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The TMC genes encode a set of homologous transmembrane proteins whose functions are not well understood. Biallelic mutations in either TMC6 or TMC8 are detected in more than half of cases of the pre-malignant skin disease epidermodysplasia verruciformis (EV). It is controversial whether EV induced by mutations in TMC6 or TMC8 originates from keratinocyte or lymphocyte defects. Quantification of TMC6 and TMC8 RNA levels in various organs revealed that lymphoid tissues have the highest levels of expression of both genes, and custom antibodies confirmed protein expression in mouse lymphocytes. To study the function of these proteins we generated mice with targeted deletion mutant alleles of Tmc6 or Tmc8. Either TMC6 or TMC8 deficiency induced a reduction in apparent molecular weight and/or amount of the other TMC molecule. Co-immunoprecipitation experiments indicated that TMC6 and TMC8 formed a protein complex in mouse and human T cells. MS and biochemical analysis demonstrated that TMC6 and TMC8 additionally interacted with the CIB1 protein to form TMC6-TMC8-CIB1 trimers. We demonstrated that TMC6 and TMC8 regulated CIB1 levels by protecting CIB1 from ubiquitination and proteasomal degradation. Reciprocally, CIB1 was needed for stabilizing TMC6 and TMC8 levels. These results suggest why inactivating mutations in any of the three human genes leads to similar clinical presentations. We also demonstrated that TMC6 and TMC8 levels are drastically lower and the proteins are less active in regulating CIB1 in keratinocytes than in T cells. Our study suggests that defects in lymphocytes may contribute to the etiology and pathogenesis of EV.

Genetic variation in the transmembrane channel-like (TMC)6/TMC8 region has been linked to β-type human papillomavirus (HPV) infection and squamous cell carcinoma (SCC) of the skin and the head and neck, α-type HPV persistence and progression to cervical cancer. The functional variant rs7208422 of the TMC8 gene was suggested to have a high impact on susceptibility to β-papillomaviruses and their oncogenic potential and to also have an influence on α-type HPV-related disease. The aim of the present study was to evaluate a possible influence of rs7208422 on penile cancer risk, a known α-type HPV-related malignancy. Therefore, the distribution of rs7208422 was determined by direct Sanger sequencing of 104 Caucasian penile SCC cases and compared to data of 3,810 controls taken from the literature. HPV detection was performed by usage of GP5+/6+ primers and subtype-specific PCR. It was observed that the distribution of rs7208422 followed the Hardy-Weinberg equilibrium in both cases and controls. HPV DNA was detected in 39% of the penile SCC cases. Overall, there was no significant difference in the distribution of rs7208422 neither between cases and controls (P=0.726) nor between HPV-positive and -negative penile SCC cases (P=0.747). There was also no association between rs7208422 genotypes and age of disease onset (P=0.740). In conclusion, the present data argue against a significant impact of rs7208422 on the risk for the development of penile SCC in Caucasians. Even in combination with the HPV status, the SNP appears not to influence the risk of penile SCC in HPV-positive cases.

The vast majority of primary immunodeficiencies (PIDs) occur due to the defects in cells originating from hematopoietic stem cells, while in some PIDs, there are defects in various genes responsible for non-leucocyte immune response such as seen in epidermodysplasia verruciformis (EV). EV caused by the mutations in TMC6, TMC8, and CIB1 genes is called "typical." "Atypical" EV may develop in patients with primary immunodeficiencies originating from hematopoietic stem cells, which include severe T-cell failure, caused by inactivating biallelic mutations of STK4, RHOH, CORO1A, ITK, TPP2, DCLRE1C, LCK, RASGRP1, or DOCK8 genes. Here, we present a family with TMC8 gene mutation leading to disseminated epidermodysplasia verruciformis including laryngeal papilloma and recurrent cutaneous squamous cell carcinomas. Typical EV with impaired local, keratinocyte-intrinsic immune response should be considered when routine immunological examinations are normal in patients presenting with clinical signs of EV. Although it is not possible to prevent EV lesions, early and appropriate surveillance for malignancy is mandatory.

Background: Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to human beta papillomavirus infections and a particular propensity to develop non-melanoma skin cancers (NMSCs). The majority of EV cases are caused by biallelic null variants in TMC6, TMC8, and CIB1. This study aimed to identify disease-causing variants in three Chinese families with EV and to elucidate their molecular pathogenesis.Methods: Genomic DNA from the probands of three EV families was analyzed by whole-exome sequencing (WES). cDNA sequencing was performed to investigate abnormal splicing of the variants. Quantitative RT-PCR (qRT-PCR) was conducted to quantify the mRNA expression of mutant TMC6 and TMC8.Results: Whole-exome sequencing identified two novel homozygous variants (c.2278-2A > G in TMC6 and c.559G > A in TMC8) in families 1 and 2, respectively. In family 3, WES revealed a recurrent and a novel compound heterozygous variant, c.559G > A and c.1389G > A, in TMC8. The c.2278-2A > G TMC6 variant led to the skipping of exon 19 and resulted in premature termination at codon 776. Subsequent qRT-PCR revealed that the aberrantly spliced transcript was partly degraded. Notably, the TMC8 c.559G > A variant created a novel acceptor splice site at c.561 and yielded three different aberrant transcripts. qRT-PCR revealed that most of the mutant transcripts were degraded via nonsense-mediated mRNA decay (NMD).Conclusion: We identified three novel disease-causing variants in TMC6 or TMC8 in three Chinese families with EV. The EV phenotypes of the three patients were due to a reduction in TMC6 or TMC8. Our findings expand the genetic causes of EV in the Chinese population.

