Xeroderma Pigmentosum Research Articles

COL4A1, negatively regulated by XPD and miR-29a-3p, promotes cell proliferation, migration, invasion and epithelial-mesenchymal transition in liver cancer cells.

Collagen type IV alpha 1 (COL4A1) exerts tumor-promoting functions in several tumors. However, its role in liver cancer remains not fully understood. Hence, this study aims to investigate the role of COL4A1 in regulating liver cancer cell behaviors and to validate its upstream regulatory mechanism. Expression of xeroderma pigmentosum D (XPD) and COL4A1 was examined by qRT-PCR and western blot. Cell proliferation, migration, and invasion were evaluated. The protein levels of N-cadherin, vimentin, and E-cadherin were determined by western blot to evaluate epithelial-mesenchymal transition (EMT). The interaction between miR-29a-3p and COL4A1 was analyzed by luciferase reporter assay. COL4A1 overexpression significantly promoted cell proliferation, migration, invasion, and EMT in Hep3B cells. In contrast, COL4A1 silencing yielded the opposite effects in HepG2 cells. Expression of COL4A1 was increased, whereas expression of XPD and miR-29a-3p was decreased in HCC tissues compared to controls. COL4A1 mRNA level was negatively correlated with expression of XPD and miR-29a-3p in HCC tissues. Furthermore, XPD silencing-mediated up-regulation of COL4A1 expression was attenuated by miR-29a-3p mimic. Moreover, miR-29a-3p mimic inhibited Hep3B cell proliferation, migration, and invasion by directly targeting COL4A1. COL4A1 is negatively regulated by XPD-miR-29a-3p axis and promotes liver cancer progression in vitro.

477 Topical treatment of human skin and cultured keratinocytes with high-dose spironolactone reduces XPB expression and induces genotoxicity

The mineralocorticoid and andogen receptor antagonist spironolactone (SP) is used to treat a variety of disparate disease states ranging from heart failure to acne. Though SP is usually taken as an oral medication, several recent studies have explored the administration of SP topically on the skin to avoid systemic effects in the body. Because SP induces the proteolytic degradation of the XPB (xeroderma pigmentosum group B) DNA translocase protein, which is involved in both DNA repair and transcription, SP may have genotoxic effects in the skin. Using skin explants, we show here that the topical application of a high concentration of either SP or its metabolite canrenone onto human skin induces the loss of the XPB protein and the phosphorylation of the histone variant H2AX, a common marker of genotoxicity. Though high concentrations of SP and canrenone both inhibit cell proliferation, induce H2AX phosphorylation, and stimulate apoptotic signaling in cultured keratinocytes in vitro, canrenone is much less potent at inducing the loss of XPB. Thus, high concentrations of SP and canrenone likely inhibit cell proliferation and induce genotoxicity via additional mechanisms besides XPB proteolytic degradation. Together, this work suggests that care may need to be taken when using high concentrations of SP directly on human skin.

574 A deep learning classifier for the analysis of tiger tail banding in trichothiodystrophy

Trichothiodystrophy (TTD) and xeroderma pigmentosum (XP) are both rare, autosomal recessive disorders of DNA repair/ transcription genes. Despite having (different) mutations in the same genes, they have markedly different phenotypes. TTD patients have multisystem developmental abnormalities involving fetal growth, and brain, eyes, bones and immune system with normal cancer risk. XP patients have normal development and a greatly increased risk of sunlight induced skin cancer. The hallmark of TTD hair is an alternating dark and light “tiger tail” banding pattern under polarized light microscopy along with defects of the hair shaft and reduced content of sulfur containing amino acids. XP patients have normal hair. Some XP/TTD complex patients may have features of both disorders making the diagnosis and evaluation of cancer risk difficult. Here we present a U-Net convolutional neural network for segmentation and classification of tiger tail hair and normal hair images from polarized light microscopy. The model was trained with 35 TTD and 35 normal hair images. The dataset was augmented using standard crops, flips, and rotations. Shears were excluded to preserve the banded features. In future studies, a third class consisting of hair images from XP/TTD complex patients will be introduced to the U-Net to evaluate the differences in banding patterns. Use of artificial intelligence deep learning may be able to assist in diagnosis of patients with different types of hair abnormalities.

