Development Of Basal Cell Carcinoma Research Articles

Role of cytoplasmic localization of discoidin domain receptor 1 in basal-cell carcinoma

Objective The objective of this study was to investigate the role of discoidin domain receptors (DDR1) in the pathogenesis of basal-cell carcinoma (BCC) through its immunohistochemical expression and to correlate its expression with clinicopathological parameters. Background BCC is the most common type of nonmelanoma skin cancer. The pathogenesis is usually combined with environmental factors, mainly ultraviolet irradiation through long-term sun exposure. Patients and methods This retrospective case–control study was carried out on 77 patients presented with BCC and 20 age-matched and gender-matched apparently healthy volunteers. Skin biopsies from controls and BCC cases were retrieved from the archives of Pathology Department, Faculty of Medicine, Menoufia University for histopathological and immunohistochemical DDR1 evaluation. Results Cytoplasmic localization of DDR1 could be incriminated in the development and progression of BCC. DDR1 offers potential targeted therapy in cancer, as none of the control groups showed cytoplasmic epithelial localization DDR1, whereas (90.9%) cytoplasmic epithelial localizations were demonstrated in BCC (P 0.001 and 0.005, respectively). Conclusion Cytoplasmic localization of DDR1 has a role in the pathogenesis of BCC which can be a new therapeutic target in BCC.

A Comparative Study of Pigmented and Non-pigmented Basal Cell Carcinoma in Reflectance Confocal Microscopy.

Basal cell carcinoma (BCC) is a common skin cancer, especially in the elderly population. The probability of BCC development increases past the age of 55. Dermoscopy and reflectance confocal microscopy (RCM) are two modern tools useful in the diagnosis of BCC. This is a retrospective study conducted on a group of 21 patients with a confirmed diagnosis of BCC. All patients were examined by dermoscopy and RCM. Dermoscopic images were taken using a videodermoscope. RCM was performed in three layers: epidermal, dermoepidermal junction (DEJ), and superficial dermal layer. In each layer, a few RCM criteria of basal cell carcinoma diagnosis were taken into consideration. Dermoscopy of pigmented BCCs revealed blue globules of pigment (p<0.05), gray and blue ovoid nests, which were absent in the entire non-pigmented carcinomas group. In RCM, the epidermis showed no differences between pigmented and non-pigmented carcinomas, however, significant differences were observed at the DEJ. In pigmented BCCs, cordlike structures and plump atypical cells were observed (p<0.05), while in non-pigmented carcinomas, dark silhouettes were present (p<0.05). To our knowledge, that is the first study comparing features between pigmented and non-pigmented BCC by RCM. Pigmented and non-pigmented BCCs presented different features in both dermoscopy and RCM. Furthermore, RCM revealed more discriminating features at the DEJ than dermoscopy, thus can be more efficient in the differential diagnosis of difficult BCC.

Spreading of Isolated Ptch Mutant Basal Cell Carcinoma Precursors Is Physiologically Suppressed and Counteracts Tumor Formation in Mice.

Basal cell carcinoma (BCC) originate from Hedgehog/Patched signaling-activated epidermal stem cells. However, the chemically induced tumorigenesis of mice with a CD4Cre-mediated biallelic loss of the Hedgehog signaling repressor Patched also induces BCC formation. Here, we identified the cellular origin of CD4Cre-targeted BCC progenitors as rare Keratin 5+ epidermal cells and show that wildtype Patched offspring of these cells spread over the hair follicle/skin complex with increasing mouse age. Intriguingly, Patched mutant counterparts are undetectable in age-matched untreated skin but are getting traceable upon applying the chemical tumorigenesis protocol. Together, our data show that biallelic Patched depletion in rare Keratin 5+ epidermal cells is not sufficient to drive BCC development, because the spread of these cells is physiologically suppressed. However, bypassing the repression of Patched mutant cells, e.g., by exogenous stimuli, leads to an accumulation of BCC precursor cells and, finally, to tumor development.