Epidermodysplasia verruciformis is a rare genodermatosis associated with mutations in the EVER1/TMC6 and EVER2/TMC8 genes. The inheritance is considered to be autosomal recessive, but reports suggesting an autosomal dominant inheritance indicate disease genetic heterogeneity. Its onset occurs in early childhood and presents as a combination of pityriasis versicolor-like, flat wart-like and seborrheic keratosis-like lesions, with a potential for malignant transformation, mainly squamous cell carcinoma.

The occurrence and prognosis of head and neck squamous cell cancer (HNSC) is closely associated with human papillomavirus (HPV) infection. Transmembrane channel-like 8 (TMC8) is a key gene affecting the susceptibility of HPV and that plays an important role in T cell regulation. However, the mechanism by which TMC8 affects T cells and whether it further affects the prognosis of patients with HNSC remains unclear. In the present study, oral cancer cell lines and independent tumor specimens were used to detect TMC8 expression in HNSC. Differential expression of TMC8, methylation status, function and associated signaling pathways were further analyzed. Then, multiple databases were cross-analyzed for the relationship of TMC8 with immune cell infiltration and its impact on the prognosis of numerous types of cancer. The results showed that TMC8 was upregulated in HNSC and high expression was predictive of an improved prognosis. Furthermore, TMC8 was concentrated in multiple immune-associated signaling pathways and the expression of TMC8 was associated with the infiltration of CD4+ T cells and their subsets, including CD8+ T cells, B cells and macrophages, suggesting that TMC8 may play an anti-HPV role by regulating CD4+ T cells. Thus, TMC8 plays an anti-HPV role by regulating the infiltration level of CD4+ T cells, and could therefore be used as a potential prognostic marker for patients with HNSC.

International audience; Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of TMC6 (encoding EVER1) or TMC8 (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human β-papillomaviruses (β-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the CIB1 gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are not dependent on CIB1, and CIB1 deficiency does not impair keratinocyte adhesion or migration. In keratinocytes, the CIB1 protein interacts with the HPV E5 and E8 proteins encoded by α-HPV16 and γ-HPV4, respectively, suggesting that this protein acts as a restriction factor against HPVs. Collectively, these findings suggest that the disruption of CIB1-EVER1-EVER2-dependent keratinocyte-intrinsic immunity underlies the selective susceptibility to β-HPVs of EV patients.

In the human genome, miR-451a, miR-144-5p (passenger strand), and miR-144-3p (guide strand) reside in clustered microRNA (miRNA) sequences located within the 17q11.2 region. Low expression of these miRNAs is significantly associated with poor prognosis of patients with renal cell carcinoma (RCC) (miR-451a: P = .00305; miR-144-5p: P = .00128; miR-144-3p: P = 9.45 × 10-5 ). We previously reported that miR-451a acted as an antitumor miRNA in RCC cells. Involvement of the passenger strand of the miR-144 duplex in the pathogenesis of RCC is not well understood. Functional assays showed that miR-144-5p and miR-144-3p significantly reduced cancer cell migration and invasive abilities, suggesting these miRNAs acted as antitumor miRNAs in RCC cells. Analyses of miR-144-5p targets identified a total of 65 putative oncogenic targets in RCC cells. Among them, high expression levels of 9 genes (FAM64A, F2, TRIP13, ANKRD36, CENPF, NCAPG, CLEC2D, SDC3, and SEMA4B) were significantly associated with poor prognosis (P < .001). Among these targets, expression of SDC3 was directly controlled by miR-144-5p, and its expression enhanced cancer cell aggressiveness. We identified genes downstream by SDC3 regulation. Data showed that expression of 10 of the downstream genes (IL18RAP, SDC3, SH2D1A, GZMH, KIF21B, TMC8, GAB3, HLA-DPB2, PLEK, and C1QB) significantly predicted poor prognosis of the patients (P = .0064). These data indicated that the antitumor miR-144-5p/oncogenic SDC3 axis was deeply involved in RCC pathogenesis. Clustered miRNAs (miR-451a, miR-144-5p, and miR-144-3p) acted as antitumor miRNAs, and their targets were intimately involved in RCC pathogenesis.

Simple Summary Nasopharyngeal carcinoma (NPC), Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC), and oral squamous cell carcinoma (OSCC) are epithelial cancers that are associated with EBV infection. However, the gene signatures and common hallmarks associated with EBV infection in EBV-associated epithelial cancers (EBVaCAs) have not been fully elucidated. Here, we performed a panel of transcriptome analyses to identify the gene signatures and common hallmarks of these EBVaCAs. Based on the changes in the expression levels of genes in EBV-infected cell lines and tumor tissues, we identified two upregulated genes, SLC26A9 and TMC8, as gene signatures for EBVaCAs. In addition, SLC26A9 and TMC8 are differentially expressed genes (DEGs) in EBV-infected cells, and their expression is highly correlated with the stimulation of genes involved in numerous biological processes and pathways, such as IL6/JAK/STAT3 and TNF-α/NF-κB signaling pathways. Here, we propose SLC26A9 and TMC8 as novel gene signatures. In addition, we propose IL6/JAK/STAT3 and TNF-α/NF-κB signaling pathways as common hallmarks of EBVaCAs. Abstract Epstein-Barr virus (EBV) is associated with various types of human malignancies, including nasopharyngeal carcinoma (NPC), EBV-associated gastric carcinoma (EBVaGC), and oral squamous cell carcinoma (OSCC). The present study aimed to identify gene signatures and common signaling pathways that can be used to predict the prognosis of EBV-associated epithelial cancers (EBVaCAs) by performing an integrated bioinformatics analysis of cell lines and tumor tissues. We identified 12 differentially expressed genes (DEGs) in the EBVaCA cell lines. Among them, only four DEGs, including BAMBI, SLC26A9, SGPP2, and TMC8, were significantly upregulated. However, SLC26A9 and TMC8, but not BAMBI and SGPP2, were significantly upregulated in EBV-positive tumor tissues compared to EBV-negative tumor tissues. Next, we identified IL6/JAK/STAT3 and TNF-α/NF-κB signaling pathways as common hallmarks of EBVaCAs. The expression of key genes related to the two hallmarks was upregulated in both EBV-infected cell lines and EBV-positive tumor tissues. These results suggest that SLC26A9 and TMC8 might be gene signatures that can effectively predict the prognosis of EBVaCAs and provide new insights into the molecular mechanisms of EBV-driven epithelial cancers.

5-aminolaevulinic acid photodynamic therapy (ALA-PDT) has emerged as a non-invasive treatment modality for premalignant and malignant skin lesions. It has the advantage of better tolerance and providing better cosmetic outcomes than conventional treatment methods. Herein, we report a patient who suffered from multiple cutaneous squamous cell carcinoma (cSCC) in situ and actinic keratosis (AK) scattered in the body's sun-exposed areas, which had led him to undergo multiple surgical resections since the age of 16. Next-generation sequencing-based on a targeted gene capture panel revealed compound heterozygous mutations c.G559A and c.G1389A in the TMC8 gene. Combined with the typical clinical manifestations and mutation analysis, the patient was diagnosed with Epidermodysplasia verruciformis (EV). Due to the multiple AK and cSCC in situ lesions, ALA-PDT was applied. After 8 courses of ALA-PDT all lesions were successfully cleared without causing any scarring. Therefore, the use of ALA-PDT treatment may constitute a very promising and effective therapeutic modality for multiple cSCC in situ and AK secondary to EV.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to cutaneous human beta-papillomavirus infections causing persistent flat warts or pityriasis versicolor–like lesions. This generalized verrucous skin disorder resembles generalized verrucosis, but these 2 conditions are distinguished by differences in clinical manifestation and the human papillomavirus types involved. A breakthrough in our understanding of EV was the discovery that homozygous inactivating mutations in TMC6 ( EVER1 ) and TMC8 ( EVER2 ) determine susceptibility to this disorder; however, they have not solved all EV cases fully. These deficiencies account for 75% of affected individuals, leaving a substantial number of patients without an underlying genetic cause. Recently, it has been revealed that mutations in additional genes ( RHOH , MST-1 , CORO1A , and IL-7 ) result in extensive human beta-papillomavirus replication and therefore manifest with an EV-like phenotype. The term "acquired EV" is used to describe an EV-like phenotype that develops in immunocompromised hosts, and the introduction of this entity further aggravates the confusion. Reevaluation of these entities is warranted. Here, we review the available data on this issue, provide up to date information on the major characteristics that differentiate between these seemingly clinically similar disorders, and highlight the different mechanisms involved in each disorder.

Epidermodysplasia verruciformis (EV) is an autosomal recessive genodermatosis characterized by susceptibility to beta-genus human papillomavirus (HPV) infection. Owing to TMC6/EVER1 and TMC8/EVER2 mutations that lead to abnormal transmembrane channels in the endoplasmic reticulum involved in immunological pathways, keratinocytes cannot combat infection from non-pathogenic HPV strains. Mutations involving RHOH, MST-1, CORO1A, and IL-7 have also been associated with EV in patients without TMC6 or TMC8 mutations. We highlight a 27-year-old man with multiple violaceous flat-topped papules with scale and irregular borders distributed on his chest, extremities, abdomen, and back. The striking physical examination and the subsequent biopsy findings of enlarged nests of cells in the granular and spinous layers with blue-gray cytoplasm and keratohyaline granules confirmed the diagnosis. We conclude with a brief discussion on the differential diagnosis, which includes confluent and reticulated papillomatosis, Darier disease, and disseminated superficial actinic porokeratosis.

There is a growing association of human papillomavirus (HPV) with some cases of mucosal squamous cell carcinoma of the head and neck (HNSCC), particularly of the oropharynx. Persistent oral HPV infection is believed to increase the likelihood of malignancy, and it is possible that host genetic factors can determine susceptibility to persistent HPV infection. Polymorphisms in the two EV genes (EVER1 and EVER2, also known as transmembrane channel protein (TMC) 6 and 8) have been identified as strong candidate genes, since a small number of critical mutations in these genes have been shown to cause profound and florid skin HPV infections, and some of them have been linked to susceptibility to cervical cancer. We sought to determine whether there was a difference in the frequency of single nucleotide polymorphisms (SNPs) in EVER1 (rs2613516, rs12449858) and EVER2 (rs7205422, rs12452890) between HNSCC patients with HPV-positive and HPV-negative tumors, and healthy controls. We used logistic regression to analyze SNPs in 219 patients with histologically confirmed primary SCC of the oropharynx, oral cavity, hypopharynx, or larynx, and 321 healthy controls. We did not find any associations with the EVER1/EVER2 SNPs and HPV status or being a HNSCC case or a control. The present data do not provide evidence for a role of genetic variations in EVER1 or EVER2 for HPV status of mucosal HNSCC or between HNSCC patients and controls.

