristianWulf 20 UltravioletExposureScenarios:BalancingRisks ofErythemaandBenefitsofCutaneousVitaminD Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 AnnR.WebbandOlaEngelsen PartVIII UV-InducedCutaneousSynthesisofVitaminD andthePhysiologicConsequences–II.PromiseandOutlook 21 ThePaleolithicNutritionModelinRelationtoUltraviolet LightandVitaminD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409 ReinholdVieth Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421