Xeroderma Pigmentosum Patients Research Articles

A rare occurrence of Hodgkin lymphoma in a Xeroderma pigmentosum patient: A case report and literature review

Xeroderma pigmentosum (XP) is a rare genetic disorder characterized by extreme sensitivity to ultraviolet (UV) radiation, resulting in an increased risk of skin cancer and other UV-induced malignancies. Reports of hematological malignancies occurring in patients with XP are found in the literature, but they seem to be quite rare. This report describes a 29-year-old male patient with XP who developed Hodgkin lymphoma. The potential increased risk of lymphoma in XP patients is highlighted in this paper; however, further studies are needed to better understand the underlying mechanisms of lymphomagenesis in XP patients and to develop optimal treatment strategies for hematological and other internal malignancies in this setting.

Evidence for persistent UV-induced DNA damage and altered DNA damage response in xeroderma pigmentosa patient corneas

Xeroderma pigmentosum (XP) is a rare genetic disorder characterized by injury to the ocular surface due to exposure to ultraviolet (UV) radiation. UV-induced damage in the cells leads to the formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine-pyrimidone photoproducts that are repaired by the NER (Nucleotide Excision Repair) pathway. Mutations in the genes coding for NER proteins, as reported in XP patients, would lead to sub-optimal damage repair resulting in clinical signs varying from photo-keratitis to cancerous lesions on the ocular surface. Here, we aimed to provide evidence for the accumulation of DNA damage and activation of DNA repair pathway proteins in the corneal cells of patients with XP. Corneal buttons of patients who underwent penetrating keratoplasty were stained to quantify DNA damage and the presence of activated DNA damage response proteins (DDR) using specific antibodies. Positive staining for pH2A.X and thymidine dimers confirmed the presence of DNA damage in the corneal cells. Positive cells were found in both control corneas and XP samples however, unlike normal tissues, positive cells were found in all cell layers of XP samples indicating that these cells were sensitive to very low levels of UV. pH2A.X-positive cells were significantly more in XP corneas (p < 0.05) indicating the presence of double strand breaks in these tissues. A positive expression of phosphorylated-forms of DDR proteins was noted in XP corneas (unlike controls) such as ataxia telangiectasia mutated/Rad-3 related proteins (ATM/ATR), breast cancer-1 and checkpoint kinases-1 and -2. Nuclear localization of XPA was noted in XP samples which co-localized (calculated using Pearson's correlation) with pATM (0.9 ± 0.007) and pATR (0.6 ± 0.053). The increased presence of these in the nucleus confirms that unresolved DNA damage was accumulating in these cells thereby leading to prolonged activation of the damage response proteins. An increase in pp53 and TUNEL positive cells in the XP corneas indicated cell death likely driven by the p53 pathway. For comparison, cultured normal corneal epithelial cells were exposed to UV-radiation and stained for DDR proteins at 3, 6 and 24 h after irradiation to quantify the time taken by cells with intact DDR pathway to repair damage. These cells, when exposed to UV showed nuclear translocation of DDR proteins at 3 and 6 h which reduced significantly by 24 h confirming that the damaged DNA was being actively repaired leading to cell survival. The persistent presence of the DDR proteins in XP corneas indicates that damage is being actively recognized and DNA replication is stalled, thereby causing accumulation of damaged DNA leading to cell death, which would explain the cancer incidence and cell loss reported in these patients.

Neurological disease in xeroderma pigmentosum: prospective cohort study of its features and progression.