Human papillomavirus (HPV) infection alone is not sufficient to explain the development of cervical cancer. Genetic variants have been linked to the development of precancerous lesions and cervical cancer. In this study, we aimed to evaluate the association of 10 single nucleotide polymorphisms (SNPs) of the Fas cell surface death receptor (FAS), trinucleotide repeat containing 6C (TNRC6C), transmembrane channel like 8 (TMC8), DNA meiotic recombinase 1 (DMC1), deoxyuridine triphosphatase (DUT), sulfatase 1 (SULF1), 2′-5-oligoadenylate synthetase 3 (OAS3), general transcription factor IIH subunit 4 (GTF2H4) and interferon gamma (IFNG) genes with susceptibility to precancerous lesions and cervical cancer. In total, 608 female participants, consisting of 199 patients with persistent low-grade precancerous lesions (CIN1), 100 with high-grade precancerous lesions (CIN2/3), 17 patients with cervical cancer and 292 healthy controls, were enrolled in this study. SNPs were tested for associations with each of the above-mentioned cervical group lesions or when considering an overall patient group. A significant difference for rs4737999 was observed between the controls and the overall patient group considering the recessive mode of inheritance [odds ratio (OR), 0.48; 95% confidence interval (CI), 0.24–0.96; P=0.033]. This effect was even stronger on the risk of CIN1 lesions. Carriers of the rs4737999 AA genotype were almost 3-fold less likely of having low grade lesions compared to the other genotypes. On the whole, this study provides evidence of an influence of the SULF1 gene rs4737999 SNP in the development of precancerous lesions/cervical cancer.

Epidermodysplasia verruciformis (EV) is an autosomal recessive skin disorder with a phenotype conditional on human beta-papillomavirus (beta-HPV) infection. Such infections are common and asymptomatic in the general population, but in individuals with EV, they lead to the development of plane wart-like and red or brownish papules or pityriasis versicolor-like skin lesions, from childhood onwards. Most patients develop non-melanoma skin cancer (NMSC), mostly on areas of UV-exposed skin, from the twenties or thirties onwards. At least half of the cases of typical EV are caused by biallelic loss-of-function mutations of TMC6/EVER1 or TMC8/EVER2. The cellular and molecular basis of disease in TMC/EVER-deficient patients is unknown, but a defect of keratinocyte-intrinsic immunity to beta-HPV is suspected. Indeed, these patients are not susceptible to other infectious diseases and have apparently normal leukocyte development. In contrast, patients with an atypical form of EV due to inborn errors of T-cell immunity invariably develop clinical symptoms of EV in the context of other infectious diseases. The features of the typical and atypical forms of EV thus suggest that the control of beta-HPV infections requires both EVER1/EVER2-dependent keratinocyte-intrinsic immunity and T cell-dependent adaptive immunity.

Background: Renal transplant recipients (RTRs) have an increased risk of developing nonmelanoma skin cancer, mainly cutaneous squamous cell carcinoma (cSCC). Two genes (TMC6/EVER1 and TMC8/EVER2), mutated in epidermodysplasia verruciformis (EV) patients with an increased risk of cSCC development, contain numerous single-nucleotide polymorphisms (SNPs). Aim: To evaluate the effect of SNPs in both TMC/EVER genes on the different susceptibilities of RTRs to cSCC. Method: We determined the occurrence of cSCC in 105 RTRs who were transplanted at least 7 years previously and investigated the frequency of 26 SNPs within both TMC/EVER genes in severely affected (n = 16) as well as in nonaffected RTRs (n = 25). Results: Our data did not indicate a significant association between any SNP genotype and risk of cSCC development in RTRs. Conclusion: To clarify the correlation between SNPs in both TMC genes and cSCC development in RTRs, integrated investigations of large cohorts including both RTRs and immunocompetent individuals with consideration of cSCC status, SNP genotype and human papillomavirus status might be necessary.

Eight paralogue members form the family of transmembrane channel-like (TMC) proteins that share considerable sequence homology to anoctamin 1 (Ano1, TMEM16A). Ano1 is a Ca(2+) activated Cl(-) channel that is related to head and neck cancer, often caused by human papilloma virus (HPV) infection. Mutations in TMC 6 and 8 (EVER1, EVER2) cause epidermodysplasia verruciformis. This rare skin disease is characterized by abnormal susceptibility to HPV infection and cancer. We found that in contrast to Ano1 the common paralogues TMC4-TMC8 did not produce Ca(2+) activated Cl(-) currents when expressed in HEK293 cells. On the contrary, TMC8 was found to be localized in the endoplasmic reticulum (ER), where it inhibited receptor mediated Ca(2+) release, activation of Ano1 and volume regulated LRRC8-related Cl(-) currents. Zn(2+) is co-released from the ER together with Ca(2+) and thereby further augments Ca(2+) store release. Because TMC8 is required to lower cytosolic Zn(2+) concentrations by the Zn(2+) transporter ZnT-1, we hypothesize that HPV infections and cancer caused by mutations in TMC8 are related to upregulated Zn(2+)/Ca(2+) signaling and activation of Ano1.

Background Epidermodysplasia verruciformis (EV) is a rare genodermatosis that causes disseminated eruptions of hypo- or hyperpigmented macules and wart-like papules that can coalesce and scale. It is uniquely characterized by an increased susceptibility to specific human papillomavirus (HPV) genotypes. Classically, EV is associated with mutations of the EVER1/TMC6 and EVER2/TMC8 genes. The term "acquired" epidermodysplasia verruciformis was coined to describe an EV-like syndrome that can develop in patients with a compromised immune system. Recent discoveries of other genes implicated in EV, including RHOH, MST-1, and CORO1A, have complicated the classification of EV and EV-like syndromes. Methods We review the available data on epidermodysplasia verruciformis in the literature in order to propose a new classification system to encompass current and future developments on EV and EV-like syndromes. Results We propose classifying EV into: (1) classic genetic EV, (2) non-classic genetic EV, and (3) acquired EV. Conclusion The proposed categorization scheme provides a simple and logical way to organize the different cases of EV that have been described in the literature. This system organizes EV by its cause, allowing for a better understanding of the disease and helps differentiate EV from other causes of generalized verrucosis.

