Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Yurchenko AA

PROVIDER: S-EPMC10160032 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Yurchenko Andrey A AA Rajabi Fatemeh F Braz-Petta Tirzah T Fassihi Hiva H Lehmann Alan A Nishigori Chikako C Wang Jinxin J Padioleau Ismael I Gunbin Konstantin K Panunzi Leonardo L Morice-Picard Fanny F Laplante Pierre P Robert Caroline C Kannouche Patricia L PL Menck Carlos F M CFM Sarasin Alain A Nikolaev Sergey I SI

Nature communications 20230504 1

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 t ...[more]

PMID: 37142601

Similar Datasets

Project description: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.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets