DNA-repair and transcriptional defects drive hematologic malignancies in xeroderma pigmentosum group C patients: A new hypothesis.

Xeroderma pigmentosum (XP) is a rare recessive autosomal genodermatosis caused by defects in nucleotide excision repair (NER). Patients with XP are extremely sensitive to ultraviolet-light, resulting in an increased incidence of skin cancers in sun-exposed areas. Thanks to improved photoprotection and therapeutic education, the life expectancy of patients with XP has increased substantially. Recently, however, it has been observed that some XP patients are also at very high risk of developing internal tumors. Notably, 50% of these tumors correspond to severe myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML) occurring in XP-C patients younger than 25 years, almost 50 years earlier than for the general population. To explain this striking susceptibility, we hypothesize that two distinct but complementary mechanisms contribute to the high risk of hematologic malignancies in XP-C patients. First, preserved transcription-coupled repair combined with defective global-genome repair in XP-C cells, in the presence of as-yet-uncharacterized endogenous bulky DNA lesions, results in a more than 25-fold increase in mutation frequency in XP-C-associated hematologic malignancies compared with corresponding tumors in the general population. Whole-genome sequencing of XP-C hematologic malignancies reveals a COSMIC SBS8 mutational signature characteristic of NER deficiency. Second, the XPC protein has been identified as a co-factor of RNA polymerase II regulating hundreds of genes. Loss of full-length XPC leads to dysregulation of multiple gene pathways, including those involved in hematopoietic, immunologic, and oncogenic processes. We propose that together, the accumulation of driver-gene mutations and the disruption of hematopoietic regulatory pathways may account for the exceptionally high incidence and severity of MDS/AML observed in young XP-C patients.