Head and neck squamous cell carcinoma (HNSCC), one of the most common cancers with high morbidity and mortality rates worldwide, has a poor prognosis. The transcriptome sequencing data of 500 patients with HNSCC in the TCGA dataset were assessed to find biomarkers associated with HNSCC prognosis so as to improve the prognosis of patients with HNSCC. The patients were divided into the training and testing sets. A model of six mRNAs (FRMD5, PCMT1, PDGFA, TMC8, YIPF4, ZNF324B) that could predict patient prognosis was identified in the training set using the Cox regression analysis. According to this model, the patients were divided into high-risk and low-risk groups. The Kaplan-Meier analysis showed that the high-risk group showed significantly shorter overall survival time compared with the low-risk group in both training and testing sets. The receiver operating characteristic analysis further confirmed high sensitivity and specificity for the model, which was more accurate compared with some known biomarkers in predicting HNSCC prognosis. Moreover, the model was applicable to patients of different ages, genders, clinical stages, tumor locations, smoking history, and human papillomavirus (HPV) status, as well as to microarray dataset. This model could be used as a novel biomarker for the prognosis of HNSCC and a significant tool for guiding the clinical treatment of HNSCC. The risk score acquired from the model might contribute to improving outcome prediction and management for patients with HNSCC, indicating its clinical significance.

Hepatocellular carcinoma (HCC) is an aggressive malignant tumor and the third leading cause of cancer-related mortality worldwide. Transmembrane channel-like protein 8 (TMC8) is reported to play a major role in several aspects of human pathophysiology, such as ion channel permeability, human papillomavirus infection and skin cancer; however, its role in HCC has not been fully elucidated. The aim of the present study was to investigate the expression levels of TMC8 in 146 pairs of liver cancer samples and adjacent non-tumorous samples using immunohistochemistry. Reverse transcription-quantitative polymerase chain reaction analysis was used to confirm the results. The association between TMC8 expression and clinicopathological characteristics, including overall survival, was analyzed. The results indicated that the expression of TMC8 was significantly upregulated in HCC tissues and associated with metastasis and hepatitis B virus infection. According to the analysis of the overall survival using Cox proportional hazard regression model, higher expression of TMC8 was associated with a poorer prognosis and the overexpression of TMC8 was an independent risk factor for HCC. By contrast, HBsAg did not significantly affect the survival of HCC patients. These results suggest that the overexpression of TMC8 in HCC predicts poor prognosis and may be a potential biomarker for this type of cancer.

Background Epidermodysplasia verruciformis (EV) is a genodermatosis leading to infections with cutaneous HPV, persistent plane warts and a high rate of non-melanoma skin cancer (NMSC). Biallelic loss-of-function mutations in TMC6 and TMC8 are known to be causative. Objective The aim of this study was to report EV-causing mutations in four patients with EV and to give an overview of all described EV patients. Patients and methods We investigated four patients with classical features of EV from two families. All patients were affected by plane warts with typical EV histology since early childhood and β-HPVs were detected on their skin. One patient had recurring cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ (Bowen type). We sequenced both TMC6/8 for disease-causing mutations and quantified levels of gene expression. We also performed a systematic literature review to discuss these patients in the context of previously reported cases, mutations already identified, as well as HPV types. Results Three patients of one family carried a homozygous splice site mutation in TMC8 resulting in aberrantly spliced transcripts that were not degraded. By contrast, no TMC6/8 mutation was detected in the patient from the other family. A systematic literature review revealed 501 described EV patients. Around 40% of EV patients analysed for genetic alterations carried no mutation in TMC6/8. While β-HPVs were identified in the majority of cases, α-HPVs were detected in several individuals. Conclusion The relatively high proportion of EV patients without mutation in TMC6/8 indicates the existence of EV-causing mutations in additional, presently unknown gene(s). However, a homozygous TMC8 splice site mutation in our patients resulted in aberrant transcripts which cannot retain the healthy phenotype. The literature review revealed that HPV-5 is the most commonly identified HPV in EV patients, but HPV-3, HPV-14, and HPV-20 were unexpectedly identified more frequently than HPV-8. This article is protected by copyright. All rights reserved.

Squamous cell skin cancer (SCSC) disproportionately affects organ transplant recipients, and may be related to increased viral replication in the setting of immune suppression. We conducted a nested case–control study among transplant recipients to determine whether SCSC is associated with antibodies to cutaneous human papillomaviruses (HPV), to genes associated with a rare genetic susceptibility to HPV (TMC6/TMC8), or to human polyomaviruses (HPyV). Cases (n = 149) had histologically confirmed SCSC, and controls (n = 290) were individually matched to cases on time since transplant, type of transplant, gender, and race. All subjects had serum drawn immediately prior to transplant surgery. Antibodies to 25 cutaneous HPVs and six HPyVs were assayed by detection of binding to virus-like particles, and 11 TMC6/8 variants were genotyped. After correction for multiple comparisons, only antibodies to HPV37 were associated with SCSC (OR 2.0, 95% CI 1.2–3.4). Common genetic variants of TMC6/8 were not associated with SCSC, but three variants in TMC8 (rs12452890, rs412611, and rs7208422) were associated with greater seropositivity for species 2 betapapillomaviruses among controls. This study suggests that some betaHPVs, but not polyomaviruses, may play a role in the excess risk of SCSC among transplant recipients.