18445 Basal cell carcinoma gene mutations and polymorphisms differ between Asian, Hispanic, and Caucasian patients

Introduction: Basal cell carcinoma (BCC) is the most common cancer worldwide, with ∼4.3 million cases annually. Research on the development of BCC has identified several genes that have a role in BCC pathogenesis, namely SMO and PTCH1. While BCC mutations have been extensively studied in Caucasian patients, research is lacking in patients of other races. Many BCC drug treatments, such as vismodegib, target specific products of mutated genes. Thus, discovering a potential difference in gene mutations for patients of different races has significant clinical relevance.

Beyond Mohs surgery and excisions: A focused review of treatment options for subtypes of basal cell carcinoma.

Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer. It originates from undifferentiated cells in the basal cell layer of the epidermis or from the outer root sheath of the hair follicle. The most important factor in development of BCC is ultraviolet radiation. Surgery is considered the gold standard of treatment for BCC. However, nonsurgical options are available for individuals who are unsuitable for surgery. The purpose of this review is to summarize the efficacy and indications of alternative, nonsurgical treatments that can be used in the management of BCC. An extensive literature review was performed for the nonsurgical options for the treatment of BCC. Resources searched included PubMed and Google Scholars, limited to the years 1995 to 2020. Key words searched included BCC, destructive methods, photodynamic therapy (PDT), radiotherapy, topical medication, laser, hedgehog pathway inhibitors (HPIs). The most relevant results such as systematic reviews, randomized controlled trials, or comparative studies were selected to provide a summary for the most common nonsurgical methods used for treating BCC. Effective nonsurgical treatments for BCC include destructive methods (eg, curettage alone, cryosurgery, or electrodessication), PDT, topical medications, radiotherapy, laser, and HPIs. Nonsurgical therapeutic alternatives are safe and effective for the treatment of BCC. Factors such as tumor location, size, and histopathological subtype should be taken into consideration when selecting optimal treatment. In addition to clinical factors, cosmetic results and patient preference should be considered.

Gorlin Syndrome: Recent Advances in Genetic Testing and Molecular and Cellular Biological Research.

Gorlin syndrome is a skeletal disorder caused by a gain of function mutation in Hedgehog (Hh) signaling. The Hh family comprises of many signaling mediators, which, through complex mechanisms, play several important roles in various stages of development. The Hh information pathway is essential for bone tissue development. It is also the major driver gene in the development of basal cell carcinoma and medulloblastoma. In this review, we first present the recent advances in Gorlin syndrome research, in particular, the signaling mediators of the Hh pathway and their functions at the genetic level. Then, we discuss the phenotypes of mutant mice and Hh signaling-related molecules in humans revealed by studies using induced pluripotent stem cells.

Recent Advances in Signaling Pathways Comprehension as Carcinogenesis Triggers in Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common malignant skin tumor. BCC displays a different behavior compared with other neoplasms, has a slow evolution, and metastasizes very rarely, but sometimes it causes an important local destruction. Chronic ultraviolet exposure along with genetic factors are the most important risk factors involved in BCC development. Mutations in the PTCH1 gene are associated with Gorlin syndrome, an autosomal dominant disorder characterized by the occurrence of multiple BCCs, but are also the most frequent mutations observed in sporadic BCCs. PTCH1 encodes for PTCH1 protein, the most important negative regulator of the Hedgehog (Hh) pathway. There are numerous studies confirming Hh pathway involvement in BCC pathogenesis. Although Hh pathway has been intensively investigated, it remains incompletely elucidated. Recent studies on BCC tumorigenesis have shown that in addition to Hh pathway, there are other signaling pathways involved in BCC development. In this review, we present recent advances in BCC carcinogenesis.

