Xeroderma Pigmentosum Research Articles

Imaging-Based High-Content Screening with Clickable Probes Identifies XPB Inhibitors.

High-content screening (HCS) has become a powerful tool in drug discovery; however, its reliance on indirect readouts and surrogate markers limits HCS's ability to directly assess drug-protein interactions at endogenous levels, particularly in subcellular contexts. Here, we report an approach to address these limitations by combining confocal imaging-based HCS and bio-orthogonal labeling with clickable probes. As a proof-of-concept, we synthesized a probe TL-alkyne (TL-alk) that rapidly and specifically labels xeroderma pigmentosum type B (XPB), a critical protein in nucleotide excision repair (NER). Probe-labeled XPB was conjugated to TAMRA to visualize the occupation of active sites, and EGFP and DAPI signals indicated the XPB expression in the nucleus. Such a colorimetric HCS assay enabled the direct and precise measurement of drug occupancy rates in nuclear XPB of live cells. With this platform, pelitinib was identified as a novel ligand to bind XPB out of 1,874 FDA-approved drugs. Pelitinib formed a covalent bond with Cys342 of XPB, suppressed XPB's ATPase activity, impaired NER, and synergistically enhanced chemotherapy. This study not only overcomes limitations of HCS, but also demonstrates the transformative potential of bio-orthogonal labeling, such as in integration with HCS technologies, offering a novel framework for drug discovery targeting challenging protein systems.

Imaging‐Based High‐Content Screening with Clickable Probes Identifies XPB Inhibitors

High‐content screening (HCS) has become a powerful tool in drug discovery; however, its reliance on indirect readouts and surrogate markers limits HCS’s ability to directly assess drug‐protein interactions at endogenous levels, particularly in subcellular contexts. Here, we report an approach to address these limitations by combining confocal imaging‐based HCS and bio‐orthogonal labeling with clickable probes. As a proof‐of‐concept, we synthesized a probe TL‐alkyne (TL‐alk) that rapidly and specifically labels xeroderma pigmentosum type B (XPB), a critical protein in nucleotide excision repair (NER). Probe‐labeled XPB was conjugated to TAMRA to visualize the occupation of active sites, and EGFP and DAPI signals indicated the XPB expression in the nucleus. Such a colorimetric HCS assay enabled the direct and precise measurement of drug occupancy rates in nuclear XPB of live cells. With this platform, pelitinib was identified as a novel ligand to bind XPB out of 1,874 FDA‐approved drugs. Pelitinib formed a covalent bond with Cys342 of XPB, suppressed XPB’s ATPase activity, impaired NER, and synergistically enhanced chemotherapy. This study not only overcomes limitations of HCS, but also demonstrates the transformative potential of bio‐orthogonal labeling, such as in integration with HCS technologies, offering a novel framework for drug discovery targeting challenging protein systems.

Skin Signals: Exploring the Intersection of Cancer Predisposition Syndromes and Dermatological Manifestations

Cutaneous manifestations can serve as early and sometimes the first clinical indicators in various hereditary cancer predisposition syndromes. This review provides a comprehensive overview of the dermatological signs associated with these syndromes, aiming to facilitate their recognition in clinical practice. Hereditary Breast and Ovarian Cancer syndrome is notably linked to an increased risk of melanoma. BAP1 tumor predisposition syndrome is characterized by BAP1-inactivated melanocytic tumors. Muir–Torre syndrome, a variant of Lynch syndrome, presents with distinctive cutaneous neoplasms such as sebaceous carcinomas, sebaceous adenomas, and keratoacanthomas. PTEN hamartoma tumor syndrome commonly features hamartomatous growths, trichilemmomas, acral keratoses, oral papillomas, and genital lentiginosis. Gorlin syndrome is marked by basal cell carcinomas and palmoplantar pits, while Peutz–Jeghers syndrome is identified by mucocutaneous pigmentation. In familial adenomatous polyposis, the cutaneous findings include epidermoid cysts, fibromas, desmoid tumors, and lipomas. Additionally, we examined monogenic disorders associated with cancer risk and skin involvement, such as xeroderma pigmentosum, neurofibromatosis type 1, familial atypical multiple-mole melanoma syndrome, and Fanconi anemia. The early recognition of these dermatologic features is essential for a timely diagnosis and the implementation of appropriate surveillance strategies in individuals with hereditary cancer syndromes.