Background: Epidermodysplasia verruciformis (EV) is a rare autosomal-recessive disorder characterized by widespread and persistent infection with human papilloma virus (HPV) and a risk of malignant degeneration. Most cases of EV are caused by mutations in the two EV genes, EVER1/TMC6 and EVER2/TMC8. The clinical presentation of EV takes two different forms, which coexist in most cases. Over a period of years, patients develop plane warts and pityriasis versicolor-like lesions. Sixteen cases of EV in HIV-positive patients have been clinically investigated and reported in the literature. However, different inherited susceptibilities towards HPV infection in immunodeficient patients, like HIV-positive patients, have only rarely been addressed. Observation: We describe a 22-year-old female patient with a congenital HIV infection, who presented with slowly progressing and confluent erythematous papules on her hands and hypopigmented macules on her extremities. The histopathology was typical for EV, and HPV5 was detected by PCR and reverse hybridization. The 44-year-old HIV-positive mother has no typical EV lesions. The patient is homozygous for an A to T single nucleotide polymorphism (SNP) at position 917 of the TMC8/EVER2 gene. The mother of the patient is heterozygous for this SNP. Conclusion: These results support the hypothesis that the combination of immunodeficiency and a susceptibility allele may contribute to the differences in occurrence of EV in HIV-positive patients.

Cervical cancer is the forth most commonly diagnosed cancer among women worldwide. It is caused by persistent infection with an oncogenic type of Human Papillomavirus (HPV). The HPV is a necessary but not sufficient cause of cervical cancer. Environmental factors such as smoking, high parity and long-term use of oral contraceptives increases the risk of cervical cancer. Genetic factors also affect the risk of developing the disease. The aim of this thesis is to search for and evaluate genetic risk factors for cervical cancer using both a candidate gene approach and a genome-wide association study (GWAS). Paper I examined the association of genetic variation in three Fanconi Anemia (FA) genes (FANCA, FANCC and FANCL), involved in DNA repair, with cervical cancer susceptibility in the Swedish population. No association was observed. Paper II evaluated the association of genetic variation in the TMC6 and TMC8 genes with susceptibility to cervical cancer in the Swedish population and an association of two SNPs (rs2290907 and rs16970849) with cervical cancer was observed. In paper III the first GWAS performed in cervical cancer was reported. Three independent loci in the major histocompatibility complex (MHC) region at 6p21.3 were found to affect the susceptibility to cervical cancer. Paper IV examined the sequence variation in the TMC6 and TMC8 region and its association with cervical cancer. A highly polymorphic 21 bp sequence was identified and found to be repeated 5 to 42 times in both cases and controls. Lack of this repeat was associated with increased risk of cervical cancer. An intronic SNP (rs2926778) located in between the TNRC6C and TMC6 genes was also found to be associated with cervical cancer. The thesis provides evidence for the importance of genes in the immune system for cervical cancer susceptibility. The genetic risk factors identified explain only a part of the genetic susceptibility, implying that other risk factors remains to be identified

Epidermodysplasia verruciformis (EV) is a rare autosomal recessive genodermatosis associated with a high risk of skin carcinoma. EV results from an abnormal susceptibility to infection by specific human papillomavirus (HPV) genotypes (beta-papillomaviruses) which include the potentially oncogenic HPV5. EV-specific HPVs are considered as harmless for the general population. EV was recently found to be caused by invalidating mutations in two adjacent, related, novel genes, EVER1/TMC6 and EVER2/TMC8. EVER genes encode transmembrane proteins located in the endoplasmic reticulum, which are likely to function as modifiers of ion transporters or channels and to be involved in signal transduction. It was proposed that EV was a primary defect of innate immunity. Our hypothesis is that EVER proteins act as restriction factors for EV-specific HPVs in keratinocytes, and that EV represents a primary deficiency of intrinsic immunity against certain papillomaviruses.

Epidermodysplasia verruciformis (EV) is a rare auto­ somal recessive disease characterised by abnormal susceptibility to disease-specific human papillomaviruses (HPVs), possibly due to suppressed cellular innate im­ munity. EVER1/TMC6 or EVER2/TMC8 gene mutations are often found in EV (1). All patients with EV usually have similar skin lesions from their childhood, involving disseminated flat warts or pityriasis versicolor. Elderly patients with EV have a high risk of developing carcino­ mas in situ and invasive squamous cell carcinoma (SCC) associated with HPV infections, mainly on sun­exposed skin. On the other hand, Merkel cell polyomavirus (MC­ PyV) is detected in most Merkel cell carcinomas (MCC) (2), which arise from Merkel cells, neuroendocrine cells in the skin. We present here a rare occurrence of MCPyV+ MCC in a patient with EV.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by increased sensitivity to infection by the β-subtype of human papillomaviruses (β-HPVs), causing persistent, tinea versicolor-like dermal lesions. In a majority of affected individuals, these macular lesions progress to invasive cutaneous squamous cell carcinoma (CSCC) in sun-exposed areas. While mutations in transmembrane channel-like 6 (TMC6 / EVER1) and 8 (TMC8 / EVER2) have been causally linked to EV, their molecular functions are unclear. It is likely that their protective effects involve regulation of the β-HPV life cycle, host keratinocyte apoptosis vs. survival balance and/or T-cell interaction with infected host cells.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by an abnormal susceptibility to infection with a specific group of related human papillomavirus (HPV) genotypes, including the oncogenic HPV5 associated with the skin carcinomas developing in about half of EV patients. EV is usually considered as an autosomal recessive condition. Taking EV as a model to identify a locus underlying the susceptibility to HPV infections, we performed a genome-wide search for linkage with 255 microsatellite genetic markers in three consanguineous EV families comprising six patients, using the homozygosity mapping approach. Homozygosity restricted to affected individuals was observed for a marker of chromosome 17q (D17S784) in two families and a marker about 17 centiMorgan (cM) distal (D17S1807) in the third family. Ten additional microsatellite markers spanning 29 cM in this region were analyzed. Two-point lod score values greater than 3 were obtained for four markers and multipoint linkage analysis yielded a maximum lod score of 10.17 between markers D17S939 and D17S802. Recombination events observed in two families allowed a candidate region for the EV susceptibility locus to be mapped to the 1 cM region defined by these two markers. The EV locus (named EV1) is included in the 17qter region recently found to contain a dominant locus for the susceptibility to familial psoriasis. It has been shown that patients suffering from psoriasis are likely to constitute the reservoir of HPV5. It is thus tempting to speculate that distinct defects affecting the same gene may be involved in the two skin conditions.