150 Peripheral nervous system degeneration in patients with xeroderma pigmentosum

150 Peripheral nervous system degeneration in patients with xeroderma pigmentosum

506 Xeroderma Pigmentosum A deficiency results in increased generation of microvesicle particles in response to Ultraviolet B Radiation

506 Xeroderma Pigmentosum A deficiency results in increased generation of microvesicle particles in response to Ultraviolet B Radiation

Bilateral ocular surface squamous neoplasia: A study of 25 patients and review of literature.

To describe the risk factors, clinical presentation, management, and outcomes of patients with bilateral ocular surface squamous neoplasia (OSSN). Retrospective case series. Of the 25 patients with bilateral OSSN, the mean age at diagnosis of OSSN was 31 years (median, 24 years; range, 2-60 years). Risk factors for bilateral OSSN included xeroderma pigmentosum (n = 15, 60%), human immunodeficiency virus infection (n = 3, 12%), conjunctival xerosis (n = 1, 4%), and topical steroid use (n = 1, 4%). There were no identifiable ocular or systemic risk factors in 7 (28%) patients. Presentation was synchronous in 14 (56%) and metachronous in 11 (44%) patients. Tumor morphology was bilaterally similar in 12 (48%) patients. Histopathological examination (n = 36) revealed conjunctival intraepithelial neoplasia (CIN) grade 1 in 4 (8%); grade 2 in 7 (14%); carcinoma in situ in 5 (10%), and invasive carcinoma in 20 (40%). Primary management of OSSN (n = 49) included excisional biopsy (n = 31, 62%), topical immunotherapy (IFN α2B) (n = 11; 22%), topical Mitomycin C (MMC) (n = 3, 6%), enucleation (n = 1, 2%), orbital exenteration (n = 2, 4%), and plaque brachytherapy (PBT) (n = 1, 2%). One patient was lost to follow-up after detection of tumor in the second eye. Recurrent tumors were noted in 16 (32%) eyes and binocular globe salvage was achieved in 16 (64%) patients at a mean follow up of 41 months (median 30 months; range, 1-164 months). OSSN occurrence can be synchronous or metachronous. Meticulous examination of the fellow eye is important for an early diagnosis of OSSN.

Ocular surface squamous neoplasia in a healthy young child

A systemically normal 12-year-old woman presented to our center with a conjunctival lesion in the left eye, which was clinically suggestive of ocular surface squamous neoplasia (OSSN) and was confirmed by histopathology. OSSN in healthy young children, in absence of systemic risk factors like Xeroderma pigmentosa (XP) or human immunodeficiency syndrome (HIV), is rare, and to the best of our knowledge it has not been reported in the literature so far. This case report indicates that OSSN can occur in healthy young children albeit rarely, and emphasizes the need for a high index of clinical suspicion, comprehensive eye evaluation, and early intervention.

XPG is Modulated by miR-4715-3p and rs873601 Genotypes in Lung Cancer

ObjectiveXPG (Xeroderma pigmentosum group G, XPG), a single strand-specific DNA endonuclease in the nucleotide excision repair pathway, has been implicated in lung cancer. Potentially functional rs873601 in XPG is consistently associated with gastrointestinal cancer, and miR-4715-3p, targeting 3UTR of XPG, also influences the process of gastrointestinal carcinogenesis, however, the relationships between XPG and miR-4715-3p and rs873601 in lung cancer have not been elucidated.MethodsA case-control study included 264 lung cancer patients and 264 cancer-free healthy controls and was designed to determine the relationships between rs873601 and lung cancer and the effect of miR-4715-3p on XPG expression in lung cancer. Fifty matched cases and controls were randomly selected from the lung cancer and control groups to assess the relationships between the expression levels of miR-4715-3p and XPG determined by using qRT-PCR. The association of rs873601 with lung cancer was analyzed by mass spectrometry, and function prediciton of rs873601 genotypes explored by web-based bioinformatics.ResultsmiR-4715-3p in the lung cancer group was significantly increased compared with that in the control group (P = 0.011), upregulation of miR-4715-3p correlated with an increase in XPG mRNA (r = 0.399, P <0.05) in the lung cancer group. The AA genotype was associated with increased risk of lung cancer compared with the AG and GG genotypes of rs873601 (AG vs AA: OR = 0.231, 95% CI: 0.155–0.345, P <0.001 GG vs AA: OR = 0.300, 95% CI: 0.131–0.719, P = 0.003). The genetic association remained significant after adjustment for age, sex, smoking, and drinking, and rs873601-AA was associated with an increase in XPG mRNA in the lung cancer group. The results of web-based bioinformatics analysis indicated rs873601 genotypes might change XPG-RNA stability and bindability between XPG and miR-4715-3p.ConclusionOur data characterized that miR-4715-3p and rs873601 genotypes modified XPG expression in lung cancer. These findings may help to elucidate the mechanisms governing lung cancer.

