Figure 1
Epidermodysplasia verruciformis (EV) lesions on (a) knees and (b) neck of patient 1. (c) Haematoxylin-eosin (HE)stained Bowenoid lesion. Typical pale blue cytoplasm and slightly polymorphic keratinocytes are visible. (d) As a rare feature, the patient showed persistent palmar lesions (marked with blue circles). (e) cSCC developing on the nose of the patient where no previous EV lesions had been present.
Source publication
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 pati...
Contexts in source publication
Context 1
... Swiss woman aged 49 was examined. Her parents were first cousins. Since early childhood, reddish skin lesions on the back of her hands and the extensor sides of her knees were visible. The lesions extended to the retroauricular area, neck, chest, arms, hands, knees and lower legs (Fig. 1a,b). They showed the typical histological appearance of plane warts with minimal hyperkeratosis, acanthosis, as well as some cells with perinuclear halos and bluish staining (Fig. 1c). The patient had few persis- tent palmar lesions similar to palmar pits which were dermato- scopically consistent with plane warts (Fig. 1d). This is a very ...
Context 2
... back of her hands and the extensor sides of her knees were visible. The lesions extended to the retroauricular area, neck, chest, arms, hands, knees and lower legs (Fig. 1a,b). They showed the typical histological appearance of plane warts with minimal hyperkeratosis, acanthosis, as well as some cells with perinuclear halos and bluish staining (Fig. 1c). The patient had few persis- tent palmar lesions similar to palmar pits which were dermato- scopically consistent with plane warts (Fig. 1d). This is a very rare feature of EV which has been described in only three patients so far. [6][7][8] The patient developed multiple cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ ...
Context 3
... knees and lower legs (Fig. 1a,b). They showed the typical histological appearance of plane warts with minimal hyperkeratosis, acanthosis, as well as some cells with perinuclear halos and bluish staining (Fig. 1c). The patient had few persis- tent palmar lesions similar to palmar pits which were dermato- scopically consistent with plane warts (Fig. 1d). This is a very rare feature of EV which has been described in only three patients so far. [6][7][8] The patient developed multiple cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ (Bowen type), mainly on her forehead and nose (Fig. 1e). After the patient provided informed consent, blood samples and skin biopsies were ...
Context 4
... lesions similar to palmar pits which were dermato- scopically consistent with plane warts (Fig. 1d). This is a very rare feature of EV which has been described in only three patients so far. [6][7][8] The patient developed multiple cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ (Bowen type), mainly on her forehead and nose (Fig. 1e). After the patient provided informed consent, blood samples and skin biopsies were taken. The whole coding sequence of TMC6 and TMC8, as well as adjacent intronic regions, was sequenced as described elsewhere. 1 Some common SNPs without effect on the protein sequence were detected, as well as a heterozygous SNP in TMC8 (rs7208422, ...
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Citations
... 2 The pathogenesis is linked to a loss of function of TMC6 and TMC8 proteins, which are coded by the EVER1 and EVER2 genes located on chromosome 17q25. 3,4 Within keratinocytes, these proteins (located on the endoplasmic reticulum) modulate the intracellular distribution of zinc and subsequently influence the activity of transcription factors necessary for HPV proliferation. In patients with EV, there is altered intracellular zinc homeostasis, increased HPV proliferation within the keratinocytes, and potential risk of malignant transformation. ...
... 12,13 More commonly, nonsense mutations, splice-site mutations, and frameshift mutations have been described internationally. 3,13,14 To the best of our knowledge, there is no published literature on the genetic profile of Indians with EV. ...