The initial link between HPV and skin cancers was a rare autosomal inherited disease called Epidermodysplasia Verruciformis (EV) first described nearly a century ago.1 The disease is characterized by cutaneous lesions that display a high rate of progression to squamous cell carcinomas (SCCs) beginning in the second decade of life. Furthermore, EV patients experience diminished cell-mediated immunity possibly resulting in an observed susceptibility to infection by specific HPV types falling into the genus β, with HPV5 and HPV8 the most prevalent infections in this patient population.2 Genome-wide linkage studies were performed to map two EV loci3,4 and to identify the EVER genes (EVER1 or EVER2, also referred to as TMC6 and TMC8, respectively) in one of these loci.5 The identification of EVER1 and EVER2 expressed sequence tags and cDNA from lymphoid tissue is consistent with a model in which EV mutations exert their direct effects in the immune system. It was recently discovered that 75% of EV patients studied have rare mutations in either of these adjacent, related, novel genes. To date, 10 truncating, loss of function mutations have been identified, 4 in EVER1 and 6 in EVER2 and were identified in EV patients from Algeria, Columbia, Poland and Japan.5 More recently, 5 additional mutations have been detected in the EVER genes supporting the hypothesis that EVER1 and EVER2 are the molecular basis of EV.6–8 β-HPV DNA has been detected in up to 50% of SCC tumors from immunocompetent individuals and in up to 90% of lesions from immunocompromised individuals,9,10 further emphasizing the role of host susceptibility in infection with these viruses. Recently, we reported that the presence of antibodies to viral proteins of HPV types in the genus β, particularly HPV5, was associated with risk of SCC.11 We hypothesize that a common nonsynonymous single nucleotide polymorphism in the EVER2 gene also may be related to infection with β-HPVs. Here we report that this particular SNP (rs7208422), located in the most highly conserved region of the gene, is not only associated with SCC of the skin but also with the presence of antibodies to genus β-HPVs in control subjects.

Epidermodysplasia verruciformis (EV; MIM#226400) is a genodermatosis characterized by susceptibility to epidermodysplasia verruciformis-human papillomavirus (EV-HPV) infections which leads to early development of disseminated pityriasis versicolor-like and flat wart-like lesions [1]. The disease was first described by Lewandowski and Lutz in [1]. Approximately half of all patients with EV will develop cutaneous malignancies, predominately Bowen’s type carcinoma in situ and invasive squamous cell carcinomas that occur mainly on sun-exposed areas in the fourth or fifth decade of life [2-4].Thus, EV is in essence a genetic cancer of viral origin, and could also be regarded as a model of cutaneous HPV oncogenesis [5, 6]. In general, EV shows an autosomal recessive pattern of inheritance [7]. The EV loci were mapped to chromosome 2p21-p24 (EV2) and 17q25 (EV1) [8], respectively. In the EV1 interval, 2 adjacent related genes, EVER1 and EVER2, were identified in 2002 [9]. EVER proteins are members of transmembrane channel-like (TMC) family. They are encoded by 8 genes (TMC1-8). EVER1 and EVER2 correspond to TMC6 and TMC8, respectively [10, 11]. Therefore the recent literature has focused on the mutation finding the culpable gene. Clinical and histologic findings, EV-HPV, cutaneous oncogenesis, and genetics will be briefly reviewed.

International audience; EVER1 and 2 confer resistance to cutaneous oncogenic human papillomavirus infections by downregulating the activating protein 1 (AP-1) signaling pathway. Defects in their expression are associated with susceptibility to epidermodysplasia verruciformis, which is characterized by persistent β-HPV infection, tumor necrosis factor alpha (TNF-α) overproduction in keratinocytes and the development of skin cancers. TNF-α-induced apoptosis is a key defense strategy, preventing the persistence of the virus within cells, but the role of EVER proteins in this cell death mechanism triggered by extrinsic stimuli is unknown. We show here that EVER2 induces TNF-α- and TRAIL-dependant apoptosis. It interacts with the N-terminal domain of TRADD, impairs the recruitment of TRAF2 and RIPK1 and promotes apoptosis. The skin cancer-associated EVER2 I306 allele results in an impaired TRADD-EVER2 interaction, with lower levels of cell death following treatment with TNF-α. These data highlight a new, critical function of EVER2 in controlling cell survival in response to death stimuli.

Germline mutations of the EVER1/TMC6 gene are associated with epidermodysplasia verruciformis (EV), which is characterized by an abnormal susceptibility to human papillomaviruses that were considered to be innocuous for the general population. In this study, we have employed polymerase chain reaction and DNA sequencing analysis to characterize the EVER1 gene in a 65-year-old Japanese EV patient. Direct sequence analyses resulted in the identification of two novel mutations. One nonsense mutation consisting of a (C>A) transversion at nucleotide 744 in exon 8 in one EVER1 allele resulted in the introduction of a premature termination codon (Y248X). Another mutation was identified in the splice acceptor site of intron 8 (892-2, IVS8-2, A>T) in another allele. This is the second report of EVER1/TMC6 mutations in EV.

Epidermodysplasia verruciformis (OMIM 226400) is a rare autosomal recessive genodermatosis associated with a high risk of skin carcinoma that results from an abnormal susceptibility to infection by specific human papillomaviruses (HPVs). We recently mapped a susceptibility locus for epidermodysplasia verruciformis (EV1) to chromosome 17q25. Here we report the identification of nonsense mutations in two adjacent novel genes, EVER1 and EVER2, that are associated with the disease. The gene products EVER1 and EVER2 have features of integral membrane proteins and are localized in the endoplasmic reticulum.

Cervical cancer (CxCa) is caused by persistent human papillomavirus (HPV) infection; genetic predisposition is also suspected to play a role. The present study is a targeted candidate gene follow-up based on: i) strong clinical evidence demonstrating that mutations in the TMC6 and TMC8 (EVER1 and EVER2) genes associate with the HPV-associated disease Epidermodysplasia Verruciformis (EV), and ii) recent epidemiological data suggesting a genetic susceptibility conferred by polymorphisms in such genes for skin and cervical cancer. Clarifying the association of the TMC6/8 genes with risk of CxCa will help in understanding why some HPV-infected women develop persistent infection, cervical lesions and eventually cancer while others do not. Twenty-two single nucleotide polymorphisms (SNP) harbouring the TMC6/8 genes were genotyped in 2,989 cases with cervical intraepithelial neoplasia grade III (CINIII) or invasive cervical cancer (ICC) and 2,281 controls from the Swedish population. Association was evaluated in logistic regression models. Two SNPs displayed association with cervical disease: rs2290907 (ORGGvsAA = 0.6, 95% CI: 0.3 - 0.9, p = 0.02) and rs16970849 (ORAGvsGG = 0.8, 95% CI: 0.66 - 0.98, p = 0.03). The present data supports the involvement of the TMC6/8 region in CxCa susceptibility but further analyses are needed to replicate our findings, fully characterize the region and understand the function of the genetic variants involved.

Background: Epidermodysplasia verruciformis Lewandowsky-Lutz (EV) is a rare genodermatosis, characterised by development of numerous verrucous skin lesions caused by specific genotypes of human papillomaviruses belonging to the β-papillomavirus genus. The EV loci were mapped to chromosome 2p21–p24 (EV2) and 17q25 (EV1). On chromosome 17, 2 adjacent related genes – EVER1/TMC6 and EVER2/TMC8 – were identified. We reinvestigated 2 patients originally described by Wilhelm Lutz in 1946 with the aim to document the natural course of the disease and confirm his diagnosis. Methods: PCR fragments specific for exons with short flanking intron sequences of EVER1/TMC6 and EVER2/TMC8 genes from patients’ DNA were amplified using sequence information. The single-nucleotide polymorphism (SNP) rs7208422 was studied, using restriction fragment length polymorphism analysis. Results: In the index patient, we identified a homozygous TT genotype in exon 8 of the EVER2/TMC8 gene (c.917A → T, p.N306I). The same mutation could thereafter be detected in her sister from paraffin-embedded skin. Conclusion: We have followed one of the first patients described with EV in Basel, Switzerland, in 1930 until today and demonstrated the TT genotype (SNP rs7208422) in the EVER2/TMC8 gene in this index patient and her sister. The results underline the possible relevance of SNP rs7208422 by influencing the susceptibility to β-papillomaviruses and their oncogenic potential.

SUMMARY Infections by human papillomaviruses (HPVs) are the most frequently occurring sexually transmitted diseases. The crucial role of genital oncogenic HPV in cervical carcinoma development is now well established. In contrast, the role of cutaneous HPV in skin cancer development remains a matter of debate. Cutaneous beta-HPV strains show an amazing ubiquity. The fact that a few oncogenic genotypes cause cancers in patients suffering from epidermodysplasia verruciformis is in sharp contrast to the unapparent course of infection in the general population. Our recent investigations revealed that a natural barrier exists in humans, which protects them against infection with these papillomaviruses. A central role in the function of this HPV-specific barrier is played by a complex of the zinc-transporting proteins EVER1, EVER2, and ZnT-1, which maintain cellular zinc homeostasis. Apparently, the deregulation of the cellular zinc balance emerges as an important step in the life cycles not only of cutaneous but also of genital HPVs, although the latter viruses have developed a mechanism by which they can break the barrier and impose a zinc imbalance. Herein, we present a previously unpublished list of the cellular partners of EVER proteins, which points to future directions concerning investigations of the mechanisms of action of the EVER/ZnT-1 complex. We also present a general overview of the pathogenesis of HPV infections, taking into account the latest discoveries regarding the role of cellular zinc homeostasis in the HPV life cycle. We propose a potential model for the mechanism of function of the anti-HPV barrier.