XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature
Author:
Yurchenko Andrey A.ORCID, Padioleau Ismael, Matkarimov Bakhyt T., Soulier Jean, Sarasin Alain, Nikolaev Sergey
Abstract
ABSTRACTRecent studies demonstrated a dramatically increased risk of leukemia in patients with a rare genetic disorder, Xeroderma Pigmentosum group C (XP-C), characterized by constitutive deficiency of global genome nucleotide excision repair (GG-NER). However, the genetic mechanisms of non-skin cancers in XP-C patients remain unexplored. In this study, we analyzed a unique collection of internal XP-C tumor genomes including 6 leukemias and 2 sarcomas. We observed an average of 25-fold increase of mutation rates in XP-C vs. sporadic leukemia which we presume leads to its elevated incidence and early appearance. In all XP-C tumors predominant mutational process is characterized by a distinct mutational signature, highlighting a specific mutational pattern in the context of GG-NER deficiency. We observed a strong mutational asymmetry with respect to transcription and the direction of replication in XP-C tumors suggesting association of mutagenesis with bulky purine DNA lesions of probably endogenous origin. These findings suggest existence of a balance between formation and repair of bulky DNA lesions by GG-NER in human body cells which is disrupted in XP-C patients leading to internal cancers.
Publisher
Cold Spring Harbor Laboratory
Reference60 articles.
1. Deciphering Signatures of Mutational Processes Operative in Human Cancer 2. Signatures of mutational processes in human cancer 3. Andrews, S. (2015). FASTQC A Quality Control tool for High Throughput Sequence Data. Babraham Inst. 4. Arnaudeau-Bégard, C. , Brellier, F. , Chevallier-Lagente, O. , Hoeijmakers, J. , Bernerd, F. , Sarasin, A. , and Magnaldo, T. (2003). Genetic correction of DNA repair-deficient/cancer-prone xeroderma pigmentosum group C keratinocytes. Hum. Gene Ther. 5. Van der Auwera, G.A. , Carneiro, M.O. , Hartl, C. , Poplin, R. , Del Angel, G. , Levy-Moonshine, A. , Jordan, T. , Shakir, K. , Roazen, D. , Thibault, J. , et al. (2002). GATK Best Practices. Curr. Protoc. Bioinformatics.
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