Enhanced expression of GABRD predicts poor prognosis in patients with colon adenocarcinoma

Neurotransmitters are reported to be involved in tumor initiation and progression. This study aimed to elucidate the prognostic value of γ-aminobutyric acid type A receptor δ subunit (GABRD) in colon adenocarcinoma (COAD) using the data from The Cancer Genome Atlas (TCGA) database. The GABRD mRNA expression levels in the COAD and normal tissues were compared using the Wilcoxon rank-sum test. The correlation between clinicopathologic characteristics and GABRD expression was analyzed by Wilcoxon rank-sum test or Kruskal-Wallis test and logistic regression. The prognostic value of GABRD mRNA expression in patients with COAD was determined using the Kaplan-Meier curve and Cox regression analysis. Finally, the molecular mechanisms of GABRD in COAD were predicted by gene set enrichment analysis (GSEA). The COAD tissues exhibited higher GABRD mRNA expression levels than the normal tissues. The logistic regression analysis revealed that GABRD mRNA expression was correlated with TNM stage, N stage, M stage, and microsatellite instability (MSI) status. The Kaplan-Meier survival curve and log-rank test revealed that patients with COAD exhibiting high GABRD mRNA expression were associated with poor overall survival (OS). The multivariate analysis indicated that increased GABRD mRNA expression was an independent prognostic factor and was correlated with a poor OS. The GSEA revealed that GABRD was involved in signaling pathways, including cell adhesion molecules, gap junction, melanogenesis, and mTOR signaling pathway, as well as the signaling pathways associated with basal cell carcinoma or bladder cancer development. In summary, enhanced GABRD mRNA expression may be a potential independent prognostic biomarker for COAD.

Association study indicates combined effect of interleukin-10 and angiotensin-converting enzyme in basal cell carcinoma development.

Cytokines involved in inflammatory and immune response have been associated with risk for development of basal cell carcinoma (BCC). In this study, three functional DNA polymorphisms affecting gene expression were investigated in 54 BCC patients and 111 healthy controls: interleukin-1b (IL-1b) +3953C/T, interleukin-10 (IL-10) -1082G/A and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms. Significant increase of the variant alleles was observed in IL-10 -1082G (P = 0.019) and in ACE D (P = 0.003) in BCC patients in comparison to controls. Multivariate logistic regression models evaluated the contribution of homozygous and heterozygous variant polymorphisms to the risk for BCC development. The studied polymorphisms influencing the expression of IL-10 and ACE genes were recognized as potential predictive factors for BCC. These findings suggest a possible molecular mechanism leading to BCC development that is likely to involve the activation of angiotensin receptors in combination with increased plasma levels of IL-10 in patients.

Impairment of Base Excision Repair in Dermal Fibroblasts Isolated From Nevoid Basal Cell Carcinoma Patients.

The nevoid basal cell carcinoma syndrome (NBCCS), also called Gorlin syndrome is an autosomal dominant disorder whose incidence is estimated at about 1 per 55,600–256,000 individuals. It is characterized by several developmental abnormalities and an increased predisposition to the development of basal cell carcinomas (BCCs). Cutaneous fibroblasts from Gorlin patients have been shown to exhibit an increased sensitivity to ionizing radiations. Mutations in the tumor suppressor gene PTCH1, which is part of the Sonic Hedgehog (SHH) signaling pathway, are responsible for these clinical manifestations. As several genetic mutations in the DNA repair genes are responsible of photo or radiosensitivity and high predisposition to cancers, we hypothesized that these effects in Gorlin syndrome might be due to a defect in the DNA damage response (DDR) and/or the DNA repair capacities. Therefore, the objective of this work was to investigate the sensitivity of skin fibroblasts from NBCCS patients to different DNA damaging agents and to determine the ability of these agents to modulate the DNA repair capacities. Gorlin fibroblasts showed high radiosensitivity and also less resistance to oxidative stress-inducing agents when compared to control fibroblasts obtained from healthy individuals. Gorlin fibroblasts harboring PTCH1 mutations were more sensitive to the exposure to ionizing radiation and to UVA. However, no difference in cell viability was shown after exposure to UVB or bleomycin. As BER is responsible for the repair of oxidative DNA damage, we decided to assess the BER pathway efficacy in Gorlin fibroblasts. Interestingly, a concomitant decrease of both BER gene expression and BER protein activity was observed in Gorlin fibroblasts when compared to control. Our results suggest that low levels of DNA repair within Gorlin cells may lead to an accumulation of oxidative DNA damage that could participate and partly explain the radiosensitivity and the BCC-prone phenotype in Gorlin syndrome.