Xeroderma Pigmentosum in Identical Twins: Synchronous Presentation of Distinct Malignancies

Xeroderma Pigmentosum in Identical Twins: Synchronous Presentation of Distinct Malignancies

Abstract P1-08-27: Unusual Presentation Of Triple-Negative Breast Cancer (TNBC) In A Young Female Patient With Xeroderma pigmentosum (XP)

Abstract Background: Xeroderma pigmentosum (XP) is a rare, autosomal recessive (1 in a million) disorder characterized by sensitivity to ultraviolet (UV) rays, resulting in a predisposition to skin cancers, primarily. This case vignette describes an unusual presentation of triple-negative breast cancer (TNBC) in a young female patient with XP. Case Presentation: A 34-year-old woman with a known history of (XP) presented with a palpable mass in her right breast. Clinical examination revealed a firm, irregular, and non-tender mass in the upper outer quadrant of the right breast, measuring approximately 6 cm in diameter. There was no axillary lymphadenopathy. Mammography and ultrasound confirmed a suspicious lesion, and a core needle biopsy was performed. No family history of breast cancer or other malignancies and gBRCA1&2 were negative. Histopathological examination of the biopsy specimen revealed grade III invasive ductal carcinoma, negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), consistent with TNBC. Management and Outcome: A neoadjuvant chemotherapy (NACT) with four cycles of doxorubicin and cyclophosphamide (AC) DD was prescribed. The response to NACT was limited. Consequently, the patient underwent surgery with a modified radical mastectomy (MRM) with tumor of 6 cm & sentinel lymph node biopsy was negative for metastasis. Postoperative follow-up included adjuvant CT with paclitaxel plus carboplatin. Immunotherapy was not accessible for her. Adjuvant radiotherapy was not prescribed. Discussion: 1.Association of XP and BC: The evidence that XP patients may also have an elevated risk of internal malignancies is scarce. Understanding the mechanisms linking XP with breast cancer, such as DNA repair deficiencies and genomic instability, could provide insights into targeted prevention and treatment strategies. 2.Addition of Carboplatin in Adjuvant Chemotherapy: Studies suggest that the inclusion of carboplatin in the NACT for TNBC can improve pathological complete response rates and survival outcomes. Given the limited response to initial chemotherapy in this patient, the addition of adjuvant carboplatin was commenced to enhance treatment efficacy and potentially reduce the risk of recurrence. 3.Consideration of Adjuvant Radiotherapy (XRT) in XP Patients: The use of XRT in XP patients is challenging due to their heightened sensitivity to UV and ionizing radiation. Protective measures and alternative modalities should be explored to minimize potential adverse effects. Our patient was offered MRM in an attempt to avoid XRT. 4. Type of Surgery: MRM vs. Breast-Conserving Surgery (BCS) : The choice between MRM and BCS in XP patients with TNBC must consider oncologic outcomes and future potential risk of XRT, especially the long -term safety of XRT in such patient is questionable. Conclusion: This case highlights the complexity of managing TNBC in patients with XP. It underscores the need for personalized treatment plans that address the unique challenges posed by XP. Multidisciplinary collaboration and further research are essential to optimize therapeutic strategies for these high-risk patients. Citation Format: Bashaer Alsaati, Nora Trabulsi, Reem Ujami, Atlal Abusanad. Unusual Presentation Of Triple-Negative Breast Cancer (TNBC) In A Young Female Patient With Xeroderma pigmentosum (XP) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-08-27.