Lung adenocarcinoma concomitant with xeroderma pigmentosum: a case report

BackgroundXeroderma pigmentosum is a rare, autosomal-recessive photosensitive dermatosis. Patients with xeroderma pigmentosum have an impaired ability to repair deoxyribonucleic acid damage caused by ultraviolet rays, resulting in skin cancer. Patients with xeroderma pigmentosum are more susceptible to some cancers. We herein report a case of xeroderma pigmentosum accompanied by lung cancer.Case presentationThe patient was a Japanese woman in her 70s with a family history of consanguineous marriage. Her medical history included squamous cell carcinoma and basal cell carcinoma, in addition to xeroderma pigmentosum. She presented with dry skin with small, pigmented spots, which were particularly focused around the areas exposed to sunlight. Chest computed tomography was conducted to assess for any evidence of metastatic skin carcinoma, and revealed a tumor in the left upper subpleural lobe of the lung. Consequently, she was referred to our department. Finally, we diagnosed lung adenocarcinoma (pT2aN0M1b: stage IVA). She had an epidermal growth factor receptor (EGFR) mutation (p.L858R). Treatment with an epidermal growth factor receptor tyrosine kinase inhibitor (gefitinib) was initiated, and the tumor gradually regressed. No side effects were observed. However, she later died from aspiration pneumonia.ConclusionsAlthough xeroderma pigmentosum is rare, a history of consanguineous marriage should be verified. Because of the severe side effects of cisplatin and radiotherapy in xeroderma pigmentosum patients, the risks and benefits of treatment should be considered thoroughly.

Nuclear Receptor Coactivator NCOA3 Regulates UV Radiation-Induced DNA Damage and Melanoma Susceptibility.

Melanoma occurs as a consequence of inherited susceptibility to the disease and exposure to UV radiation (UVR) and is characterized by uncontrolled cellular proliferation and a high mutational load. The precise mechanisms by which UVR contributes to the development of melanoma remain poorly understood. Here we show that activation of nuclear receptor coactivator 3 (NCOA3) promotes melanomagenesis through regulation of UVR sensitivity, cell-cycle progression, and circumvention of the DNA damage response (DDR). Downregulation of NCOA3 expression, either by genetic silencing or small-molecule inhibition, significantly suppressed melanoma proliferation in melanoma cell lines and patient-derived xenografts. NCOA3 silencing suppressed expression of xeroderma pigmentosum C and increased melanoma cell sensitivity to UVR. Suppression of NCOA3 expression led to activation of DDR effectors and reduced expression of cyclin B1, resulting in G2-M arrest and mitotic catastrophe. A SNP in NCOA3 (T960T) reduced NCOA3 protein expression and was associated with decreased melanoma risk, given a significantly lower prevalence in a familial melanoma cohort than in a control cohort without cancer. Overexpression of wild-type NCOA3 promoted melanocyte survival following UVR and was accompanied by increased levels of UVR-induced DNA damage, both of which were attenuated by overexpression of NCOA3 (T960T). These results describe NCOA3-regulated pathways by which melanoma can develop, with germline NCOA3 polymorphisms enabling enhanced melanocyte survival in the setting of UVR exposure, despite an increased mutational burden. They also identify NCOA3 as a novel therapeutic target for melanoma. SIGNIFICANCE: This study explores NCOA3 as a regulator of the DDR and a therapeutic target in melanoma, where activation of NCOA3 contributes to melanoma development following exposure to ultraviolet light.