Basal Cell Carcinoma: A Comprehensive Review.

Basal cell carcinoma (BCC) is the most common type of carcinoma worldwide. BCC development is the result of a complex interaction between environmental, phenotypic and genetic factors. However, despite the progress in the field, BCC biology and mechanisms of resistance against systemic treatments have been poorly investigated. The aim of the present review is to provide a revision of BCC histological and molecular features, including microRNA (miRNA) dysregulation, with a specific focus on the molecular basis of BCC systemic therapies. Papers from the last ten years regarding BCC genetic and phenotypic alterations, as well as the mechanism of resistance against hedgehog pathway inhibitors vismodegib and sonidegib were included. The involvement of miRNAs in BCC resistance to systemic therapies is emerging as a new field of knowledge.

Genomic profiling of late-onset basal cell carcinomas from two brothers with nevoid basal cell carcinoma syndrome.

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant genetic disorder. It is commonly caused by mutations in PTCH1 and chiefly characterized by multiple basal cell carcinomas (BCCs) developing prior to the age of 30years. In rare cases, NBCCS presents with a late onset of BCC development. To investigate BCC tumorigenesis in two brothers, who showed characteristic features of NBCCS but developed their first BCCs only after the age of 40years. Two other siblings did not show signs of NBCCS. We obtained blood samples from four siblings and nine BCCs from the two brothers with NBCCS. Whole exome sequencing and RNA sequencing revealed loss of heterozygosity (LOH) of PTCH1 in eight out of nine tumours that consistently involved the same haplotype on chromosome 9. This haplotype contained a germinal splice site mutation in PTCH1 (NM_001083605:exon9:c.763-6C>A). Analysis of germline DNA confirmed segregation of this mutation with the disease. All BCCs harboured additional somatic loss-of-function (LoF) mutations in the remaining PTCH1 allele which are not typically seen in other cases of NBCCS. This suggests a hypomorphic nature of the germinal PTCH1 mutation in this family. Furthermore, all BCCs had a similar tumour mutational burden compared to BCCs of unrelated NBCCS patients while harbouring a higher number of damaging PTCH1 mutations. Our data suggest that a sequence of three genetic hits leads to the late development of BCCs in two brothers with NBCCS: a hypomorphic germline mutation, followed by somatic LOH and additional mutations that complete PTCH1 inactivation. These genetic events are in line with the late occurrence of the first BCC and with the higher number of damaging PTCH1 mutations compared to usual cases of NBCCS.

Retinol and α-Tocopherol Levels in the Serum and Subcutaneous Adipose Tissue of Newly Diagnosed Basal Cell Carcinoma Patients

Nonmelanoma skin cancers are the most frequently occurring skin cancers. Vitamin A is involved in epithelial cell differentiation and may control skin tumor development. Vitamin E is a powerful lipophilic antioxidant that can quench and scavenge reactive oxygen species. However, there is little consistent evidence considering micronutrients and the development of basal cell carcinoma (BCC). Therefore, we aimed to investigate the possible difference between retinol and α-tocopherol in BCC patients and controls in Iranian population. This case-control study was conducted on adults with newly diagnosed BCC referred to Razi Hospital, Tehran, Iran in 2015. Serum and subcutaneous fat tissue retinol and α-tochopherol were measured by HPLC method. Overall, serum retinol level was lower significantly in BCC patients (0.237±0.01 μg/ml) in comparison with control group (0.27±0.02 μg/ml, P-value: 0.038). However serum α-tocopherol level was not significantly different between BCC patients (4.41±0.33 μg/ml) and control subjects (4.06±0.35 μg/ml, P-value=0.18). Sub-cutaneous adipose tissue retinol was lower significantly in BCC patients (38.60±3.30 ng/mg) compared with control group (54.78±3.49 ng/mg, P-value=0.002). Furthermore, results revealed lower subcutaneous adipose tissue α-tocopherol in BCC patients (4.41±0.33 μg/ml) in comparison with control group (4.06±0.35 μg/ml, P-value=0.18). Skin tissue concentration of retinol and α-tocopherol and serum retinol level was lower in BCC patients in comparison with control group but serum α-tocopherol was not different between groups.