Ophthalmic and Cutaneous Manifestation of Xeroderma Pigmentosum in a 21-Year-Old Man: A Case Report

Ophthalmic and Cutaneous Manifestation of Xeroderma Pigmentosum in a 21-Year-Old Man: A Case Report

Photoprevention with Oral Polypodium leucotomos Extract and Treatment with Medium-Depth Chemical Peeling in Xeroderma Pigmentosum: A Case Report

Photoprevention with Oral Polypodium leucotomos Extract and Treatment with Medium-Depth Chemical Peeling in Xeroderma Pigmentosum: A Case Report

Case Report of Xeroderma Pigmentosum of A 67- Year- Old Patient

Introduction: Xeroderma pigmentosum (XP) is a rare autosomal recessive genodermatosis characterized by severe photosensitivity, skin pigmentary changes, malignant tumor development, and occasionally progressive neurologic degeneration. The median age of death in patients with XP without neurodegeneration is about 37 years old. The median age of death in patients with XP with neurodegeneration is younger at about 29 years old. Case Report: A 67-year-old man presented to the Clinic of Dermatology to diagnose a painful nodular hemorrhagic growth on the right shoulder, an eroded hyperpigmented plaque in the right retro auricular region and 3 ulcerated crusted lesions with elevated borders at the frontal and temporal regions. On examination, the patient had diffuse freckle-like pigmentation, xerosis, actinic damage in sun-exposed areas, multiple Actinic Keratoses (AK) and a large scar in the lumbar region, resulting from the excision of a Squamous Cell Carcinoma (SCC) located on that area. He denied early blistering in his childhood, also refereed that due to its condition he had always worked indoor. He also reported being diagnosed with XP at a young age and, since then has been advised by a dermatologist to avoid sun exposure and to undergo regular examinations for any suspicious lesions suggestive for Carcinoma lesions in his body. His neurologic examination was normal and lymph node examination was negative. Dermoscopy of the lesions was performed showing characteristic features for Basal Cell Carcinoma (BCC), SCC and Actinic Keratoses. The lesions were removed surgically and the biopsies confirmed the clinical and dermoscopic diagnoses. Conclusion: Early detection and proper treatment of XP can prevent the onset of common malignancies and increase the life expectancy of the patients.

Comprehensive Neuropsychological Assessment of Confirmed Xeroderma Pigmentosum a Variant with Neurological Manifestations: Case Report.

Comprehensive Neuropsychological Assessment of Confirmed Xeroderma Pigmentosum a Variant with Neurological Manifestations: Case Report.

Cigarette smoke and decreased DNA repair by Xeroderma Pigmentosum Group C use a double hit mechanism for epithelial cell lung carcinogenesis.

Emerging evidence suggests a complex interplay of environmental and genetic factors in non-small cell lung cancer (NSCLC) development. Among these factors, compromised DNA repair plays a critical but incompletely understood role in lung tumorigenesis and concurrent lung diseases, such as chronic obstructive lung disease (COPD). In this study, we investigated the interplay between cigarette smoke, DNA damage and repair, focusing on the Nucleotide Excision Repair (NER) protein Xeroderma Pigmentosum Group C (XPC). We found decreased XPC mRNA expression in most NSCLCs compared to subject-matched, non-cancerous lung. In non-cancerous bronchial epithelial cells, cigarette smoke decreased NER, increased total DNA damage and resultant apoptosis, each exacerbated by XPC deficiency. In contrast, lung cancer cells exhibit greater resilience to cigarette smoke, requiring higher doses to induce comparable DNA damage and apoptosis, and are less reliant on XPC expression for survival. Importantly, XPC protects against chromosomal instability in benign bronchial epithelial cells, but not in lung cancer cells. Our findings support a "double hit" mechanism wherein early decreased XPC expression and resultant aberrant DNA repair, when combined with cigarette smoke exposure, may lead to loss of non-malignant epithelial cells (as observed in COPD), and contributes to early NSCLC transition through altered DNA damage response.

XPD Regulates MIAT/miR-29a-3p/COL4A1 Axis to Impede Hepatocellular Carcinoma Development.

Xeroderma pigmentosum group D (XPD) has been reported to inhibit cell growth of hepatocellular carcinoma (HCC). This work attempted to reveal the underlying mechanism of XPD in HCC. In this study, XPD and miR-29a-3p were down-regulated, and MIAT and COL4A1 were up-regulated in tumor tissues of HCC patients. The same phenomena were also observed in HCC cell lines. XPD overexpression enhanced E-cadherin expression, reduced N-cadherin and Vimentin expression, and repressed the migration and invasion of HepG2 and Hep3B cells. MIAT or COL4A1 overexpression reversed the effect of XPD on the invasion, migration, and epithelial-mesenchymal transition (EMT) of HCC cells. MIAT overexpression-mediated promotion of malignant phenotypes of HCC cells was reversed by COL4A1 deficiency. In terms of mechanics, MIAT enhanced COL4A1 expression by sponging miR-29a-3p. XPD interacted with P53. XPD overexpression repressed MIAT expression, which was abrogated by P53 silencing. Thus, XPD recruited P53 to repress MIAT expression. Invivo, XPD up-regulation inhibited tumor growth and reduced the metastatic lesions in intrahepatic, lung, and kidney tissues of mice. In conclusion, this study demonstrated that XPD recruited P53 to regulate the MIAT/miR-29a-3p/COL4A1 axis, which contributed to inhibiting migration, invasion, EMT, and metastasis of HCC. Thus, XPD may be a valuable target for HCC treatment.

ROMANTICIZING ILLNESS: THE REPRESENTATION OF LOVE AND DISEASE IN THE MOVIES 'MIDNIGHT SUN' AND 'MEET ME AFTER SUNSET'

This study aims to find out how love and disease are represented as discourse in the movies entitled Midnight Sun (2018) and Meet Me After Sunset (2018). How the discourse of disease and love is constructed simultaneously in the stories of two characters with different social and cultural backgrounds is crucial to probe because discourses convey and create power and hierarchy. This study compares two characters who suffer from a rare disease named xeroderma pigmentosum. The disease makes them sensitive to sunlight in the teenage phase during which they experience falling in love. The main objects of comparison are the movie characters Katie from Midnight Sun and Gadis in Meet Me After Sunset. This study employs comparative methods which are appropriate to analyze how different socio-cultures can influence the discourse on love and illness. Discourses and constructs regarding love and illness in popular literature, including movies, cannot be fully understood without referring to gender and socio-culture. Illness is romanticized in Meet Me After Sunset and Midnight Sun. In the Indonesian context, the discourse of love as freedom is less obvious. In contrast, the discourse of isolation and the lack of agency are more advocated compared to the American counterpart. It is due to the differences in cultural patterns that operate in both movies. The discourse of illness in both stories leads to a binary gender hierarchy that associates masculinity with health, while femininity is associated with illness. The isolation caused by disease can also be associated with domestic femininity, which then becomes the idealized value of femininity in both movies.

Biological Models of Oxidative Purine DNA Damage in Neurodegenerative Disorders.

Most DNA damage caused by oxidative metabolism consists of single lesions that can accumulate in tissues. This review focuses on two classes of lesions: the two 8-oxopurine (8-oxo-Pu) lesions that are repaired by the base excision repair (BER) enzyme and the four 5',8-cyclopurine (cPu) lesions that are repaired exclusively by the nucleotide excision repair (NER) enzyme. The aim is to correlate the simultaneous quantification of these two classes of lesions in the context of neurological disorders. The first half is a summary of reactive oxygen species (ROS) with particular attention to the pathways of hydroxyl radical (HO•) formation, followed by a summary of protocols for the quantification of six lesions and the biomimetic chemistry of the HO• radical with double-stranded oligonucleotides (ds-ODN) and calf thymus DNA (ct-DNA). The second half addresses two neurodegenerative diseases: xeroderma pigmentosum (XP) and Cockayne syndrome (CS). The quantitative data on the six lesions obtained from genomic and/or mitochondrial DNA extracts across several XP and CS cell lines are discussed. Oxidative stress contributes to oxidative DNA damage by resulting in the accumulation of cPu and 8-oxo-Pu in DNA. The formation of cPu is the postulated culprit inducing neurological symptoms associated with XP and CS.

Epidemiological and Histological Study of Malignant Cutaneous Tumors of the Face: Experience of the Plastic Surgery Department at CHU Med VI, Marrakech

Malignant tumors of the face mainly include carcinomas (basal cell and squamous cell) and, more rarely, melanomas. Through this study, we aim to define the epidemiological profile of patients with malignant cutaneous facial tumors, identify risk factors, and examine the histological characteristics and anatomo-clinical varieties of these tumors in our context. Our work is a 5-year retrospective study involving 223 cases of facial tumors managed at the Plastic Surgery Department of CHU Mohamed VI between January 2016 and December 2021, consisting of epidemiological, clinical, and histological analysis. Patient age ranged from 8 to 83 years, with an average age of 54, and a clear male predominance. Most patients were exposed to sunlight through their occupations, without significant protection. The most common precancerous lesions were actinic keratoses followed by xeroderma pigmentosum. All regions of the face were affected. Macroscopically, ulcerative-exophytic lesions were predominant (56%). Basal cell carcinoma was the most frequent histological type (47%), followed by squamous cell carcinoma (39%) and melanoma (3%). Malignant facial skin tumors are a common dermatological pathology in our setting. Diagnosis is primarily based on clinical examination and histopathology. Prevention relies on avoiding risk factors. Early diagnosis and proper excision are key to prognosis.

Identification of a novel pathogenic XPC:c.2420 + 1 G>C variant in a patient with xeroderma pigmentosum.

Identification of a novel pathogenic XPC:c.2420 + 1 G>C variant in a patient with xeroderma pigmentosum.

Amy and Friends: improving the lives of individuals affected by DNA repair disorders.

Amy and Friends: improving the lives of individuals affected by DNA repair disorders.

Early-onset squamous cell carcinoma in xeroderma pigmentosum: A rare case

Xeroderma pigmentosum (XP) is a rare autosomal recessive genodermatosis characterised by photosensitivity, dry skin, pigmentary abnormalities, premature skin aging, and skin cancers at an early age. This case report aims to alert health professionals about this disease, considering the rarity of the disease and the need for an early diagnosis of patients with XP. A 4-year-old boy was referred to our department with multiple painful ulcerated masses over his head and face, which had developed over the past two years. At the age of 6 months, the patient started to develop hyperpigmented spots of numerous sizes on his face, and gradually spread to the other sun-exposed areas of his body. He also had dry skin, photophobia, redness, and watery eyes. Dermatological examination showed multiple ulcerated erythematous nodules at the temporal and frontotemporal region; multiple scaly, hyperpigmented macules, papules, and cutaneous horns at the facial region; multiple hypopigmented and hyperpigmented macules, generalised distributed, predominantly over the sun-exposed areas. A biopsy examination from one of the nodules showed keratinising squamous cell carcinoma (SCC). The patient was diagnosed with xeroderma pigmentosum and was treated with multidisciplinary assessment involving dermatology, paediatric, oncology surgery, ophthalmology, and otolaryngology. The diagnosis in this patient is made clinically based on history taking, physical examination, and confirmation of malignancy from biopsy. Early diagnosis of XP is crucial for decreasing the development of neoplasms, which could improve the patient’s quality of life.

Abstract 208: Epigenomic characterization of keratinocyte carcinomas in xeroderma pigmentosum