Epidermodysplasia verruciformis (EV) is a rare autosomal recessive genodermatosis due to mutations in EVER1 and EVER2 genes. The genetic profile of Indian patients with EV has not been previously studied. This report describes the clinical presentation and molecular analysis of a family with EV. Using genomic DNA from two affected probands and healthy controls (two other siblings), conventional polymerase chain reaction (PCR) was conducted with novel primer sets designed to amplify the coding and splice-site regions in the genes EVER1 and EVER 2. This revealed no amplification with a primer set for exons 16 to 18 in the EVER1 gene of both the probands. Subsequently, long-range PCR spanning the length of exon 15-20 and next-generation sequencing demonstrated a homozygous deletion of 2078 bp in the EVER1 gene (EVER1:c.2072_2278del). Screening the family revealed the same homozygous deletion (similar to index cases) in two other affected siblings. The parents and two asymptomatic siblings were heterozygous carriers for the deletion while one healthy sibling was negative. These results were validated with Sanger sequencing. This deletion in exons 17 and 18 of the EVER1 gene results in a frameshift, followed by a premature termination resulting in a severe phenotype. The identification and validation of this large deletion was detected using stepwise amplicon-based target enrichment and long-range PCR, respectively. In this family, this simple strategy greatly enhanced genetic counseling as well as early genetic diagnosis and screening. However, functional assays and larger studies are required to characterize and validate the genetic diversity among Indians with EV.
... HPVs can be categorized into mucosal and cutaneous HPVs based on which tissue types they predominately infect (5). Cutaneous HPVs cause benign hyperplastic lesions known as warts but a subset of cutaneous HPVs, predominately HPV 5 and 8, can cause non-melanoma skin cancer in individuals with the hereditary condition epidermodyspla sia verruciformis (EV) or long-term immunosuppressed organ transplant patients (6,(8)(9)(10)(11)(12)(13). In addition, a subset of mucosal HPVs referred to as high-risk HPVs cause lesions in mucosal tissues that if allowed to persist can progress to anogenital and head and neck cancer (1)(2)(3)(4)14). ...
The E6 protein encoded by the murine papillomavirus (MmuPV1) is essential for MmuPV1-induced skin disease. Our previous work has identified a number of cellular interacting partners of MmuPV1 E6 and E7 through affinity purification/mass spectrometry analysis. These studies revealed that MmuPV1 E6 potently inhibits keratinocyte differentiation through multiple molecular mechanisms including inhibition of NOTCH and TGF-β signaling. Here, we report that MmuPV1 E6 has additional important oncogenic activities when expressed in its natural host cells, mouse keratinocytes, including increasing proliferation, overcoming density-mediated growth arrest, and proliferation under conditions of limited supply of growth factors. Unbiased proteomic/transcriptomic analyses of mouse keratinocytes expressing MmuPV1 E6 substantiated its effect on these cellular processes and divulged that some of these effects may be mediated in part through it upregulating E2F activity. Our analyses also revealed that MmuPV1 E6 may alter other cancer hallmarks including evasion of growth suppressors, inhibition of immune response, resistance to cell death, and alterations in DNA damage response. Collectively, our results suggest that MmuPV1 E6 is a major driver of multiple hallmarks of cancer in MmuPV1’s natural host cells, mouse keratinocytes.
IMPORTANCE
The Mus musculus papillomavirus 1 (MmuPV1) E6 and E7 proteins are required for MmuPV1-induced disease. Our understanding of the activities of MmuPV1 E6 has been based on affinity purification/mass spectrometry studies where cellular interacting partners of MmuPV1 E6 were identified, and these studies revealed that MmuPV1 E6 can inhibit keratinocyte differentiation through multiple mechanisms. We report that MmuPV1 E6 encodes additional activities including the induction of proliferation, resistance to density-mediated growth arrest, and decreased dependence on exogenous growth factors. Proteomic and transcriptomic analyses provided evidence that MmuPV1 E6 increases the expression and steady state levels of a number of cellular proteins that promote cellular proliferation and other hallmarks of cancer. These results indicate that MmuPV1 E6 is a major driver of MmuPV1-induced pathogenesis.
... Six cases of autosomal dominant inheritance and five of X-linked inheritance have been reported [8][9][10][11]. EV is very rare, with only 500 cases reported up to 2017 [12]. The congenital type of EV may be either familial or sporadic due to de novo mutation. ...
... HPV5 and HPV8 are the most commonly identified HPV types found in EV-related cancers (up to 90%) [14]. Some PW-like HPV types (HPV3, HPV10) are associated with EV, while others are more specific to EV, including types 5, 8,9,12,14,15, and 17. Molecular techniques used to identify the type of HPV lesions in individual patients with EV who frequently express several HPV types can influence the most commonly recognized HPV types. ...
