[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-457850-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-457850-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","does-basal-cell-carcinoma-arise-from-a-precursor-lesion","Does Basal Cell Carcinoma Arise from a Precursor Lesion?","","Basal cell carcinoma (BCC) is driven in nearly all cases by mutations that constitutively activate upstream Hedgehog (HH) signaling, either via loss-of-function PTCH1 or gain-of-function SMO alterations. Unlike squamous cell carcinoma, no clinically apparent BCC precursor has been identified. Genomic studies indicate BCC requires PTCH1/SMO changes plus additional genetic hits, supporting a stepwise progression model. Based on Gorlin syndrome, the authors speculate that a subset may originate from a subclinical basaloid follicular hamartoma or related precursor lesion.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/does-basal-cell-carcinoma-arise-from-a-precursor-lesion/457850/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/does-basal-cell-carcinoma-arise-from-a-precursor-lesion/457850.png","ImageObject",300,407,{"name":42,"@type":43},"CatatanPagi","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-31","2026-09-30",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",8,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What genetic events commonly drive basal cell carcinoma (BCC)?","Question",{"text":63,"@type":64},"Most BCCs are driven by mutations that activate upstream Hedgehog (HH) signaling, including PTCH1 loss-of-function and SMO gain-of-function changes.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"Why has a clear precursor lesion for BCC been difficult to identify clinically?",{"text":68,"@type":64},"Unlike other skin cancers, a clinically apparent precursor lesion for BCC has not been identified, and genomic evidence suggests multiple additional genetic changes are needed for progression.",{"name":70,"@type":61,"acceptedAnswer":71},"How might Gorlin syndrome inform the idea of BCC arising from a precursor lesion?",{"text":72,"@type":64},"Gorlin syndrome patients carry germline PTCH1 mutations and form BCCs early, leading the authors to speculate that some BCCs may arise from a subclinical basaloid follicular hamartoma or similar precursor lesion.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},457850,1790825588,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":111,"show_sort_weight":112,"slug":113},"Research & Report",30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145,"preview_page_count":4},962090894170,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Author Manuscript Author Manuscript Author Manuscript Author Manuscript  \n\n| | HHS Public Access\u003Cbr>Author manuscript\u003Cbr>J Invest Dermatol. Author manuscript; available in PMC 2026 January 09. |\n| --- | --- |\n\nPublished in final edited form as:  \nJ Invest Dermatol. 2026 April ; 146(4): 905–913. doi:10.1016/j.jid.2025.09.381 .  \nDoes Basal Cell Carcinoma Arise from a Precursor Lesion?  \nSunny Y. Wong 1,2 , Paul W. Harms 1,3 , Andrzej A. Dlugosz 1,2  \n1 Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA  \n2 Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA  \n3 Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA  \nAbstract  \nBasal cell carcinoma (BCC) is driven in nearly all cases by mutations that constitutively activate upstream Hedgehog (HH) signaling, either through loss-of-function mutations in PTCH1 or gainof-function mutations in SMO. Unlike other skin cancers such as squamous cell carcinoma, a clinically apparent precursor lesion for BCC has not been identified. Recent genomic analyses of both human and mouse tumors suggest that BCC formation requires not only PTCH1 or SMO mutations but also additional genetic changes. These findings imply that some BCCs may follow a stepwise tumor progression model, whereby the accumulation of multiple mutational“hits” is needed to convert an indolent precursor lesion into malignant disease. On the basis of studies in patients with Gorlin syndrome who harbor germline PTCH1 mutations and are genetically predisposed to forming BCC, we speculate that at least a subset of BCCs arises from a subclinical basaloid follicular hamartoma or similar precursor lesion. Altogether, convergent evidence suggests that activating upstream HH signaling is necessary but not sufficient for BCC formation. This evolving view of BCC has important implications for our basic understanding of these tumors, for our interpretation of findings from BCC mouse models, and for guiding treatment.  \nKeywords  \nBasaloid follicular hamartoma; BCC; BFH; Hedgehog signaling; Nonmelanoma skin cancer  \nBASAL CELL CARCINOMA: NO LONGER A “SIMPLE” CANCER  \nEach year, over 4 million individuals are diagnosed with basal cell carcinoma (BCC) in the United States, making this by far the most common cancer (Krakowski et al, 2022) .  \nThis is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)).  \nCorrespondence: Sunny Y. Wong, Department of Dermatology, University of Michigan, 1500 East Medical Center Drive, 3217 Cancer Center, Ann Arbor, Michigan 48109, USA. sunnyw@umich.edu and Andrzej A. Dlugosz, Department of Dermatology, University of Michigan, 1500 East Medical Center Drive, 3316 Cancer Center, Ann Arbor, Michigan 48109, [USA. dlugosza@umich.edu](USA. dlugosza@umich.edu).  \nAUTHOR CONTRIBUTIONS  \nFunding Acquisition: SYW, AAD; Supervision: SYW, AAD; Writing—Original Draft Preparation: SYW, PWH, AAD CONFLICT OF INTEREST  \nThe authors state no conflict of interest.  \nAuthor Manuscript Author Manuscript Author Manuscript Author Manuscript  \nWong et al. Page 2  \nRoughly 1 in 6 Americans will develop BCC in their lifetimes, and the incidence of this nonmelanoma skin cancer has risen steadily over the past few decades, coinciding with increased UV exposure from the widespread use of cosmetic tanning beds and possibly from environmental factors (Ferrucci et al, 2012; Parker, 2021) . Consequently, treating BCC is among the most common dermatologic procedures and represents a substantial burden on our healthcare system (Wu et al, 2015) .  \nAlthough most BCCs arise sporadically beginning at middle age, patients suffering from a rare disorder known as Gorlin syndrome (also known as basal cell nevus syndrome [BCNS]) are genetically predisposed to forming numerous BCCs beginning in the first decade of life (Nguyen et al, 2021; Rehefeldt-Erne et al, 2","cbCaio528VeW2dl4","https://ap.wps.com/l/cbCaio528VeW2dl4","pdf",1418107,17,"English","# Abstract\n# Basal Cell Carcinoma: No Longer a “Simple” Cancer\n## Epidemiology and Burden\n## Genetic Predisposition (Gorlin Syndrome)\n## Hedgehog (HH) Pathway and Therapeutic Implications","[{\"question\":\"What genetic events commonly drive basal cell carcinoma (BCC)?\",\"answer\":\"Most BCCs are driven by mutations that activate upstream Hedgehog (HH) signaling, including PTCH1 loss-of-function and SMO gain-of-function changes.\"},{\"question\":\"Why has a clear precursor lesion for BCC been difficult to identify clinically?\",\"answer\":\"Unlike other skin cancers, a clinically apparent precursor lesion for BCC has not been identified, and genomic evidence suggests multiple additional genetic changes are needed for progression.\"},{\"question\":\"How might Gorlin syndrome inform the idea of BCC arising from a precursor lesion?\",\"answer\":\"Gorlin syndrome patients carry germline PTCH1 mutations and form BCCs early, leading the authors to speculate that some BCCs may arise from a subclinical basaloid follicular hamartoma or similar precursor lesion.\"}]","Does Basal Cell Carcinoma Arise from a Precursor Lesion? | PDF",1790750675,43]