Keratinocyte carcinomas (KCs), comprising basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), arise in the epidermis due to chronic exposure to solar ultraviolet (UV) radiation. KCs account for 99% of skin neoplasms and represent the most prevalent form of cancer worldwide. DNA methylation, an epigenetic modification of CpG dinucleotides, modulates gene expression, thereby defining cell identity and mediating cellular responses to external stimuli. Aging and environmental stressors, including UV radiation, progressively alter epidermal methylomes, thus influencing KC development and progression. Xeroderma pigmentosum (XP) is a rare genetic disorder characterized by mutations in genes of major cellular response mechanisms to UV-induced DNA damage, such as the nucleotide excision repair (NER) system or the translesion synthesis (TLS) DNA polymerase η. Consequently, XP patients exhibit a more than 10,000-fold increase in KC incidence, with tumors potentially manifesting as early as childhood. Epigenomic analysis of tumors derived from XP patients could provide valuable insights into the deregulation of DNA methylation in KC tumorigenesis, thereby contributing to the development of novel antitumor therapies for both XP patients and the broader population. Here, we used Infinium MethylationEPIC BeadChips to assess the DNA methylation status of 30 epidermal samples from XP patients with mutations in the XPC and POLH genes, representing roughly 50% of all XP cases and significantly impacted by KCs. Our sample set comprised BCC and cSCC tumors, non-tumorous epidermis, and actinic keratosis (AK), a precancerous lesion that frequently progresses to cSCC. DNA methylation analysis of XP samples clearly distinguished between BCC and cSCC tumors, whereas non-tumorous epidermis unexpectedly clustered with AK samples, reflecting substantial methylome dysregulation that is consistent with the heightened risk of KC development in XP patients. In line with this, further examination of non-tumorous XP methylomes relative to non-XP counterparts revealed features indicative of premature aging, including significant erosion of DNA methylation profiles and increased mitotic rates. Analysis of XP-derived BCC and cSCC methylation profiles also identified a higher frequency of copy number variation (CNV) events and a potential bias towards an epidermal stem cell (EpSC)-like cell-of-origin in cSCC tumors. These findings may suggest an elevated aggressiveness of XP tumors, which we now aim to verify using cellular models of KC deficient in key XP genes. Citation Format: Bea Riebesehl,Lea S. Beensen,Felix Bormann,Wilfried Roth,Carlos F. Menck,Thomas G. Hofmann,Frank Lyko,Manuel Rodríguez Paredes. Epigenomic characterization of keratinocyte carcinomas in xeroderma pigmentosum [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 208.

Pediatric Ocular Surface Squamous Neoplasia in the Absence of Known Risk Factors and Systemic Conditions: A Case Series

Introduction: Ocular surface squamous neoplasia (OSSN) includes precancerous and cancerous epithelial lesions of the conjunctiva and cornea, typically affecting older adults with risk factors like immunosuppression, sun exposure, and viral infections. Pediatric OSSN is rare, with few reported cases. We present a series of 16 pediatric and adolescent OSSN cases without known genetic or infectious risk factors. Methods: Descriptive case series at a single tertiary eye care center in Nepal where children with histopathologically proven OSSN were identified, and their disease was characterized. Results: OSSN was observed in 16 eyes of 16 pediatric patients (6–18 years old) with no identifiable risk factors. All patients were seen at Tilganga Institute of Ophthalmology, Kathmandu, Nepal, between May 2018 and June 2022. All lesions were histopathologically proven as OSSN and characterized by type. Nine (56%) were conjunctival intraepithelial neoplasia (CIN) I, 5 (31%) were CIN II, and 2 (13%) were CIN III. There were no cases of squamous cell carcinoma. None of the patients had xeroderma pigmentosum, HIV, or hepatitis B or C. Conclusions: This work reports a case series of pediatric OSSN in the absence of risk factors and systemic conditions. More than half of the patients had mild CIN. Though rare, this case series highlights the importance of considering OSSN in the differential diagnosis of pediatric ocular surface lesions, perhaps especially in this geographic location.

A Rare Case of Xeroderma Pigmentosum: Nivolumab Treatment for Three Cutaneous Malignancies with Clinical and Metabolic Imaging Correlation.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by extreme ultraviolet (UV) sensitivity, predisposing patients to multiple cutaneous malignancies. We present the case of a 26-year-old male with XP diagnosed with three distinct skin cancers: superficial spreading melanoma (SSM), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Among these, the melanoma had metastasized. A computed tomography (CT) scan revealed a suspicious pulmonary nodule, prompting further metabolic characterization via positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose ([18F]FDG). The scan detected significant hypermetabolism not only in the lung lesion but also in an unsuspected right parotid gland lesion, refining disease staging and guiding treatment decisions. The patient underwent immunotherapy with nivolumab, achieving a complete metabolic response in both metastatic lesions, as confirmed by follow-up PET/CT. This case underscores the critical role of [18F]FDG PET/CT in staging and treatment monitoring for selected patients with XP, a population in which advanced imaging is rarely employed. Moreover, the patient's remarkable response to immunotherapy suggests a potential link between XP-related DNA repair defects and increased sensitivity to PD-1 blockade. These findings highlight the importance of integrating metabolic imaging into XP management and warrant further investigation into the immunogenicity of XP-associated malignancies.