Investigating Expression of Skin Basal Cell Carcinoma Molecular Biomarkers

Basal cell carcinoma (BCC) of skin is the most common type of human cancer. It is strongly linked with exposure to UV radiations and tumors mostly develop on the sun-exposed skin. Although BCC rarely metastasizes or causes mortality, it can result in broad morbidity through local invasion and causing tissue destruction. Hedgehog signaling pathway (Hh) have been linked to the development of BCC. The aim of this study was to investigate the expression level of the SHH, PTCH1, GLI1, P53 and SMO genes in BCC skin tissue in order to identify reliable biomarkers for clinical applications in the diagnosis of skin BCC. BCC and healthy skin samples were collected from patients who had pre-operation pathological verification, RNA extracted, cDNA synthesized and RT-qPCR was carried out to analyze the expression levels of SHH, PTCH1, GLI1, P53 and SMO genes. Results of the RT-qPCR analysis revealed significant statistical difference in relative expression of SHH, PTCH1, GLI1, P53 and SMO genes between the BCC and healthy tissue groups. The RT-qPCR analysis also showed that expressions of the target genes were upregulated in BCC skin compared to the healthy skin tissue: GLI1 by 3.1 folds, P53 by 0.844 folds, PTCH1 by 4.64 folds, SHH by 1.75 folds and SMO by 2.46 folds. Results of this study suggest that PTCH1 gene can be used as a molecular biomarker for diagnosing BCC of skin. Further studies of the BCC development signalling pathway genes may lead to improved methods for diagnosis and treatment of this common cancer.

LB919 Aging does not facilitate nodular BCC development in mice expressing oncogenic Smo

Aberrant Hedgehog (Hh) signaling drives the development of basal cell carcinomas (BCCs), which arise mainly in elderly patients. Loss-of-function PTCH1 or gain-of-function SMO mutations are oncogenic drivers in human BCC, but neither of these genetic alterations effectively yield nodular BCCs in genetically-engineered mice. Because nearly all prior BCC modeling studies have been performed in juvenile mice, we set out to assess whether aging is permissive for BCC development using a Cre-inducible oncogenic SmoM2 allele, activated in skin of young versus aged mice. As expected, young (4 month-old) SmoM2-expressing mice formed microscopic basaloid hamartomas following 9 weeks of transgene activation, with nodular BCC-like lesions never detected. Similarly, aged (22-24 month-old) mice, expressing SmoM2 for up to 8 months, also failed to develop nodular BCCs. Histology of SmoM2-driven hamartomas in skin of young and aged mice was indistinguishable, and nearly all epithelial cells in lesions from both groups expressed K5, K17, and Sox9. Remarkably, while Ki67+ proliferating cells were abundant in cells at the periphery of hamartomas in young mice, proliferation was markedly reduced in hamartomas in aged mice. Our findings show that oncogenic Smo expression yields similar histologic phenotypes in both young and old mice and an apparent reduction in proliferating cells in aged mice. The absence of BCCs both in young and elderly SmoM2-expressing mice argues against a critical role for aging in facilitating full-blown skin tumorigenesis in this mouse model.

