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• W4380996161 abstract "Dystrophic epidermolysis bullosa is a rare genetic skin disorder caused by COL7A1 sequence variations that result in type VII collagen deficits and cutaneous and extracutaneous manifestations. One serious complication of dystrophic epidermolysis bullosa is cutaneous squamous cell carcinoma, a leading driver of morbidity and mortality, especially among patients with recessive dystrophic epidermolysis bullosa. Type VII collagen deficits alter TGFβ signaling and evoke multiple other cutaneous squamous cell carcinoma progression–promoting activities within epidermal microenvironments. This review examines cutaneous squamous cell carcinoma pathophysiology in dystrophic epidermolysis bullosa with a focus on known oncogenesis pathways at play and explores the idea that therapeutic type VII collagen replacement may reduce cutaneous squamous cell carcinoma risk. Dystrophic epidermolysis bullosa is a rare genetic skin disorder caused by COL7A1 sequence variations that result in type VII collagen deficits and cutaneous and extracutaneous manifestations. One serious complication of dystrophic epidermolysis bullosa is cutaneous squamous cell carcinoma, a leading driver of morbidity and mortality, especially among patients with recessive dystrophic epidermolysis bullosa. Type VII collagen deficits alter TGFβ signaling and evoke multiple other cutaneous squamous cell carcinoma progression–promoting activities within epidermal microenvironments. This review examines cutaneous squamous cell carcinoma pathophysiology in dystrophic epidermolysis bullosa with a focus on known oncogenesis pathways at play and explores the idea that therapeutic type VII collagen replacement may reduce cutaneous squamous cell carcinoma risk. Dystrophic epidermolysis bullosa (DEB) is a major subtype of the epidermolysis bullosa (EB) family of genetic skin fragility disorders (Has et al., 2020Has C. Bauer J.W. Bodemer C. Bolling M.C. Bruckner-Tuderman L. Diem A. et al.Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.Br J Dermatol. 2020; 183: 614-627Crossref PubMed Scopus (310) Google Scholar). This rare disease has an estimated prevalence ranging from 3 to 12 cases per million across a number of countries, although these data may reflect underdiagnosis of milder cases (Eichstadt et al., 2019Eichstadt S. Tang J.Y. Solis D.C. Siprashvili Z. Marinkovich M.P. Whitehead N. et al.From clinical phenotype to genotypic modelling: incidence and prevalence of recessive dystrophic epidermolysis bullosa (RDEB).Clin Cosmet Investig Dermatol. 2019; 12: 933-942Crossref PubMed Scopus (8) Google Scholar; Feinstein et al., 2019Feinstein J.A. Jambal P. Peoples K. Lucky A.W. Khuu P. Tang J.Y. et al.Assessment of the timing of milestone clinical events in patients with epidermolysis bullosa from North America.JAMA Dermatol. 2019; 155: 196-203Crossref PubMed Scopus (26) Google Scholar; Fine, 2016Fine J.D. Epidemiology of inherited epidermolysis bullosa based on incidence and prevalence estimates from the national epidermolysis bullosa registry.JAMA Dermatol. 2016; 152: 1231-1238Crossref PubMed Scopus (150) Google Scholar; Has et al., 2023Has C. Hess M. Anemüller W. Blume-Peytavi U. Emmert S. Fölster-Holst R. et al.Epidemiology of inherited epidermolysis bullosa in Germany.J Eur Acad Dermatol Venereol. 2023; 37: 402-410Crossref Scopus (0) Google Scholar; Petrof et al., 2022Petrof G. Papanikolaou M. Martinez A.E. Mellerio J.E. McGrath J.A. Bardhan A. et al.The epidemiology of epidermolysis bullosa in England and Wales: data from the national epidermolysis bullosa database.Br J Dermatol. 