Xeroderma pigmentosum (XP) results from biallelic mutations in any of eight genes involved in DNA repair systems, thus defining eight different genotypes (XPA, XPB, XPC, XPD, XPE, XPF, XPG and XP variant or XPV). In addition to cutaneous and ophthalmological features, some patients present with XP neurological disease. It is unknown whether the different neurological signs and their progression differ among groups. Therefore, we aim to characterize the XP neurological disease and its evolution in the heterogeneous UK XP cohort. Patients with XP were followed in the UK National XP Service, from 2009 to 2021. Age of onset for different events was recorded. Cerebellar ataxia and additional neurological signs and symptoms were rated with the Scale for the Assessment and Rating of Ataxia (SARA), the Inventory of Non-Ataxia Signs (INAS) and the Activities of Daily Living questionnaire (ADL). Patients' mutations received scores based on their predicted effects. Data from available ancillary tests were collected. Ninety-three XP patients were recruited. Thirty-six (38.7%) reported neurological symptoms, especially in the XPA, XPD and XPG groups, with early-onset and late-onset forms, and typically appearing after cutaneous and ophthalmological symptoms. XPA, XPD and XPG patients showed higher SARA scores compared to XPC, XPE and XPV. SARA total scores significantly increased over time in XPD (0.91 points/year, 95% confidence interval: 0.61, 1.21) and XPA (0.63 points/year, 95% confidence interval: 0.38, 0.89). Hyporeflexia, hypopallesthaesia, upper motor neuron signs, chorea, dystonia, oculomotor signs and cognitive impairment were frequent findings in XPA, XPD and XPG. Cerebellar and global brain atrophy, axonal sensory and sensorimotor neuropathies, and sensorineural hearing loss were common findings in patients. Some XPC, XPE and XPV cases presented with abnormalities on examination and/or ancillary tests, suggesting underlying neurological involvement. More severe mutations were associated with a faster progression in SARA total score in XPA (0.40 points/year per 1-unit increase in severity score) and XPD (0.60 points/year per 1-unit increase), and in ADL total score in XPA (0.35 points/year per 1-unit increase). Symptomatic and asymptomatic forms of neurological disease are frequent in XP patients, and neurological symptoms can be an important cause of disability. Typically, the neurological disease will be preceded by cutaneous and ophthalmological features, and these should be actively searched in patients with idiopathic late-onset neurological syndromes. Scales assessing cerebellar function, especially walking and speech, and disability can show progression in some of the groups. Mutation severity can be used as a prognostic biomarker for stratification purposes in clinical trials.

Retrospective study of efficacy and adverse events of immune checkpoint inhibitors in 22 xeroderma pigmentosum patients with metastatic or unresectable cancers.

Xeroderma pigmentosum (XP), a rare disease with defects in DNA repair genes, has >1,000-fold increased risk of ultraviolet-induced skin cancers. Immune checkpoint inhibitors (ICIs) are used for treating cancers with large numbers of mutations but may also promote adverse events (AEs). Deficient DNA repair in XP patients may lead to increased numbers of mutations, leading to enhanced efficacy of cancer response or, alternatively, to increased AE in response to ICI. We sought to compare the efficacy and AE of ICI in XP patients with metastatic or unresectable cancers to that of ICI-treated patients in the general population. In this retrospective study, we reviewed medical records of XP patients treated in the United States and in London (UK). We also reviewed published reports of ICI-treated XP patients and patients in the general population. Metastatic or unresectable cancers in all 22 (100%) XP patients showed regression or remission in response to ICI. The types and frequencies of AE in XP patients were similar to those reported among ICI-treated patients in the general population. However, two XP patients had concurrent additional cancers that did not respond to ICI, two XP patients had cancer recurrence or progression after initial response, and eight XP patients developed new skin cancers during or after ICI treatment. In this retrospective study with small sample size, XP patients demonstrated positive responses to ICI and the treatment was well tolerated but some patients developed new skin cancers while being treated. ICIs can be considered in treating metastatic or unresectable cancers in XP patients.

XERODERMAPIGMENTOSUM: EPIDEMIOLOGICAL, CLINICAL AND THERAPEUTIC ASPECTS

Xeroderma Pigmentosum (XP) is a rare and disabling genetic dermatosis that was first described in 1874. It is characterized by photo-induced cutaneous alterations, often associated with ocular lesions and sometimes with neurological involvement. The transmission of XP is on an autosomal recessive mode, and it is relatively frequent in countries with high consanguinity rates and large family sizes, such as those in the Maghreb region. This study aims to present an epidemiological, clinical, and histological profile of XP patients treated in the plastic surgery department in southern Morocco, reflecting the regions epidemiological reality and specifying the modalities of oncologic and reparative surgical treatment.

