Predisposition to hematologic malignancies in patients with xeroderma pigmentosum

Germline predisposition is a contributing etiology of hematologic malignancies, especially in children and young adults. Germline predisposition in myeloid neoplasms was added to the World Health Organization 2016 classification,1 and current management recommendations emphasize the importance of screening appropriate patients.2 Rare syndromes of DNA repair defects can lead to myeloid and/or lymphoid neoplasms.3 Here, we describe our experience with hematologic neoplasms in the defective DNA repair syndrome, xeroderma pigmentosum (XP), including myelodysplastic syndrome (MDS), secondary acute myeloid leukemia (AML), high-grade lymphoma, and an extremely unusual presentation of mixed phenotype acute leukemia (MPAL) with B, T and myeloid blasts.

XP is a rare, autosomal recessive, nucleotide excision repair (NER) disorder, characterized by failure to repair ultraviolet radiation-induced and other DNA damage. XP arises from mutations in the DNA repair/transcription genes XPA, ERCC3/XPB, XPC, ERCC2/XPD, DDB2/XPE, ERCC4/XPF/FANCQ and ERCC5/XPG, or in the bypass polymerase, POLH/XPV.4 Many cancers of the skin and sun-exposed mucus membranes develop in childhood,64 and about 25% of patients develop progressive neurologic degeneration. XP is considered a disorder of premature aging with associated skin changes, sensorineural deafness and accelerated neuronal loss. As vigilance in skin cancer prevention, diagnosis and management has extended the life expectancy of patients with XP, other premature aging features are being identified, including premature menopause7 and internal cancers. Internal malignancies in XP, primarily of the central nervous system, occur with an estimated 10- to 20-fold increased incidence compared to the general population.5 Isolated cases of MDS and/or acute leukemia have previously been reported85 and cited.9 Most recently, the occurrence of MDS and secondary AML has been described9 in patients with a frequent North African XPC founder mutation c.1643-1644delTG, resulting in a frameshift mutation in exon 9.10

To study the natural history of XP, a cohort of 117 patients and their families were enrolled at the National Institutes of Health (NIH) from 1971 to 2018.6 This study was approved by the National Cancer Institute review board, and informed consent was obtained for all participants. Mutation testing in XP associated genes was performed by PCR and Sanger sequencing. Within this cohort of 117 XP patients, 65 were identified with mutations in XPC, including three patients with homozygous XPC c.1643-1644delTG, a North African founder mutation, and two with compound heterozygous XPC c.1643-1644delTG.1211

Four patients in our cohort developed hematologic neoplasms, including MDS, acute leukemias, and high-grade lymphoma (Table 1), and all four had germline mutations in XPC. None of the four patients had received prior systemic chemotherapy or reported a family history of hematologic neoplasms. The North African founder mutation c.1643-1644delTG was homozygous in two of these patients and compound heterozygous in one patient. The fourth patient had a homozygous mutation affecting a splice site, c.622 −2A>C. There were two additional patients with the founder mutation in this cohort, XP394BE homozygous,12 and XP132BE compound heterozygous,11 and they developed basal and squamous cell carcinomas but no internal cancer by the age of 29 years and 9 years, respectively.

Table 1.Hematologic malignancies in a cohort of patients with xeroderma pigmentosum at National Institutes of Health.