2022; 186: 843-848Crossref PubMed Scopus (0) Google Scholar). In DEB, COL7A1 sequence variations lead to deficits in type VII collagen (COL7), the primary component of the anchoring fibrils that bind elements within the epidermal basement membrane and entrap dermal collagen fibrils (Burgeson, 1993Burgeson R.E. Type VII collagen, anchoring fibrils, and epidermolysis bullosa.J Invest Dermatol. 1993; 101: 252-255Abstract Full Text PDF PubMed Google Scholar), thus promoting epidermal-dermal adhesion (Has et al., 2020Has C. Bauer J.W. Bodemer C. Bolling M.C. Bruckner-Tuderman L. Diem A. et al.Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.Br J Dermatol. 2020; 183: 614-627Crossref PubMed Scopus (310) Google Scholar; Mariath et al., 2020Mariath L.M. Santin J.T. Schuler-Faccini L. Kiszewski A.E. Inherited epidermolysis bullosa: update on the clinical and genetic aspects.An Bras Dermatol. 2020; 95: 551-569Crossref Scopus (27) Google Scholar). The most visible consequence of anchoring fibril deficiencies may be skin blistering and wounding in response to minimal friction or mechanical trauma (Has et al., 2020Has C. Bauer J.W. Bodemer C. Bolling M.C. Bruckner-Tuderman L. Diem A. et al.Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.Br J Dermatol. 2020; 183: 614-627Crossref PubMed Scopus (310) Google Scholar). However, symptoms extend beyond cutaneous manifestations and include a range of complications involving the musculoskeletal, ocular, gastrointestinal, cardiovascular, and genitourinary systems (Fine et al., 2014Fine J.D. Bruckner-Tuderman L. Eady R.A. Bauer E.A. Bauer J.W. Has C. et al.Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification.J Am Acad Dermatol. 2014; 70: 1103-1126Abstract Full Text Full Text PDF PubMed Scopus (649) Google Scholar). DEB can be inherited as an autosomal recessive (RDEB) or autosomal dominant (DDEB) trait, with RDEB characterized by more severe symptoms than DDEB; however, symptom severity varies across the two subtypes with considerable overlap (Bardhan et al., 2020Bardhan A. Bruckner-Tuderman L. Chapple I.L.C. Fine J.D. Harper N. Has C. et al.Epidermolysis bullosa.Nat Rev Dis Primers. 2020; 6: 78Crossref PubMed Scopus (126) Google Scholar; Bruckner-Tuderman, 2010Bruckner-Tuderman L. Dystrophic epidermolysis bullosa: pathogenesis and clinical features.Dermatol Clin. 2010; 28: 107-114Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar; Devries et al., 2004Devries D.T. Johnson L.B. Weiner M. Fine J.D. Relative extent of skin involvement in inherited epidermolysis bullosa (EB): composite regional anatomic diagrams based on the findings of the National EB Registry, 1986 to 2002.J Am Acad Dermatol. 2004; 50: 572-581Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; Fine et al., 2009Fine J.D. Johnson L.B. Weiner M. Li K.P. Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986–2006.J Am Acad Dermatol. 2009; 60: 203-211Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Fine et al., 2004Fine J.D. Johnson L.B. Weiner M. Stein A. Cash S. DeLeoz J. et al.Genitourinary complications of inherited epidermolysis bullosa: experience of the national epidermylosis bullosa registry and review of the literature.J Urol. 2004; 172: 2040-2044Crossref PubMed Scopus (0) Google Scholar, Fine et al., 2005Fine J.D. Johnson L.B. Weiner M. Stein A. Cash S. Deleoz J. et al.Pseudosyndactyly and musculoskeletal contractures in inherited epidermolysis bullosa: experience of the National Epidermolysis Bullosa Registry, 1986–2002.J Hand Surg Br. 2005; 30: 14-22Crossref PubMed Scopus (0) Google Scholar; Fulchand et al., 2021Fulchand S. Harris N. Li S. Barriga M. Gorell E. De Souza M. et al.Patient-reported outcomes and quality of life in dominant dystrophic epidermolysis bullosa: a global cross-sectional survey.Pediatr Dermatol. 2021; 38: 1198-1201Crossref PubMed Scopus (0) Google Scholar). One of the most serious complications of EB and DEB in particular is an aggressive form of cutaneous squamous cell carcinoma (cSCC) that tends to develop within areas of wounded skin, often on the extremities and over bony prominences (Figure 1a) (Fine et al., 2009Fine J.D. Johnson L.B. Weiner M. Li K.P. Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986–2006.J Am Acad Dermatol. 2009; 60: 203-211Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; Kim et al., 2018Kim M. Li M. Intong-Wheeler L.R.A. Tran K. Marucci D. Murrell D.F. Epidemiology and outcome of squamous cell carcinoma in epidermolysis bullosa in Australia and New Zealand.Acta Derm Venereol. 2018; 98: 70-76Crossref PubMed Scopus (0) Google Scholar; Montaudié et al., 2016Montaudié H. Chiaverini C. Sbidian E. Charlesworth A. Lacour J.P. Inherited epidermolysis bullosa and squamous cell carcinoma: a systematic review of 117 cases.Orphanet J Rare Dis. 2016; 11: 117Crossref PubMed Scopus (66) Google Scholar; Paganelli et al., 2022Paganelli A. Giordano E. Fiorentini C. Ferrari B. Reggiani C. Garbarino F. et al.Surgical management and oncological follow-up of cutaneous squamous cell carcinomas arising in epidermolysis bullosa patients.Int J Dermatol. 2022; 61: 1171-1174Crossref PubMed Scopus (0) Google Scholar; Robertson et al., 2021Robertson S.J. Orrin E. Lakhan M.K. O'Sullivan G. Felton J. Robson A. et al.Cutaneous squamous cell carcinoma in epidermolysis bullosa: a 28-year retrospective study.Acta Derm Venereol. 2021; 101adv00523Crossref PubMed Scopus (7) Google Scholar). Patients with DEB are at considerable risk for developing cSCC: the average age of cSCC onset in general RDEB, severe RDEB, and DDEB is 32.5 years, 29.5 years, and 45 years, respectively, and risk increases with age such that nearly all individuals (90.1%) with severe RDEB develop tumors by 55 years (Figure 1b) (Fine et al., 2009Fine J.D. Johnson L.B. Weiner M. Li K.P. Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986–2006.J Am Acad Dermatol. 2009; 60: 203-211Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; Montaudié et al., 2016Montaudié H. Chiaverini C. Sbidian E. Charlesworth A. Lacour J.P. Inherited epidermolysis bullosa and squamous cell carcinoma: a systematic review of 117 cases.Orphanet J Rare Dis. 2016; 11: 117Crossref PubMed Scopus (66) Google Scholar; Robertson et al., 2021Robertson S.J. Orrin E. Lakhan M.K. O'Sullivan G. Felton J. Robson A. et al.Cutaneous squamous cell carcinoma in epidermolysis bullosa: a 28-year retrospective study.Acta Derm Venereol. 2021; 101adv00523Crossref PubMed Scopus (7) Google Scholar). DEB-associated risk factors for cSCC, namely chronic wounding and subsequent tissue remodeling, differ from those of non-EB cSCC, which is associated with UV radiation exposure and typically occurs much later in life, with an average age at diagnosis of 80 years and a prevalence of approximately 20% among White adults by age 70 years (Föll et al., 2018Föll M.C. Fahrner M. Gretzmeier C. Thoma K. Biniossek M.L. Kiritsi D. et al.Identification of tissue damage, extracellular matrix remodeling and bacterial challenge as common mechanisms associated with high-risk cutaneous squamous cell carcinomas.Matrix Biol. 2018; 66: 1-21Crossref PubMed Scopus (32) Google Scholar; Montaudié et al., 2016Montaudié H. Chiaverini C. Sbidian E. Charlesworth A. Lacour J.P. Inherited epidermolysis bullosa and squamous cell carcinoma: a systematic review of 117 cases.Orphanet J Rare Dis. 2016; 11: 117Crossref PubMed Scopus (66) Google Scholar; Nagarajan et al., 2019Nagarajan P. Asgari M.M. Green A.C. Guhan S.M. Arron S.T. Proby C.M. et al.Keratinocyte carcinomas: current concepts and future research priorities.Clin Cancer Res. 2019; 25: 2379-2391Crossref PubMed Scopus (71) Google Scholar; Stern, 2010Stern R.S. Prevalence of a history of skin cancer in 2007: results of an incidence-based model.Arch Dermatol. 