SKIN CANCER IN CHILDREN WITH XERODERMA PIGMENTOSUM

Introduction: Xeroderma pigmentosum) is a rare disease, inherited in an autosomal recessive manner with disturbances in the repair of deoxyribonucleic acid (DNA) which often occur in malignancy. Irreversible DNA lesions and mutations also occur in the genes which regulate skin cancer development in Xeroderma Pigmentosum. Purpose: To explain the signs, symptoms, and management of skin cancer Xeroderma Pigmentosum. Case Report : A 6 year old girl with basal cell carcinoma arising from Xeroderma pigmentosum. The histopathological picture of the left nasolabial biopsy preparation was found to show basal cell carcinoma (BCC). The patient was treated with 5FU administration and were followed after 6 week In the second patient, a 3 year old boy, squamous cell carcinoma in the oocipital area. From the histopathological picture, moderately differentiated squamous cell carcinoma on the left frontalis occipital dextra and corresponds to mottled hypermegrance on the parietal dextra. In this patient, a wide excision of the occipital lump was performed and the defect was closed with a full-thickness skin graft. Provided education to the parents of both patients for direct prevention of sun exposure by using sunscreen/hats. Discussion and Conclusion: Xeroderma Pigmentosum patients who are Xeroderma Pigmentosum to ultraviolet radiation (UV) can result in the development of highly cancerous lesions consisting of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and malignant melanoma (MM). Clinical management of Xeroderma Pigmentosum includes sun avoidance, minimizing UV eXeroderma Pigmentosumosure, early detection, skin lesions, and genetic counseling. Topical application of 5-fluorouracil or imiquimod is used for premalignant lesions, and surgical excision is performed for malignant neoplasms of the skin, tongue, eyelids, conjunctiva, and cornea.

A clickable melphalan for monitoring DNA interstrand crosslink accumulation and detecting ICL repair defects in Fanconi anemia patient cells.

Fanconi anemia (FA) is a genetic disorder associated with developmental defects, bone marrow failure and cancer. The FA pathway is crucial for the repair of DNA interstrand crosslinks (ICLs). In this study, we have developed and characterized a new tool to investigate ICL repair: a clickable version of the crosslinking agent melphalan which we name click-melphalan. Our results demonstrate that click-melphalan is as effective as its unmodified counterpart in generating ICLs and associated toxicity. The lesions induced by click-melphalan can be detected in cells by post-labelling with a fluorescent reporter and quantified using flow cytometry. Since click-melphalan induces both ICLs and monoadducts, we generated click-mono-melphalan, which only induces monoadducts, in order to distinguish between the two types of DNA repair. By using both molecules, we show that FANCD2 knock-out cells are deficient in removing click-melphalan-induced lesions. We also found that these cells display a delay in repairing click-mono-melphalan-induced monoadducts. Our data further revealed that the presence of unrepaired ICLs inhibits monoadduct repair. Finally, our study demonstrates that these clickable molecules can differentiate intrinsic DNA repair deficiencies in primary FA patient cells from those in primary xeroderma pigmentosum patient cells. As such, these molecules may have potential for developing diagnostic tests.

A rare association between Xeroderma pigmentosum and diffuse large B-cell lymphoma: A case report

Xeroderma pigmentosum (XP) is a rare genetic disorder characterized by extreme sensitivity to ultraviolet (UV) radiation, resulting in an increased risk of skin cancer and other UV-induced malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL). It belongs to a group of cancers that affect the lymphatic system. Reports of DLBCL occurring in patients with XP are found in the literature but it seems to be quite rare. This report described a 31-year-old female patient with XP who developed DLBCL. The potential increased risk of lymphoma in XP patients is highlighted in this paper however further studies are needed to better understand the underlying mechanisms of lymphomagenesis in XP patients and to develop optimal treatment strategies for DLBCL in this setting.

The French Cohort of DNA Repair-Deficient Xeroderma Pigmentosum Patients: Risk of Hematological Malignancies.