1. Abstract Epidermodysplasia verruciformis (EV) is a rare genodermatosis associated with decreased immunity against certain types of human papillomaviruses that are associated with a high risk for cuta-neous dysplasia and skin cancer. Herein, we present the case of a 35-year-old man with seborrheic keratosis-like lesions on his face, plane wart-like lesions on both hands, erythematous macules bilaterally on his neck, and pityriasis versicolor-like lesions on both arms. The onset occurred in the second decade of his life, at which time he reported similar lesions affecting his father and brother. Histopathological findings confirmed the diagnosis of EV. Interestingly , this is the first such case to be reported in Yemen. 2. Significance This first reported case of epidermodysplasia verruciformis indicates the prevalence of this unusual and rare skin disease in Yemen and raises awareness about the need for early identification by cli-nicians and treatment. 3. Introduction Epidermodysplasia verruciformis (EV) is a rare autosomal reces-sive genodermatosis caused by a mutation of either EVER1 or EVER2, leading to a specific defect in immunity against certain types of human papillomaviruses (HPV) [1]. It presents with disseminated and persistent HPV infection, giving rise to a typical presentation with three types of lesions: plane wart-like lesions, pityriasis versicolor-like lesions, and reddish plaques [2-4]. Although it is commonly associated with the development of malignant tumors, metastasis is rare [5]. The onset of the highly pol-ymorphic cutaneous lesions of EV commonly occurs during the second decade of life [5]. Approximately 50% of patients develop precancerous lesions and malignant tumors, such as squamous cell carcinomas (SCC) of the skin, subsequently form on sun-exposed sites [6]. The disease is typically characterized by cutaneous pol-ymorphic lesions simulating pityriasis versicolor (PV-like), plane warts (PW-like), or seborrheic keratosis (SK-like). 4. Case Report A 35-year-old man presented to the dermatology outpatient clinic of the University Hospital in Sana'a, Yemen, with PW-like lesions over the dorsal sides of his hands, SK-like lesions over his face, er-ythematous macules, and PV-like lesions on both sides of the neck (Figures 1A-D, 2A-D, and 3A). The lesions emerged at 18 years of age. The patient was the oldest of 11 siblings (six brothers and five sisters), but except for the second and ninth brothers, no other siblings had similar lesions. However, when the lesions emerged, his father and his 17-year-old son had similar facial lesions.
... The "malignant form" is characterized by polymorphic lesions, with a tendency to malignant transformation and it is usually associated with HPV types 5, 8, and 14 [3]. Many of these lesions take on the appearance of tree bark or tree roots, typically on the face, neck, torso, hands, and feet. ...
... Cutaneous warts are generally benign lesions that are caused by infections with specific, cutaneous HPVs [6]. A subset of cutaneous HPVs, most prominently HPV5 and 8, cause cutaneous squamous cell carcinoma (cSCC) in individuals who are genetically predisposed to develop the rare skin disease, epidermodysplasia verruciformis (EV) [7][8][9][10][11]. HPV5 and 8 potentially also contribute to cSCC in other patients including immunocompromised individuals [12]. ...
Human papillomaviruses (HPVs) contribute to approximately 5% of all human cancers. Species-specific barriers limit the ability to study HPV pathogenesis in animal models. Murine papillomavirus (MmuPV1) provides a powerful tool to study the roles of papillomavirus genes in pathogenesis arising from a natural infection. We previously identified Protein Tyrosine Phosphatase Non-Receptor Type 14 (PTPN14), a tumor suppressor targeted by HPV E7 proteins, as a putative cellular target of MmuPV1 E7. Here, we confirmed the MmuPV1 E7-PTPN14 interaction. Based on the published structure of the HPV18 E7/PTPN14 complex, we generated a MmuPV1 E7 mutant, E7K81S, that was defective for binding PTPN14. Wild-type (WT) and E7K81S mutant viral genomes replicated as extrachromosomal circular DNAs to comparable levels in mouse keratinocytes. E7K81S mutant virus (E7K81S MmuPV1) was generated and used to infect FoxN/Nude mice. E7K81S MmuPV1 caused neoplastic lesions at a frequency similar to that of WT MmuPV1, but the lesions arose later and were smaller than WT-induced lesions. The E7K81S MmuPV1-induced lesions also had a trend towards a less severe grade of neoplastic disease. In the lesions, E7K81S MmuPV1 supported the late (productive) stage of the viral life cycle and promoted E2F activity and cellular DNA synthesis in suprabasal epithelial cells to similar degrees as WT MmuPV1. There was a similar frequency of lateral spread of infections among mice infected with E7K81S or WT MmuPV1. Compared to WT MmuPV1-induced lesions, E7K81S MmuPV1-induced lesions had a significant expansion of cells expressing differentiation markers, Keratin 10 and Involucrin. We conclude that an intact PTPN14 binding site is necessary for MmuPV1 E7's ability to contribute to papillomavirus-induced pathogenesis and this correlates with MmuPV1 E7 causing a delay in epithelial differentiation, which is a hallmark of papillomavirus-induced neoplasia.