2010; 146: 279-282Crossref PubMed Scopus (311) Google Scholar). Other risk factors for non-EB cSCC include cutaneous infection with human papillomavirus (Rollison et al., 2021Rollison D.E. Amorrortu R.P. Zhao Y. Messina J.L. Schell M.J. Fenske N.A. et al.Cutaneous human papillomaviruses and the risk of keratinocyte carcinomas.Cancer Res. 2021; 81: 4628-4638Crossref PubMed Scopus (11) Google Scholar) and immunosuppressed or immunodeficient states, such as those following organ transplant or during hematologic malignancies, indicating a procancerogenic or promoter role for impaired immune function (Nagarajan et al., 2019Nagarajan P. Asgari M.M. Green A.C. Guhan S.M. Arron S.T. Proby C.M. et al.Keratinocyte carcinomas: current concepts and future research priorities.Clin Cancer Res. 2019; 25: 2379-2391Crossref PubMed Scopus (71) Google Scholar). In addition, cSCC outcomes in those with DEB tend to be poor because of frequent metastases and recurrences that yield a relapse rate of 40% despite radical surgical treatment, whereas non-EB cSCC can often be successfully treated with surgical excision (Christiano et al., 1999Christiano A.M. Crollick J. Pincus S. Uitto J. Squamous cell carcinoma in a family with dominant dystrophic epidermolysis bullosa: a molecular genetic study.Exp Dermatol. 1999; 8: 146-152Crossref PubMed Google Scholar; Condorelli et al., 2019Condorelli A.G. Dellambra E. Logli E. Zambruno G. Castiglia D. Epidermolysis bullosa-associated squamous cell carcinoma: from pathogenesis to therapeutic perspectives.Int J Mol Sci. 2019; 20: 5707Crossref PubMed Scopus (57) Google Scholar; Paganelli et al., 2022Paganelli A. Giordano E. Fiorentini C. Ferrari B. Reggiani C. Garbarino F. et al.Surgical management and oncological follow-up of cutaneous squamous cell carcinomas arising in epidermolysis bullosa patients.Int J Dermatol. 2022; 61: 1171-1174Crossref PubMed Scopus (0) Google Scholar). The relative manageability of non-EB cSCC results in a mortality rate of 0.44 cases per 100,000 people per year (Weinstock et al., 1991Weinstock M.A. Bogaars H.A. Ashley M. Litle V. Bilodeau E. Kimmel S. Nonmelanoma skin cancer mortality. A population-based study.Arch Dermatol. 1991; 127: 1194-1197Crossref PubMed Google Scholar). In contrast, morbidity and mortality are substantially higher in DEB, especially among patients with RDEB, who face near-certain development of cSCC (Fine et al., 2009Fine J.D. Johnson L.B. Weiner M. Li K.P. Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986–2006.J Am Acad Dermatol. 2009; 60: 203-211Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) and a median survival of ≤5 years from cSCC diagnosis (Kim et al., 2018Kim M. Li M. Intong-Wheeler L.R.A. Tran K. Marucci D. Murrell D.F. Epidemiology and outcome of squamous cell carcinoma in epidermolysis bullosa in Australia and New Zealand.Acta Derm Venereol. 2018; 98: 70-76Crossref PubMed Scopus (0) Google Scholar; Robertson et al., 2021Robertson S.J. Orrin E. Lakhan M.K. O'Sullivan G. Felton J. Robson A. et al.Cutaneous squamous cell carcinoma in epidermolysis bullosa: a 28-year retrospective study.Acta Derm Venereol. 