Xeroderma pigmentosum (XP) is a rare genetic disorder characterized by a high incidence of skin cancers. These patients are deficient in nucleotide excision repair caused by mutations in one of the 7 XP genes. We diagnosed 181 XP patients using UV-induced DNA repair measurements and/or DNA sequencing from 1982 to 2022 in France. As all XP patients, the French ones are very sensitive to UV exposure but since they are usually very well protected, they develop relatively few skin cancers. A majority of French XP patients originate from North Africa and bear a founder mutation on the XPC gene. The striking discovery is that these patients are at a very high risk to develop aggressive and lethal internal tumors such as hematological malignancies (more than a 100-fold risk compared to the general population for myelodysplasia/leukemia) with a median age of death of 25 years, and brain, gynecological, and thyroid tumors with even lower median ages of death. The high mutation rates found in XP-C internal tumors allow us to think that these XP patients could be successfully treated by immunotherapies. A full analysis of the molecular origins of these DNA repair-deficient tumors is discussed. Several explanations for this high predisposition risk are proposed. As the age of the XP population is increasing due to better photo-protection, the risk of lethal internal tumors is a new Damocles sword that hangs over XP-C patients. This review of the French cohort is of particular importance for alerting physicians and families to the prevention and early detection of aggressive internal tumors in XP patients.

Nucleotide excision repair in Human cell lines lacking both XPC and CSB proteins.

Nucleotide excision repair removes UV-induced DNA damage through two distinct sub-pathways, global repair and transcription-coupled repair (TCR). Numerous studies have shown that in human and other mammalian cell lines that the XPC protein is required for repair of DNA damage from nontranscribed DNA via global repair and the CSB protein is required for repair of lesions from transcribed DNA via TCR. Therefore, it is generally assumed that abrogating both sub-pathways with an XPC-/-/CSB-/- double mutant would eliminate all nucleotide excision repair. Here we describe the construction of three different XPC-/-/CSB-/- human cell lines that, contrary to expectations, perform TCR. The XPC and CSB genes were mutated in cell lines derived from Xeroderma Pigmentosum patients as well as from normal human fibroblasts and repair was analyzed at the whole genome level using the very sensitive XR-seq method. As predicted, XPC-/- cells exhibited only TCR and CSB-/- cells exhibited only global repair. However, the XPC-/-/CSB-/- double mutant cell lines, although having greatly reduced repair, exhibited TCR. Mutating the CSA gene to generate a triple mutant XPC-/-/CSB-/-/CSA-/- cell line eliminated all residual TCR activity. Together, these findings provide new insights into the mechanistic features of mammalian nucleotide excision repair.

Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients

Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis DNA polymerase η (V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyze 38 skin cancer genomes from five XP groups. We find that the activity of NER determines heterogeneity of the mutation rates across skin cancer genomes and that transcription-coupled NER extends beyond the gene boundaries reducing the intergenic mutation rate. Mutational profile in XP-V tumors and experiments with POLH knockout cell line reveal the role of polymerase η in the error-free bypass of (i) rare TpG and TpA DNA lesions, (ii) 3’ nucleotides in pyrimidine dimers, and (iii) TpT photodimers. Our study unravels the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population.

Marginal Mandibulectomy and Oral Rehabilitation of Xeroderma Pigmentosum Patient.

Xeroderma pigmentosum (XP) may cause tissue deformation in patients who have undergone oral cancer surgery requiring resection of any part of the mandible. Oral rehabilitation is a pivotal factor in the restoration of function and esthetics. The aim of this study was to report a clinical case of successful prosthetic rehabilitation of a 57-year-old woman who presented with marginal mandibulectomy and a significant reduction in maximal mouth opening after treatment for XP. With her reduced opening and considerable loss of structure and tissue, she had difficulty speaking, swallowing, and altered esthetics. The oral rehabilitation was performed with complete maxilla denture and mandible overdenture retained by 2 implants. This case demonstrates that the rehabilitation with mandible overdentures and complete maxilla dentures provide function and esthetic improvement in the mutilated area for XP patients with marginal mandibulectomies.

Imiquimod chemoprophylaxis for field cancerization in xeroderma pigmentosum patients-A prospective study.

Australasian Journal of DermatologyEarly View RESEARCH LETTER Imiquimod chemoprophylaxis for field cancerization in xeroderma pigmentosum patients—A prospective study Lílian Kelly Faria Licarião Rocha MD, PhD, Corresponding Author Lílian Kelly Faria Licarião Rocha MD, PhD [email protected] orcid.org/0000-0003-3010-1526 Department of Dermatology, Hospital das Clínicas of São Paulo University, São Paulo, Brazil Correspondence Lílian Kelly Faria Licarião Rocha, Department of Dermatology, Hospital das Clínicas of São Paulo University, Av. Dr. Enéas de Carvalho, 255, São Paulo, Brazil. Email: [email protected],Search for more papers by this authorPaula Ferreira MD, Paula Ferreira MD Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorMarcelo A. Gianotti MD, Marcelo A. Gianotti MD Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorJoão Avancini MD, João Avancini MD Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorCarlos F. M. Menck PhD, Carlos F. M. Menck PhD orcid.org/0000-0003-1941-0694 Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, BrazilSearch for more papers by this authorLigia P. Castro PhD, Ligia P. Castro PhD Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, BrazilSearch for more papers by this authorZilda Najjar Prado de Oliveira PhD, Zilda Najjar Prado de Oliveira PhD Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorMaria C. Rivitti PhD, Maria C. Rivitti PhD Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorLuciana P. Samorano MD, Luciana P. Samorano MD Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorNaiura Vieira Pereira PhD, Naiura Vieira Pereira PhD Laboratory of Dermatologia Tropical, Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorCyro Festa Neto PhD, Cyro Festa Neto PhD Department of Dermatology, Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this author Lílian Kelly Faria Licarião Rocha MD, PhD, Corresponding Author Lílian Kelly Faria Licarião Rocha MD, PhD [email protected] orcid.org/0000-0003-3010-1526 Department of Dermatology, Hospital das Clínicas of São Paulo University, São Paulo, Brazil Correspondence Lílian Kelly Faria Licarião Rocha, Department of Dermatology, Hospital das Clínicas of São Paulo University, Av. Dr. Enéas de Carvalho, 255, São Paulo, Brazil. Email: [email protected],Search for more papers by this authorPaula Ferreira MD, Paula Ferreira MD Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorMarcelo A. Gianotti MD, Marcelo A. Gianotti MD Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorJoão Avancini MD, João Avancini MD Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorCarlos F. M. Menck PhD, Carlos F. M. Menck PhD orcid.org/0000-0003-1941-0694 Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, BrazilSearch for more papers by this authorLigia P. Castro PhD, Ligia P. Castro PhD Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, BrazilSearch for more papers by this authorZilda Najjar Prado de Oliveira PhD, Zilda Najjar Prado de Oliveira PhD Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorMaria C. Rivitti PhD, Maria C. Rivitti PhD Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorLuciana P. Samorano MD, Luciana P. Samorano MD Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorNaiura Vieira Pereira PhD, Naiura Vieira Pereira PhD Laboratory of Dermatologia Tropical, Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this authorCyro Festa Neto PhD, Cyro Festa Neto PhD Department of Dermatology, Hospital das Clínicas of São Paulo University, São Paulo, BrazilSearch for more papers by this author First published: 13 April 2023 https://doi.org/10.1111/ajd.14029Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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Bilateral ocular surface squamous neoplasia in xeroderma pigmentosum patient - A case report

A rare case of a 13yr old male patient presented with photophobia in both eyes and gradually progressive painless mass with watering, itching, and redness in the right eye for 2 months. Best-corrected visual acuity in Right eye 20/200 and Left eye 20/120. On examination, Right eye has a 6 x 6 mm fleshy pink oval pedunculated mass lesion arising from the temporal limbus and a 2mm hyperpigmented lesion in the nasal limbus. Left eye has a gelatinous white flat diffuse lesion with the pigmentation of 3mm both in the nasal and temporal limbus. Both eyes' Anterior segment, ocular motility, and fundus are normal. The patient had multiple hyperpigmented spots (freckles) and scaly skin on the face and trunk suggestive of Xeroderma pigmentosum for which he was on irregular treatment. Right eye tumor mass was excised with intraoperative control of surgical margins with adjunctive cryotherapy and sent for histopathology examination, which was confirmed as squamous neoplasia. Postoperatively, Both eyes started on Topical Mitomycin-c 0.02% 4 cycles, and the patient was carefully followed for any recurrence.