Therapeutics of xeroderma pigmentosum: A PRISMA-compliant systematic review.

Xeroderma pigmentosum is a rare hereditary autosomal recessive genodermatosis. At present, there are many treatment options for xeroderma pigmentosum, covering medical/procedural, surgical and combined modalities. However, the quality of these interventions has not been assessed. Our study aimed to perform a systematic review of the literature regarding the treatment of xeroderma pigmentosum. Multiple medical databases were accessed with the Medical Subject Headings terms; "xeroderma pigmentosum," "therapeutics" and "surgical procedures, operative" from January 2000 to April 2019, including articles published in Portuguese, Spanish and English (PROSPERO-CRD42018114858). Two hundred and ninety-eight studies were found in the databases researched, of which, after applying the inclusion criteria, only 33 studies remained. The 33 complete articles were read by three of the authors, having been found: 16 reported medical/procedural and 17 reported surgical treatments. Only one clinical study presented a good level of evidence (EL: 2): a randomized clinical trial using a T4 endonuclease V (T4N5) liposome lotion which reduced the development of skin lesions in patients with xeroderma pigmentosum. Amongst surgical modalities, all studies presented low evidence level (EL: 4). Three illustrative cases are also presented, to emphasize the multiple number of times that surgical modalities may be required in these patients. The therapeutic modalities, both clinical and surgical, for xeroderma pigmentosum presented a low level of scientific evidence which did not allow meta-analysis. More therapeutic studies, both clinical and surgical, with better scientific evidence are needed.

Switch-like control of helicase processivity by single-stranded DNA binding protein.

Helicases utilize nucleotide triphosphate (NTP) hydrolysis to translocate along single-stranded nucleic acids (NA) and unwind the duplex. In the cell, helicases function in the context of other NA-associated proteins such as single-stranded DNA binding proteins. Such encounters regulate helicase function, although the underlying mechanisms remain largely unknown. Ferroplasma acidarmanus xeroderma pigmentosum group D (XPD) helicase serves as a model for understanding the molecular mechanisms of superfamily 2B helicases, and its activity is enhanced by the cognate single-stranded DNA binding protein replication protein A 2 (RPA2). Here, optical trap measurements of the unwinding activity of a single XPD helicase in the presence of RPA2 reveal a mechanism in which XPD interconverts between two states with different processivities and transient RPA2 interactions stabilize the more processive state, activating a latent 'processivity switch' in XPD. A point mutation at a regulatory DNA binding site on XPD similarly activates this switch. These findings provide new insights on mechanisms of helicase regulation by accessory proteins.

Inherited skin disorders presenting with poikiloderma.

Poikiloderma is a skin condition that combines atrophy, telangiectasia, and macular pigment changes (hypo- as well as hyperpigmentation). It is often mistaken for mottled pigmentation by general practitioners or nondermatology specialists. Poikiloderma can be a key presenting symptom of Rothmund-Thomson syndrome (RTS), dyskeratosis congenita (DC), hereditary sclerosing poikiloderma (HSP), hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP), xeroderma pigmentosum (XP), Bloom syndrome (BS), Kindler syndrome (KS), and Clericuzio-type poikiloderma with neutropenia (PN). In these conditions, poikiloderma starts early in life, usually before the second or third year. They may also be associated with photosensitivity and other significant multi-organ manifestation developed later in life. Poikiloderma could indicate the presence of a genetic disorder with potentially serious consequences. Poikiloderma almost always precedes more severe manifestations of these genodermatoses. Prompt diagnosis at the time of presentation could help to prevent complications and mitigate the course of the disease. This review discusses these to help the practicing clinician manage patients presenting with the symptom. To further facilitate early recognition, this paper also proposes a simple diagnostic algorithm.

Xeroderma Pigmentosum: Important Oral Manifestations Case Report

The Xeroderma pigmentosum [XP] is a rare inherited skin disorder and transmitted in an autosomal recessive manner. The aim of the present article is to report a XP case with oral manifestations and to discuss the role of the dental professional management of this entity. A 5 year old male presented lentigos all over the skin and predominated in photoexposed areas. Oral hygiene was good and dental affection was important. No lesions were observed in the lips, tongue and the rest of the bucal mucosa but multiples teeth with cavities were observed. Antibiotic treatment was started and surgical treatment. Besides dermatological, ophtamological and neurological management, XP patients require constant dental care and follow –up in order to control the occurrence of new lesions on the lips or inside oral cavity.