2021; 101adv00523Crossref PubMed Scopus (7) Google Scholar) (Figure 1c). For patients with severe RDEB, cSCC is the most common cause of death (Condorelli et al., 2019Condorelli A.G. Dellambra E. Logli E. Zambruno G. Castiglia D. Epidermolysis bullosa-associated squamous cell carcinoma: from pathogenesis to therapeutic perspectives.Int J Mol Sci. 2019; 20: 5707Crossref PubMed Scopus (57) Google Scholar). These statistics underscore the inadequacy of current prevention and treatment regimens for cSCC in patients with DEB. Although surgical excision focuses on local tumor control, subclinical persistence of residual tumor tissue is common because of the difficulty in achieving complete removal of cancerous tissue from chronically wounded and scarred skin (Christiano et al., 1999Christiano A.M. Crollick J. Pincus S. Uitto J. Squamous cell carcinoma in a family with dominant dystrophic epidermolysis bullosa: a molecular genetic study.Exp Dermatol. 1999; 8: 146-152Crossref PubMed Google Scholar; Condorelli et al., 2019Condorelli A.G. Dellambra E. Logli E. Zambruno G. Castiglia D. Epidermolysis bullosa-associated squamous cell carcinoma: from pathogenesis to therapeutic perspectives.Int J Mol Sci. 2019; 20: 5707Crossref PubMed Scopus (57) Google Scholar; Fine et al., 2009Fine J.D. Johnson L.B. Weiner M. Li K.P. Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986–2006.J Am Acad Dermatol. 2009; 60: 203-211Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Traditional cytotoxic chemotherapies (e.g., carboplatin and paclitaxel) have been evaluated in patients with DEB who have cSCC, but these therapies tend to be disfavored because of minimal efficacy and a substantial burden of treatment that includes a high risk of life-threatening infection (Dunbar et al., 2014Dunbar A. Tai E. Nielsen D.B. Shropshire S. Richardson L.C. Preventing infections during cancer treatment: development of an interactive patient education website.Clin J Oncol Nurs. 2014; 18: 426-431Crossref PubMed Scopus (12) Google Scholar; Mellerio et al., 2016Mellerio J.E. Robertson S.J. Bernardis C. Diem A. Fine J.D. George R. et al.Management of cutaneous squamous cell carcinoma in patients with epidermolysis bullosa: best clinical practice guidelines.Br J Dermatol. 2016; 174: 56-67Crossref PubMed Scopus (77) Google Scholar). In UV-associated cSCC, the sequence variation burden is characteristically high (Cho et al., 2018Cho R.J. Alexandrov L.B. den Breems N.Y. Atanasova V.S. Farshchian M. Purdom E. et al.APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa.Sci Transl Med. 2018; : 10Google Scholar), which implicates a strong tumorigenic immunogenicity. As such, immune checkpoint inhibitors have become the current standard of care and first-line treatment of advanced non-EB cSCC, providing effectiveness as single-agent immunotherapy in approximately 50% of all squamous cell carcinoma (SCC) (Hanna et al., 2020Hanna G.J. Ruiz E.S. LeBoeuf N.R. Thakuria M. Schmults C.D. Decaprio J.A. et al.Real-world outcomes treating patients with advanced cutaneous squamous cell carcinoma with immune checkpoint inhibitors (CPI).Br J Cancer. 2020; 123: 1535-1542Crossref PubMed Scopus (33) Google Scholar). The use of immune checkpoint inhibitors in treating cSCC in DEB needs further validation, although small studies evaluating immunomodulation of programmed cell death protein 1 pathways with cemiplimab or pembrolizumab have shown disease control in several cases (Duong et al., 2021Duong T. Wong D. Barrett A. Price H. Successful use of immunotherapy to treat advanced cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa.BMJ Case Rep. 2021; 14e238966Crossref Scopus (7) Google Scholar; Khaddour et al., 2020Khaddour K. Gorell E.S. Dehdashti F. Tang J.Y. Ansstas G. Induced remission of metastatic squamous cell carcinoma with an immune checkpoint inhibitor in a patient with recessive dystrophic epidermolysis bullosa.Case Rep Oncol. 2020; 13: 911-915Crossref PubMed Scopus (0) Google Scholar; Piccerillo et al., 2020Piccerillo A. El Hachem M. De Vito R. De Luca E.V. Peris K. Pembrolizumab for treatment of a patient with multiple cutaneous squamous cell carcinomas and recessive dystrophic epidermolysis bullosa.JAMA Dermatol. 2020; 156: 708-710Crossref PubMed Scopus (0) Google Scholar; Robertson et al., 2021Robertson S.J. Orrin E. Lakhan M.K. O'Sullivan G. Felton J. Robson A. et al.Cutaneous squamous cell carcinoma in epidermolysis bullosa: a 28-year retrospective study.Acta Derm Venereol. 2021; 101adv00523Crossref PubMed Scopus (7) Google Scholar), and nivolumab is currently under investigation for treatment of advanced cSCC in a phase 2 trial (Prodinger et al., 2019Prodinger C. Reichelt J. Bauer J.W. Laimer M. Epidermolysis bullosa: advances in research and treatment.Exp Dermatol. 2019; 28: 1176-1189Crossref PubMed Scopus (30) Google Scholar). Likewise, mild, short-lived improvements followed treatment with the epidermal growth factor receptor inhibitor cetuximab (Arnold et al., 2009Arnold A.W. Bruckner-Tuderman L. Zuger C. Itin P.H. Cetuximab therapy of metastasizing cutaneous squamous cell carcinoma in a patient with severe recessive dystrophic epidermolysis bullosa.Dermatology. 2009; 219: 80-83Crossref PubMed Scopus (0) Google Scholar; Diociaiuti et al., 2019Diociaiuti A. Steinke H. Nyström A. Schwieger-Briel A. Meiss F. Pfannenberg C. et al.EGFR inhibition for metastasized cutaneous squamous cell carcinoma in dystrophic epidermolysis bullosa.Orphanet J Rare Dis. 2019; 14: 278Crossref PubMed Scopus (0) Google Scholar; Kim et al., 2018Kim M. Li M. Intong-Wheeler L.R.A. Tran K. Marucci D. Murrell D.F. Epidemiology and outcome of squamous cell carcinoma in epidermolysis bullosa in Australia and New Zealand.Acta Derm Venereol. 2018; 98: 70-76Crossref PubMed Scopus (0) Google Scholar, Kim et al., 2013Kim M. Li M. Intong L.R. Tran K. Melbourne W. Marucci D. et al.Use of cetuximab as an adjuvant agent to radiotherapy and surgery in recessive dystrophic epidermolysis bullosa with squamous cell carcinoma.Br J Dermatol. 2013; 169: 208-210Crossref PubMed Scopus (0) Google Scholar; Medek et al., 2019Medek K. Koelblinger P. Koller J. Diem A. Ude-Schoder K. Bauer J.W. et al.Wound healing deficits in severe generalized recessive dystrophic epidermolysis bullosa along anticancer treatment with cetuximab.J Dtsch Dermatol Ges. 2019; 17: 448-450Google Scholar; Reimer et al., 2020Reimer A. Lu S. He Y. Bruckner-Tuderman L. Technau-Hafsi K. Meiss F. et al.Combined anti-inflammatory and low-dose antiproliferative therapy for squamous cell carcinomas in recessive dystrophic epidermolysis bullosa.J Eur Acad Dermatol Venereol. 2020; 34: e1-e3Crossref PubMed Scopus (0) Google Scholar), whereas sustained tumor remission was reported in the first patient treated with systemic rigosertib (Laimer et al., 2021Laimer MS, South AP, Diem A, Ude-Schoder K, Mayr E, Kitzmuller S, et al. Rigosertib for locally advanced/metastatic EB-associated SCC. Poster presented at: Austrian Society of Dermatology and Venereology Annual Conference. 26 September 2021; Salzburg, Vienna.Google Scholar), an inhibitor of polo-like kinase 1 currently in early-phase clinical trials (ClinicalTrials.gov, 2022aClinicalTrials.govRigosertib for RDEB-SCC.https://www.clinicaltrials.gov/ct2/show/NCT03786237Date: 2022Date accessed: October 1, 2022Google Scholar, ClinicalTrials.gov, 2022bClinicalTrials.govRigosertib in patients with recessive dystrophic epidermolysis bullosa associated SCC.https://www.clinicaltrials.gov/ct2/show/NCT04177498Date: 2022Date accessed: October 1, 2022Google Scholar). Preclinical results point to Janus kinase 1/2 inhibition as a potential therapeutic target for cSCC through interception of inflammation-promoting activities and tissue remodeling, despite some inconsistent toxicity findings (Elli et al., 2019Elli E.M. Baratè C. Mendicino F. Palandri F. Palumbo G.A. Mechanisms underlying the anti-inflammatory and immunosuppressive activity of Ruxolitinib.Front Oncol. 