Inflammatory landscape in Xeroderma pigmentosum patients with cutaneous melanoma

Xeroderma pigmentosum (XP) is a DNA repair disease that predisposes to early skin cancers as cutaneous melanoma. Melanoma microenvironment contains inflammatory mediators, which would be interesting biomarkers for the prognosis or for the identification of novel therapeutic targets. We used a PCR array to evaluate the transcriptional pattern of 84 inflammatory genes in melanoma tumors obtained from XP patients (XP-Mel) and in sporadic melanoma (SP-Mel) compared to healthy skin. Commonly expressed inflammatory genes were further explored via GTEx and GEPIA databases. The differentially expressed inflammatory genes in XP were compared to their expression in skin exposed to UVs, and evaluated on the basis of the overall survival outcomes of patients with melanoma. Monocyte subsets of patients with SP-Mel, XP and healthy donors were also assessed. PCR array data revealed that 34 inflammatory genes were under-expressed in XP-Mel compared to SP-Mel. Differentially expressed genes that were common in XP-Mel and SP-Mel were correlated with the transcriptomic datasets from GEPIA and GTEx and highlighted the implication of KLK1 and IL8 in the tumorigenesis. We showed also that in XP-Mel tumors, there was an overexpression of KLK6 and KLK10 genes, which seems to be associated with a bad survival rate. As for the innate immunity, we observed a decrease of intermediate monocytes in patients with SP-Mel and in XP. We highlight an alteration in the immune response in XP patients. We identified candidate biomarkers involved in the tumorigenesis, and in the survival of patients with melanoma. Intermediate monocyte’s in patients at risk could be a prognostic biomarker for melanoma outcome.

Increased risk of internal tumors in DNA repair-deficient xeroderma pigmentosum patients: analysis of four international cohorts

BackgroundXeroderma pigmentosum (XP) is a rare, autosomal, recessive DNA repair-deficiency disorder with a frequency of 1–3 per million livebirths in Europe and USA but with higher frequencies in isolated islands or in countries with a high level of consanguinity. XP is characterized by high incidence of skin cancers on sun-exposed sites. Recent improvement in life expectancy of XP patients suggests an increased risk of frequently aggressive and lethal internal tumors. Our purpose was to quantify relative risks of internal tumor development for XP patients by tumor type, XP-subtype, patients’ ages and ethnicity through comparison with the US general population.MethodsWe analyzed four independent international well-characterized XP cohorts (from USA, UK, France and Brazil) with a total of 434 patients, where 11.3% developed internal tumors and compared them to the American general population. We also compiled, through PubMed/Medline, a dataset of 89 internal tumors in XP patients published between 1958 and 2020.ResultsIn the combined 4-XP cohort, relative risk of internal tumors was 34 (95% confidence interval (CI) 25–47) times higher than in the general population (p-value = 1.0E−47) and tumor arose 50 years earlier. The XP-C group was at the highest risk for the 0–20 years old-patients (OR = 665; 95% CI 368–1200; p-value = 4.3E−30). The highest risks were observed for tumors of central nervous system (OR = 331; 95% CI 171–641; p-value = 2.4E−20), hematological malignancies (OR = 120; 95% CI 77–186; p-value = 3.7E−36), thyroid (OR = 74; 95% CI 31–179; p-value = 1.2E−8) and gynecological tumors (OR = 91; 95% CI 42–193; p-value = 3.5E−12). The type of mutation on the XPC gene is associated with different classes of internal tumors. The majority of French XP-C patients (80%) are originated from North Africa and carried the XPC delTG founder mutation specific from the South Mediterranean area. The OR is extremely high for young (0–20 years) patients with more than 1300-fold increase for the French XPs carrying the founder mutation.ConclusionBecause the age of XP population is increasing due to better sun-protection and knowledge of the disease, these results are of particular importance for the physicians to help in early prevention and detection of internal tumors in their XP patients. Few preventive blood analyses or simple medical imaging may help to better detect early cancer appearance in this population.