Skin tumors in xeroderma pigmentosum: Evaluation of a large series and a literature review

Xeroderma pigmentosum (XP) is a rare genodermatosis with a lifelong propensity to develop malignant skin tumors. In this retrospective study, 24 XP patients were evaluated with regard to frequency and clinicopathological features of benign and malignant skin tumors. Seventeen patients had at least one malignant skin tumor diagnosed: basal cell carcinoma (BCC) in 13 patients (n=72), basosquamous carcinoma in three patients (n=4), squamous cell carcinoma in six patients (n=13), keratoacanthoma in three patients (n=15), and melanoma in six patients (n=18). Most melanomas (n=15) were in situ lesions. Several benign skin tumors were noted such as tricholemmoma (n=1), trichoepithelioma (n=1), trichoblastoma (n=1), follicular infundibulum tumor (n=1), keratoacanthoma-like follicular lesion (n=1), adnexal tumors with folliculosebaceous (n=1) and tricholemmal differentiation (n=1), and neurofibroma (n=1). Benign vascular proliferations including pyogenic granulomas (n=8), widespread telangiectasias, and senile angioma-like lesions were also observed in 3, 5, and 5 patients, respectively. Similar to many reports, BCC was found to be the most common malignant skin tumor. The high prevalence of benign adnexal tumors of follicular differentiation, some of them showing mixed histopathological features and various vascular proliferations in our series raises the question of whether they indicate a formerly undescribed association with XP.

In Silico Drug Repurposing by Structural Alteration after Induced Fit: Discovery of a Candidate Agent for Recovery of Nucleotide Excision Repair in Xeroderma Pigmentosum Group D Mutant (R683W).

Xeroderma pigmentosum complementation group D (XPD) is a UV-sensitive syndrome and a rare incurable genetic disease which is caused by the genetic mutation of the excision repair cross-complementation group 2 gene (ERCC2). Patients who harbor only XPD R683W mutant protein develop severe photosensitivity and progressive neurological symptoms. Cultured cells derived from patients with XPD (XPD R683W cells) demonstrate a reduced nucleotide excision repair (NER) ability. We hope to ameliorate clinical symptoms if we can identify candidate agents that would aid recovery of the cells’ NER ability. To investigate such candidates, we created in silico methods of drug repurposing (in silico DR), a strategy that utilizes the recovery of ATP-binding in the XPD R683W protein after the induced fit. We chose 4E1RCat and aprepitant as the candidates for our in silico DR, and evaluated them by using the UV-induced unscheduled DNA synthesis (UDS) assay to verify the recovery of NER in XPD R683W cells. UDS values of the cells improved about 1.4–1.7 times after 4E1RCat treatment compared with solvent-only controls; aprepitant showed no positive effect. In this study, therefore, we succeeded in finding the candidate agent 4E1RCat for XPD R683W. We also demonstrated that our in silico DR method is a cost-effective approach for drug candidate discovery.

KERA: analysis tool for multi-process, multi-state single-molecule data.

Molecular machines within cells dynamically assemble, disassemble and reorganize. Molecular interactions between their components can be observed at the single-molecule level and quantified using colocalization single-molecule spectroscopy, in which individual labeled molecules are seen transiently associating with a surface-tethered partner, or other total internal reflection fluorescence microscopy approaches in which the interactions elicit changes in fluorescence in the labeled surface-tethered partner. When multiple interacting partners can form ternary, quaternary and higher order complexes, the types of spatial and temporal organization of these complexes can be deduced from the order of appearance and reorganization of the components. Time evolution of complex architectures can be followed by changes in the fluorescence behavior in multiple channels. Here, we describe the kinetic event resolving algorithm (KERA), a software tool for organizing and sorting the discretized fluorescent trajectories from a range of single-molecule experiments. KERA organizes the data in groups by transition patterns, and displays exhaustive dwell time data for each interaction sequence. Enumerating and quantifying sequences of molecular interactions provides important information regarding the underlying mechanism of the assembly, dynamics and architecture of the macromolecular complexes. We demonstrate KERA’s utility by analyzing conformational dynamics of two DNA binding proteins: replication protein A and xeroderma pigmentosum complementation group D helicase.