2019; 9: 1186Crossref PubMed Scopus (117) Google Scholar; Jacków et al., 2021Jacków J. Rami A. Hayashi R. Hansen C. Guo Z. DeLorenzo D. et al.Targeting the jak/signal transducer and activator of transcription 3 pathway with ruxolitinib in a mouse model of recessive dystrophic epidermolysis bullosa-squamous cell carcinoma.J Invest Dermatol. 2021; 141: 942-946Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; Mittapalli et al., 2020Mittapalli V.R. Kühl T. Kuzet S.E. Gretzmeier C. Kiritsi D. Gaggioli C. et al.STAT3 targeting in dystrophic epidermolysis bullosa.Br J Dermatol. 2020; 182: 1279-1281Crossref PubMed Scopus (6) Google Scholar; Zehender et al., 2018Zehender A. Huang J. Györfi A.H. Matei A.E. Trinh-Minh T. Xu X. et al.The tyrosine phosphatase SHP2 controls TGFbeta-induced STAT3 signaling to regulate fibroblast activation and fibrosis.Nat Commun. 2018; 9: 3259Crossref PubMed Scopus (71) Google Scholar). Overall, although these limited successes offer encouragement for management of DEB-associated cSCC, an urgent unmet need remains for safe, effective, and long-lasting disease control, particularly with preventive intention (Jacków et al., 2021Jacków J. Rami A. Hayashi R. Hansen C. Guo Z. DeLorenzo D. et al.Targeting the jak/signal transducer and activator of transcription 3 pathway with ruxolitinib in a mouse model of recessive dystrophic epidermolysis bullosa-squamous cell carcinoma.J Invest Dermatol. 2021; 141: 942-946Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; Mittapalli et al., 2020Mittapalli V.R. Kühl T. Kuzet S.E. Gretzmeier C. Kiritsi D. Gaggioli C. et al.STAT3 targeting in dystrophic epidermolysis bullosa.Br J Dermatol. 2020; 182: 1279-1281Crossref PubMed Scopus (6) Google Scholar). New insights into cSCC have been gained by examining TGFβ, a multifunctional cytokine active in diverse pathways involved in oncogenesis (Massagué, 2008Massagué J. TGFβ in cancer.Cell. 2008; 134: 215-230Abstract Full Text Full Text PDF PubMed Scopus (3128) Google Scholar), and therefore, it may be an important, albeit multifaceted, link between DEB pathophysiology and the development of cSCC. In this review, we examine the relationship between mechanisms of cSCC, TGFβ activity, and COL7 deficits in DEB and discuss investigational therapies that directly address the underlying pathophysiology of DEB. The increased risk of carcinogenesis in DEB may result from pathophysiologic processes associated with chronic healing per se or could be more specifically linked to the deficiency of COL7 that ultimately leads to the development of these wounds. If COL7 deficiency itself can be implicated, that could manifest in varying genotype-phenotype correlations depending on the nature of the sequence variation. The unusual behavior of cSCC in DEB, particularly the combination of high risk, early onset, and histological differentiation of tumors, has prompted investigations into disease-specific cancer drivers. Ongoing research into genetic, immunologic, and extrinsic pathogenic factors underlying cSCC in DEB is summarized below. Whereas genetic drivers of non-EB cSCC have been observed in DEB, influences unique to DEB are an area of ongoing study. Several genes implicated in both non-EB and DEB cSCC include members of the CASP, p53, p16ink4a, and NOTCH gene families (Arbiser et al., 2004Arbiser J.L. Fan C.Y. Su X. Van Emburgh B.O. Cerimele F. Miller M.S. et al.Involvement of p53 and p16 tumor suppressor genes in recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma.J Invest Dermatol. 