Ultraviolet radiation exposure to the face in patients with xeroderma pigmentosum and healthy controls: applying a novel methodology to define photoprotection behaviour.

SummaryBackgroundIn xeroderma pigmentosum (XP), the main means of preventing skin and eye cancers is extreme protection against ultraviolet radiation (UVR). Protection is most important for the face.ObjectivesWe aimed to assess how well patients with XP adhere to medical advice to protect against UVR by objectively estimating the mean daily dose of UVR to the face.MethodsWe objectively estimated the UVR dose to the face in 36 patients with XP and 25 healthy individuals over 3 weeks in the summer. We used a new methodology which combined UVR dose measurements from a wrist‐worn dosimeter with an activity diary record of face photoprotection behaviour for each 15‐min period spent outside. A protection factor was associated with each behaviour, and the data were analysed using a negative binomial mixed‐effects model.ResultsThe mean daily UVR dose (weighted for DNA damage capacity) to the face in the patients with XP was 0·13 standard erythemal doses (SEDs) (mean in healthy individuals = 0·51 SED). There was wide variation between patients (range < 0·01–0·48 SED/day). Self‐caring adult patients had a very similar UVR dose to the face as cared‐for patients (0·13 vs. 0·12 SED/day), despite photoprotecting much more poorly when outside, because the self‐caring adults were outside in daylight much less.ConclusionsPhotoprotection behaviour varies widely within the XP group indicating that nonadherence to photoprotection advice is a significant issue. The timing and duration of going outside are as important as photoprotective measures taken when outside, to determine the UVR exposure to the face. This new methodology will be of value in identifying the sources of UVR exposure in other conditions in which facial UVR exposure is a key outcome, particularly in patients with multiple nonmelanoma skin cancers.

Elevated Levels of Soluble CTLA-4, PD-1, PD-L1, LAG-3 and TIM-3 and Systemic Inflammatory Stress as Potential Contributors to Immune Suppression and Generalized Tumorigenesis in a Cohort of South African Xeroderma Pigmentosum Patients.

Xeroderma Pigmentosum (XP), an autosomal recessive disorder characterized by ultraviolet radiation-induced abnormalities of DNA excision and repair pathways is associated with early development of cutaneous cancers. Intracellular oxidative stress has also been proposed as a contributor to the occurrence of skin cancers. However, little is known about the possible augmentative contributions of chronic inflammation, immune suppression and oxidative stress to the pathogenesis of malignancies associated with other subtypes of XP. This has been addressed in the current study, focused on the measurement of systemic biomarkers of inflammation, immune dysfunction and oxidative damage in XP patients, consisting of XP-C, XP-D and XP-E cases, including those XP-C cases who had already developed multiple skin malignancies. The inflammatory biomarker profile measured in XP patients and healthy control subjects included the cytokines, interleukins (ILs)-2, -4, -6, -10, interferon-γ (IFN- γ) and tumor-necrosis factor-α (TNF-α), the acute phase reactant, C-reactive protein (CRP), and cotinine (as an objective indicator of smoking status). Immune suppression was detected according to the levels of five soluble inhibitory immune checkpoint proteins (CTLA-4, PD-1, PD-L1, LAG-3 and TIM-3), as well as those of vitamin D, while oxidative stress was determined according to the circulating levels of the DNA adduct, 8-hydroxy-2-deoxyguanosine (8-OH-dG). These various biomarkers were measured in plasma using immunofluorimetric, nephelometric and ELISA procedures. Significant elevations in IL-6 (P<0.01) and TNF-α (P<0.0001), but none of the other cytokines, as well as increased levels of all five soluble inhibitory immune checkpoints (P=0.032-P=0.0001) were detected in the plasma of the XP patients. C-reactive protein and vitamin D were increased and decreased, respectively (both P<0.0001), while only one participant had an elevated level of plasma cotinine. Surprisingly, the levels of 8-OH-dG were significantly (P=0.0001) lower in the group of XP patients relative to a group of healthy control subjects. The findings of increased levels of pro-inflammatory cytokines and, in particular, those of the soluble immune checkpoints, in the setting of decreased vitamin D and moderately elevated levels of CRP in XP patients suggest a possible secondary role of ongoing, inflammatory stress and immune suppression in the pathogenesis of XP-associated malignancies.