388 Natural history and management of basal cell nevus syndrome: Updates from the gorlin syndrome registry

Background: Patients with basal cell nevus syndrome (BCNS) are at increased risk of developing basal cell carcinomas (BCCs). Long-term data on tumor burden, co-morbidities, and management of BCNS is limited. Method: A prospective, cross-sectional study of self-reported questionnaire responses collected from BCNS patients from Feb 2012 to Oct 2016 through the national Gorlin Syndrome Registry. BCC burden was characterized based on frequency and anatomic distribution. Logistic regression analysis was performed to determine the association of BCC development with risk factors such as sex, family history, age of diagnosis/symptoms, and sun exposure. Treatment of BCCs and other co-morbid tumors are additionally characterized. Results: 87 BCNS participants (current age: 39.8 ± 20.0 years; age at diagnosis: 16.5 ± 12.4 years) reported a median of 172 BCCs (range 1 – 1715 BCCs) developing over their lifetime. The number of lifetime BCCs significantly associated with family history of BCNS (p = 0.02) and age (Lifetime BCCs = 5.4*Age, p < 0.0001). A median of 100 BCCs presented on the head, 56 BCCs on the trunk and extremities, and 10 BCCs on the breast and groin. Of the 27/87 (31%) participants with locally advanced or metastatic BCCs, roughly half (13/27) had tried a hedgehog inhibitor such as vismodegib, sonidegib, or itraconazole. Participants with BCNS are found to have an increased prevalence of tumors of the skin (KCOT, actinic keratosis, SCC, melanoma), brain (meningioma, medulloblastoma), and ovaries (fibroma, cyst). Conclusion: The results of this study demonstrate the high burden of BCCs among patients with BCNS. BCCs predominantly developed on sun-exposed area and strongly correlated with increased age. Additional interventions to prevent and treat BCCs are needed. This study establishes a clinical baseline for emerging therapies such as hedgehog inhibitors in the BCNS population.

Genetic and environmental factors underlying keratinocyte carcinoma risk.

Recent large-scale GWAS and large epidemiologic studies have accelerated the discovery of genes and environmental factors that contribute to the risk of keratinocyte carcinoma (KC), which includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). This Review summarizes the genomic regions associated with SCC and BCC risk, examines the genetic overlap between SCC and BCC, and discusses biological pathways involved in SCC and BCC development. Next, we review environmental factors that are associated with KC risk, including those that are shared between SCC and BCC as well as others that associated with only one type of KC. We conclude with a critical appraisal of current research and potential directions for future research.

Identification of Potential Biomarkers Associated with Basal Cell Carcinoma.

Purpose This work is aimed at identifying several molecular markers correlated with the diagnosis and development of basal cell carcinoma (BCC). Methods The available microarray datasets for BCC were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified between BCC and healthy controls. Afterward, the functional enrichment analysis and protein-protein interaction (PPI) network analysis of these screened DEGs were performed. An external validation for the DEG expression level was also carried out, and receiver operating characteristic curve analysis was used to evaluate the diagnostic values of DEGs. Result In total, five microarray datasets for BCC were downloaded and 804 DEGs (414 upregulated and 390 downregulated genes) were identified. Functional enrichment analysis showed that these genes including CYFIP2, HOXB5, EGFR, FOXN3, PTPN3, CDC20, MARCKSL1, FAS, and PTCH1 were closely correlated with the cell process and PTCH1 played central roles in the BCC signaling pathway. Moreover, EGFR was a hub gene in the PPI network. The expression changes of six genes (CYFIP2, HOXB5, FOXN3, PTPN3, MARCKSL1, and FAS) were validated by an external GSE74858 dataset analysis. Finally, ROC analysis revealed that CYFIP2, HOXB5, PTPN3, MARCKSL1, PTCH1, and CDC20 could distinguish BCC and healthy individuals. Conclusion Nine gene signatures (CYFIP2, HOXB5, EGFR, FOXN3, PTPN3, CDC20, MARCKSL1, FAS, and PTCH1) may serve as promising targets for BCC detection and development.

Risk Factors for Keratinocyte Carcinoma in Recipients of Allogeneic Hematopoietic Cell Transplants