2004; 123: 788-790Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar; Brash et al., 1991Brash D.E. Rudolph J.A. Simon J.A. Lin A. McKenna G.J. Baden H.P. et al.A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma.Proc Natl Acad Sci U S A. 1991; 88: 10124-10128Crossref PubMed Google Scholar; Chang and Shain, 2021Chang D. Shain A.H. The landscape of driver mutations in cutaneous squamous cell carcinoma.NPJ Genom Med. 2021; 6: 61Crossref PubMed Scopus (28) Google Scholar; Cho et al., 2018Cho R.J. Alexandrov L.B. den Breems N.Y. Atanasova V.S. Farshchian M. Purdom E. et al.APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa.Sci Transl Med. 2018; : 10Google Scholar; Condorelli et al., 2021Condorelli A.G. El Hachem M. Zambruno G. Nystrom A. Candi E. Castiglia D. Notch-ing up knowledge on molecular mechanisms of skin fibrosis: focus on the multifaceted Notch signalling pathway.J Biomed Sci. 2021; 28: 36Crossref PubMed Scopus (17) Google Scholar; Govindarajan et al., 2002Govindarajan B. Klafter R. Miller M.S. Mansur C. Mizesko M. Bai X. et al.Reactive oxygen-induced carcinogenesis causes hypermethylation of p16(Ink4a) and activation of MAP kinase.Mol Med. 2002; 8: 1-8Crossref PubMed Scopus (17) Google Scholar; Loganathan et al., 2020Loganathan S.K. Schleicher K. Malik A. Quevedo R. Langille E. Teng K. et al.Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling.Science. 2020; 367: 1264-1269Crossref PubMed Scopus (104) Google Scholar; Poeta et al., 2007Poeta M.L. Manola J. Goldwasser M.A. Forastiere A. Benoit N. Califano J.A. et al.TP53 mutations and survival in squamous-cell carcinoma of the head and neck.N Engl J Med. 2007; 357: 2552-2561Crossref PubMed Scopus (589) Google Scholar; Terragni et al., 2014Terragni J. Zhang G. Sun Z. Pradhan S. Song L. Crawford G.E. et al.Notch signaling genes: myogenic DNA hypomethylation and 5-hydroxymethylcytosine.Epigenetics. 2014; 9: 842-850Crossref PubMed Scopus (43) Google Scholar), but the mutational burden of DEB cSCC is an order of magnitude lower than that observed in UV-associated cSCC and results from different processes. In non-EB cSCC, 78% of sequence variations carry sequence variational signatures associated with UV radiation exposure, whereas these signatures are found in only 38% of DEB cSCC-associated sequence variations. Sequence variant signatures identified in driver genes in RDEB cSCC, however, are associated with enhanced activity of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide–like family of endogenous nucleic acid deaminases (Cho et al., 2018Cho R.J. Alexandrov L.B. den Breems N.Y. Atanasova V.S. Farshchian M. Purdom E. et al.APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa.Sci Transl Med. 2018; : 10Google Scholar). Interestingly, these sequence variational signatures have been observed in other types of SCC (Bergstrom et al., 2022Bergstrom E.N. Luebeck J. Petljak M. Khandekar A. Barnes M. Zhang T. et al.Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA.Nature." @default.
• W4380996161 created "2023-06-17" @default.
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• W4380996161 date "2023-06-01" @default.
• W4380996161 modified "2023-10-14" @default.
• W4380996161 title "Type VII Collagen Deficiency in the Oncogenesis of Cutaneous Squamous Cell Carcinoma in Dystrophic Epidermolysis Bullosa" @default.
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