The Prognostic and Predictive Role of Xeroderma Pigmentosum Gene Expression in Melanoma.

BackgroundAssessment of immune-specific markers is a well-established approach for predicting the response to immune checkpoint inhibitors (ICIs). Promising candidates as ICI predictive biomarkers are the DNA damage response pathway genes. One of those pathways, which are mainly responsible for the repair of DNA damage caused by ultraviolet radiation, is the nucleotide excision repair (NER) pathway. Xeroderma pigmentosum (XP) is a hereditary disease caused by mutations of eight different genes of the NER pathway, or POLH, here together named the nine XP genes. Anecdotal evidence indicated that XP patients with melanoma or other skin tumors responded impressively well to anti-PD-1 ICIs. Hence, we analyzed the expression of the nine XP genes as prognostic and anti-PD-1 ICI predictive biomarkers in melanoma.MethodsWe assessed mRNA gene expression in the TCGA-SKCM dataset (n = 445) and two pooled clinical melanoma cohorts of anti-PD-1 ICI (n = 75). In TCGA-SKCM, we applied hierarchical clustering on XP genes to reveal clusters, further utilized as XP cluster scores. In addition, out of 18 predefined genes representative of a T cell inflamed tumor microenvironment, the TIS score was calculated. Besides these scores, the XP genes, immune-specific single genes (CD8A, CXCL9, CD274, and CXCL13) and tumor mutational burden (TMB) were cross-correlated. Survival analysis in TCGA-SKCM was conducted for the selected parameters. Lastly, the XP response prediction value was calculated for the two pooled anti-PD-1 cohorts by classification models.ResultsIn TCGA-SKCM, expression of the XP genes was divided into two clusters, inversely correlated with immune-specific markers. A higher ERCC3 expression was associated with improved survival, particularly in younger patients. The constructed models utilizing XP genes, and the XP cluster scores outperformed the immune-specific gene-based models in predicting response to anti-PD-1 ICI in the pooled clinical cohorts. However, the best prediction was achieved by combining the immune-specific gene CD274 with three XP genes from both clusters.ConclusionOur results suggest pre-therapeutic XP gene expression as a potential marker to improve the prediction of anti-PD-1 response in melanoma.

XPC and POLH/XPV Genes Mutated in a Genetic Cluster of Xeroderma Pigmentosum Patients in Northeast Brazil

Xeroderma pigmentosum (XP) is a rare genetic condition in which exposure to sunlight leads to a high tumor incidence due to defective DNA repair machinery. Herein, we investigated seven patients clinically diagnosed with XP living in a small city, Montanhas (Rio Grande do Norte), in the Northeast region of Brazil. We performed high-throughput sequencing and, surprisingly, identified two different mutated genes. Six patients carry a novel homozygote mutation in the POLH/XPV gene, c.672_673insT (p.Leu225Serfs*33), while one patient carries a homozygote mutation in the XPC gene, c.2251-1G>C. This latter mutation was previously described in Southeastern Africa (Comoro Island and Mozambique), Pakistan, and in a high incidence in Brazil. The XP-C patient had the first symptoms before the first year of life with aggressive ophthalmologic tumor progression and a melanoma onset at 7 years of age. The XP-V patients presented a milder phenotype with later onset of the disorder (mean age of 16 years old), and one of the six XP-V patients developed melanoma at 72 years. The photoprotection is minimal among them, mainly for the XP-V patients. The differences in the disease severity between XP-C (more aggressive) and XP-V (milder) patients are obvious and point to the major role of photoprotection in the XPs. We estimate that the incidence of XP patients at Montanhas can be higher, but with no diagnosis, due to poor health assistance. Patients still suffer from the stigmatization of the condition, impairing diagnosis, education for sun protection, and medical care.