[Letter] A distinct genotype of XP complementation group A: surprisingly mild phenotype highly prevalent in Northern India/ Pakistan/ Afghanistan

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Dramatic response of metastatic cutaneous angiosarcoma to an immune checkpoint inhibitor in a patient with xeroderma pigmentosum: whole-genome sequencing aids treatment decision in end-stage disease.

"Mutational signatures" are patterns of mutations that report DNA damage and subsequent repair processes that have occurred. Whole-genome sequencing (WGS) can provide additional information to standard diagnostic techniques and can identify therapeutic targets. A 32-yr-old male with xeroderma pigmentosum developed metastatic angiosarcoma that was unresponsive to three lines of conventional sarcoma therapies. WGS was performed on his primary cancer revealing a hypermutated tumor, including clonal ultraviolet radiation-induced mutational patterns (Signature 7) and subclonal signatures of mutated DNA polymerase epsilon (POLE) (Signature 10). These signatures are associated with response to immune checkpoint blockade. Immunohistochemistry confirmed high PD-L1 expression in metastatic deposits. The anti-PD-1 monoclonal antibody pembrolizumab was commenced off-label given the POLE mutation and high mutational load. After four cycles, there was a significant reduction in his disease with almost complete resolution of the metastatic deposits. This case highlights the importance of WGS in the analysis, interpretation, and treatment of cancers. We anticipate that as WGS becomes integral to the cancer diagnostic pathway, treatments will be stratified to the individual based on their unique genomic and/or transcriptomic profile, enhancing classical approaches of histologically driven treatment decisions

Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes

SummarySomatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC−/− background. XPC−/− cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk

Molecular analysis directs the prognosis, management and treatment of patients with xeroderma pigmentosum

Xeroderma pigmentosum (XP) is a well-studied disorder of (in most cases) nucleotide excision repair. The establishment in 2010 of a multidisciplinary XP clinic in the UK has enabled us to make a detailed analysis of genotype-phenotype relationships in XP patients and in several instances to make confident prognostic predictions. Splicing mutations in XPA and XPD and a specific amino acid change in XPD are associated with mild phenotypes, and individuals assigned to the XP-F group appear to have reduced pigmentation changes and a lower susceptibility to skin cancer than XPs in other groups. In an XP-C patient with advanced metastatic cancer arising from an angiosarcoma, molecular analysis of the tumour DNA suggested that immunotherapy, not normally recommended for angiosarcomas, might in this case be successful, and indeed the patient showed a dramatic recovery following immunotherapy treatment. These studies show that molecular analyses can improve the management, prognoses and therapy for individuals with XP.</p

Xeroderma pigmentosum: overview of pharmacology and novel therapeutic strategies for neurological symptoms

Xeroderma pigmentosum (XP) encompasses a group of rare diseases characterized in most cases by malfunction of nucleotide excision repair (NER), which results in an increased sensitivity to UV radiation in affected individuals. Approximately 25–30% of XP patients present with neurological symptoms, such as sensorineural deafness, mental deterioration and ataxia. Although it is known that dysfunctional DNA repair is the primary pathogenesis in XP, growing evidence suggests that mitochondrial pathophysiology may also occur. This appears to be secondary to dysfunctional NER but may contribute to the neurodegenerative process in these patients. The available pharmacological treatments in XP mostly target the dermal manifestations of the disease. In the present review, we outline how current understanding of the pathophysiology of XP could be used to develop novel therapies to counteract the neurological symptoms. Moreover, the coexistence of cancer and neurodegeneration present in XP led us to focus on possible new avenues targeting mitochondrial pathophysiology. Linked Articles: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.</p

Metronidazole-induced hepatitis in a teenager with xeroderma pigmentosum and trichothiodystrophy overlap

A teenage girl had the rare combined phenotype of xeroderma pigmentosum and trichothiodystrophy, resulting from mutations in the XPD (ERCC2) gene involved in nucleotide excision repair (NER). After treatment with antibiotics, including metronidazole for recurrent infections, she showed signs of acute and severe hepatotoxicity, which gradually resolved after withdrawal of the treatment. Cultured skin fibroblasts from the patient revealed cellular sensitivity to killing by metronidazole compared with cells from a range of other donors. This reveals that the metronidazole sensitivity was an intrinsic property of her cells. It is well recognized that patients with Cockayne syndrome, another NER disorder, are at high risk of metronidazole-induced hepatotoxicity, but this had not been reported in individuals with other NER disorders. We would urge extreme caution in the use of metronidazole in the management of individuals with the xeroderma pigmentosum and trichothiodystrophy overlap or trichothiodystrophy phenotypes.</p