... More than half of patients with typical EV have pathogenic variants in either TMC6 or TMC8. 2,3 Biallelic pathogenic variants in CIB1 have also been associated with EV. 4 Here, we studied the genetic basis of EV in a consanguineous family from Pakistan ( Figure 1a) using a molecular diagnostic approach. Four of 11 siblings developed the phenotype in early childhood. ...
We identified a novel homozygous disease-causing variant in TMC8 in a Pakistani family with Epidermodysplasia Verruciformis (EV). The phenotype of EV in the affected individuals was most probably caused by an aberrant splicing process. The molecular genetic findings from our patients expand the mutational spectrum of the disease.
... 87 In EV, dysregulated proliferation of HPVinfected keratinocytes can be observed 88 and clinically lead to childhood-onset flat warts and pityriasis versicolorelike lesions that persist throughout life. 89 About two-thirds of EV patients develop nonmelanoma skin cancers that occur in Ultraviolet lighteexposed skin regions and test positive for HPV types 5 and 8. 90 A reliable and early genetic diagnosis of EV is crucial because this has major impact on prevention and screening or treatment of patient skin lesions (Figure 2). ...
Inborn errors of immunity are genetically and clinically heterogeneous disorders, that in addition to infection susceptibility and immune dysregulation, can have an enhanced cancer predisposition. The increasing availability of upfront next generation sequencing diagnostics in immunology and oncology have uncovered substantial overlap of germline and somatic genetic conditions that can result in immunodeficiency and cancer. However, broad application of unbiased genetics in these neighboring disciplines still needs to be deployed, and joined therapeutic strategies guided by germline and somatic genetic risk factors are lacking. We illustrate the current difficulties encountered in clinical practice, summarize the historical development of pathophysiological concepts of cancer predisposition, and review select genetic, molecular, and cellular mechanisms of well-defined and illustrative disease entities such as DNA repair defects, combined immunodeficiencies with EBV susceptibility, autoimmune lymphoproliferative syndromes, regulatory T-cell disorders, and defects in cell intrinsic immunity. We review genetic variants that when present in the germline cause inborn errors of immunity with cancer predisposition, but when arising as somatic variants behave as oncogenes and cause specific cancer entities. We finally give examples of small molecular compounds that are developed and studied to target genetically defined cancers but might also proof useful to treat inborn errors of immunity.
... Liu et al. found that TRA2A can target RSRC2 AS to confer paclitaxel resistance and promote tumour progression in breast cancer [44]. Imahorn et al. revealed a novel TMC6/8 splice site mutation interlinked with HPV infection and cervical cancer [45]. CASP8 plays a significant role in the apoptosis pathway, and its abnormal expression is associated with tumour cell differentiation, the cancer risk, and prognosis [46]. ...
Purpose
Pancreatic adenocarcinoma (PAAD) is characterized by low antitumour immune cell infiltration in an immunosuppressive microenvironment. This study aimed to systematically explore the impact on prognostic alternative splicing events (ASs) of tumour immune microenvironment (TIME) in PAAD.
Methods
The ESTIMATE algorithm was implemented to compute the stromal/immune-related scores of each PAAD patient, followed by Kaplan–Meier (KM) survival analysis of patients with different scores grouped by X-tile software. TIME-related differentially expressed ASs (DEASs) were determined and evaluated through functional annotation analysis. In addition, Cox analyses were implemented to construct a TIME-related signature and an AS clinical nomogram. Moreover, comprehensive analyses, including gene set enrichment analysis (GSEA), immune infiltration, immune checkpoint gene expression, and tumour mutation were performed between the two risk groups to understand the potential mechanisms. Finally, Cytoscape was implemented to illuminate the AS-splicing factor (SF) regulatory network.
Results
A total of 437 TIME-related DEASs significantly related to PAAD tumorigenesis and the formation of the TIME were identified. Additionally, a robust TIME-related prognostic signature based on seven DEASs was generated, and an AS clinical nomogram combining the signature and four clinical predictors also exhibited prominent discrimination by ROC (0.762 ~ 0.804) and calibration curves. More importantly, the fractions of CD8 T cells, regulatory T cells and activated memory CD4 T cells were lower, and the expression of four immune checkpoints—PD-L1, CD47, CD276, and PVR—was obviously higher in high-risk patients. Finally, functional analysis and tumour mutations revealed that aberrant immune signatures and activated carcinogenic pathways in high-risk patients may be the cause of the poor prognosis.
Conclusion
We extracted a list of DEASs associated with the TIME through the ESTIMATE algorithm and constructed a prognostic signature on the basis of seven DEASs to predict the prognosis of PAAD patients, which may guide advanced decision-making for personalized precision intervention.
... EV is generally inherited in an autosomal recessive manner, but X-linked recessive and autosomal dominant inheritance patterns have also been reported (Androphy et al., 1985;Orth, 2006;Przybyszewska et al., 2017). Biallelic null variants in TMC6 (MIM: 605828) and TMC8 (MIM: 605829) encoding EVER1 and EVER2 account for 50-60% of typical EV cases worldwide (Ramoz et al., 2002;Imahorn et al., 2017). Additionally, biallelic null variants in CIB1 (MIM: 602293) encoding calcium-and integrin-binding protein-1 explain at least a portion of the remaining typical EV cases (de Jong et al., 2018). ...
... C1 was set to 1.0, and data are presented as the mean ± SD (n ≥ 3, *p < 0.05). Imahorn et al., 2017). According to our results, all three variants were classified as pathogenic according to the ACMG criteria (Richards et al., 2015). ...
... One patient with TMC8 variants suffered from Merkel cell carcinoma at 82 years of age (Mizuno et al., 2015). Consistent with the previous report by Imahorn et al. (2017), the most frequent EV-HPV in the 25 patients was HPV-5 (12/25), followed by HPV-14 (7/25) and HPV-20 (4/25), and the rare EV-HPVs included 22,38,93,3,8,9,12,[21][22][23][24]47, and so on. Interestingly, except for two EV patients (one of the patients was only 18 years old), most of the EV patients with potentially oncogenic HPV-5 infection developed NMSC. ...
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, autosomal recessive skin disorder, reported a total 501 patients in literature [16]. It is characterized by high susceptibility to certain types of human papillomaviruses. ...
... Patients have an increased risk of developing non-melanoma skin cancers [17]. The pathogenesis is not completely understood but it is thought to be related to agent selective immunodeficiency [16]. Our patient's skin biopsy showed epidermodysplasia verruciformis. ...
Castleman disease is a rare, heterogeneous disorder that driven by proinflammatory responses. Human herpes virus-8 has a major role in pathogenesis of multicentric Castleman disease. There is also a subgroup of cases, human herpes virus-8 negative, idiopathic multicentric Castleman disease. The role of primary immunodeficiencies in idiopathic Castleman disease are poorly described. DOCK8 deficiency is a combined primary immunodeficiency. It has a broad clinic spectrum including atopy, autoimmunity and cancer. We present a 10-year-old, DOCK8 deficient patient. He had giant lobular capillary hemangiomas on his neck, iliac and gluteal regions and multiple lymphadenopathies. Abdominal lymph node pathology revealed hyaline vascular type Castleman disease and human herpes virus-8 staining was negative. His lesions were shown to be infected with orf virus. Our case is the first case to relate idiopathic multicentric Castleman disease and DOCK8 deficiency; also, very unusual presentation of orf virus infection in humans.