Allogeneic hematopoietic cell transplant (alloHCT) is known to increase the risk for keratinocyte carcinoma. The extent to which host characteristics, including pigmentary phenotype and UV radiation exposure, contribute is unknown. To identify and validate independent risk factors for keratinocyte carcinoma after alloHCT, including those associated with the transplant and the host. This retrospective cohort study analyzed a consecutive sample of alloHCT recipients from January 1, 2000, to December 31, 2014, at the Mayo Clinic, Rochester, Minnesota (n = 872) and University Hospitals Cleveland Medical Center, Cleveland, Ohio (n = 147). Participants from the Mayo Clinic were randomly allocated (2:1) into discovery (n = 581) and validation (n = 291) cohorts. Time to first keratinocyte carcinoma and information about transplant- and host-associated risk factors were extracted. A multivariate keratinocyte carcinoma risk model was created using a stepwise Cox proportional hazards regression model with P ≤ .05 for entry that incorporated all covariates that were individually statistically significant at α = 0.05 in the discovery cohort. The risk model was first internally validated using the Mayo Clinic validation cohort and then externally validated using the independent cohort of alloHCT recipients at University Hospitals Cleveland Medical Center. Data were analyzed from March 13, 2018, to June 12, 2019. Allogeneic hematopoietic cell transplant. The primary outcome was time to development of the first cutaneous keratinocyte carcinoma after alloHCT; secondary outcome, time to development of the first individual basal and/or squamous cell carcinoma after alloHCT. Of the 872 alloHCT recipients identified in the Mayo Clinic cohort (520 men [59.6%]; mean [SD] age, 48.3 [12.6] years), 95 (10.9%) developed keratinocyte carcinoma after alloHCT during 5349 person-years of follow-up. Of the 147 alloHCT recipients in the exernal validation cohort (86 men [58.5%]; mean [SD] age, 47.9 [17.5] years), 18 (12.2%) developed keratinocyte carcinoma after alloHCT in 880 person-years of follow up. Risk factors independently associated with keratinocyte carcinoma after alloHCT included age (hazard ratio [HR] per 10 years, 1.72; 95% CI, 1.21-2.42), chronic lymphocytic leukemia (HR, 2.47; 95% CI, 1.20-5.09), clinically photodamaged skin (HR, 3.47; 95% CI, 1.87-6.41), and history of cutaneous squamous cell carcinoma (HR, 2.60; 95% CI, 1.41-5.91). Harrell concordance statistics were 0.81 (95% CI, 0.72-0.90) and 0.86 (95% CI, 0.74-0.98) for internal and external validation of the keratinocyte carcinoma risk model, respectively. This study found validated independent risk factors for keratinocyte carcinoma after alloHCT that are enriched with host- compared with transplant-associated risk factors. These findings highlight the importance of assessing host-associated risk factors for keratinocyte carcinoma in patients eligible for alloHCT. Future studies should examine whether keratinocyte carcinoma risk stratification before alloHCT may inform long-term surveillance strategies.

SHARPIN regulates cell proliferation of cutaneous basal cell carcinoma via inactivation of the transcriptional factors GLI2 and c‑JUN.

SHANK-associated RH domain-interacting protein (SHARPIN) is a component of the linear ubiquitin chain assembly complex that can enhance the NF-κB and JNK signaling pathways, acting as a tumor-associated protein in a variety of cancer types. The present study investigated the role of SHARPIN in cutaneous basal cell carcinoma (BCC). Human BCC (n=26) and normal skin (n=5) tissues, and BCC (TE354.T) and normal skin (HaCaT) cell lines were used to evaluate SHARPIN expression level using immunohistochemistry and western blotting, respectively. A lentivirus carrying SHARPIN-targeting or negative control short hairpin RNA was infected into TE354.T cells, and the infected stable cells were assayed to analyze tumor cell proliferation, cell cycle, apoptosis, migration and invasion by Cell Counting Kit-8 and 5-ethynyl-2′-deoxyuridine incorporation assays, flow cytometry and Transwell assays. Western blotting was performed to assess the protein expression levels of gene signaling in SHARPIN-silenced BCC cells. SHARPIN protein expression levels were downregulated or absent in BCC cancer nests and precancerous lesions compared with normal skin samples. In addition, SHARPIN expression levels were lower in TE354.T cells compared with HaCaT cells. SHARPIN shRNA enhanced tumor cell proliferation and the S phase of the cell cycle, whereas BCC cell apoptotic rates, and migratory and invasive abilities were not significantly altered. The expression levels of cyclin D1, cyclin-dependent kinase 4, phosphorylated-c-JUN and GLI family zinc finger 2 proteins were increased, whereas Patched 1 (PTCH1) and PTCH2 were decreased in the SHARPIN-shRNA-infected BCC cells. Therefore, the present results suggested that SHARPIN may act as a tumor suppressor during BCC development.