Chemical-Genetic Interactions of Bacopa monnieri Constituents in Cells Deficient for the DNA Repair Endonuclease RAD1 Appear Linked to Vacuolar Disruption.

Colorectal cancer is a common cancer worldwide and reduced expression of the DNA repair endonuclease XPF (xeroderma pigmentosum complementation group F) is associated with colorectal cancer. Bacopa monnieri extracts were previously found to exhibit chemical-genetic synthetic lethal effects in a Saccharomyces cerevisiae model of colorectal cancer lacking Rad1p, a structural and functional homologue of human XPF. However, the mechanisms for B. monnieri extracts to limit proliferation and promote an apoptosis-like event in RAD1 deleted yeast was not elucidated. Our current analysis has revealed that B. monnieri extracts have the capacity to promote mutations in rad1∆ cells. In addition, the effects of B. monnieri extracts on rad1∆ yeast is linked to disruption of the vacuole, similar to the mammalian lysosome. The absence of RAD1 in yeast sensitizes cells to the effects of vacuole disruption and the release of proteases. The combined effect of increased DNA mutations and release of vacuolar contents appears to induce an apoptosis-like event that is dependent on the meta-caspase Yca1p. The toxicity of B. monnieri extracts is linked to sterol content, suggesting saponins may be involved in limiting the proliferation of yeast cells. Analysis of major constituents from B. monnieri identified a chemical-genetic interaction between bacopasaponin C and rad1∆ yeast. Bacopasaponin C may have potential as a drug candidate or serve as a model for the development of analogs for the treatment of colorectal cancer.

Clinical and Mutational Spectrum of Xeroderma Pigmentosum in Egypt: Identification of Six Novel Mutations and Implications for Ancestral Origins

Xeroderma pigmentosum is a rare autosomal recessive skin disorder characterized by freckle-like dry pigmented skin, photosensitivity, and photophobia. Skin and ocular symptoms are confined to sun exposed areas of the body. Patients have markedly increased risk for UV-induced skin, ocular, and oral cancers. Some patients develop neurodegenerative symptoms, including diminished tendon reflexes and microcephaly. In this study, we describe clinical and genetic findings of 36 XP patients from Egypt, a highly consanguineous population from North Africa. Thorough clinical evaluation followed by Sanger sequencing of XPA and XPC genes were done. Six novel and seven previously reported mutations were identified. Phenotype-genotype correlation was investigated. We report clinical and molecular findings consistent with previous reports of countries sharing common population structure, and geographical and historical backgrounds with implications on common ancestral origins and historical migration flows. Clinical and genetic profiling improves diagnosis, management, counselling, and implementation of future targeted therapies.

Xeroderma Pigmentosum with Malignant Cutaneous Tumors in Two Siblings

Abstract: Xeroderma pigmentosum is an autosomal recessive genetic disease that accompanied by abnormalities in deletion and repair of DNA due to enzymatic damage by ultraviolet radiation. It is described by photo hypersensitivity of areas exposed to sun radiation, changes in the skin pigmentation, cutaneous premature aging and increased risk of developing cutaneous and ocular malignant tumors early in life. Most common types of malignant cutaneous tumors detected are basal cell and squamous cell carcinoma and less commonly malignant melanoma. It is very frequent in certain areas of the world, most markedly Middle East, like Egypt and North Africa with positive consanguinity. In patients with Xeroderma pigmentosum prior to the age of 20 years, the risk of developing skin cancer is several thousand times greater. In patients with XP for non-melanoma skin cancers, the median age of onset is eight years relative to the non-XP population with a median age of onset of sixty years. This research study presents two siblings; 18-years-old sister and 16-years-old brother; from relative parents that had xeroderma pigmentosum with development of different malignant skin tumors. Treatment protocol was surgical excision of the malignant tumor with adequate safety margin and removal of enlarged lymph nodes. Reconstruction options were directed mainly to flap surgery. Postoperative follow up reveled no recurrence.