Xeroderma pigmentosum as a germline predisposition syndrome for haematological malignancies

Abstract

Abstract IntroductionXeroderma pigmentosum (XP) is a rare autosomal recessive disorder caused by defects in the nucleotide excision repair pathway, resulting in genomic instability and increased cancer susceptibility. In Saudi Arabia, the prevalence of XP is significantly higher than the global average due to the high rate of consanguineous marriages. While XP is associated with skin malignancies, it might also be a cancer predisposition, including haematological malignancies (HMs) driven by inherited germline variants. In this study, we describe HMs cases among genetically confirmed XP patients in Saudi Arabia and present the germline variants that may contribute to this cancer predisposition.MethodsWe retrospectively identified 47 patients diagnosed with XP at King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia, between 2003 and 2025. Of these, 29 patients belonged to 11 families. The cohort included 25 females and 22 males, with ages ranging from birth to 44 years (median age: 15 years). Parental consanguinity was reported in 35 patients (74.5%). Clinical and genetic data were reviewed, including the diagnosis of cancers, age at onset, cancer type, and germline variants identified through targeted gene panels, exome or genome sequencing.ResultsAmong the 47 patients, 23 (48.9%) developed basal or squamous cell carcinoma. The lower observed frequency of basal cell carcinoma in our cohort may be partly due to underreporting, as routine dermatological follow-up was not consistently performed. HMs including myelodysplastic syndrome or acute myeloid leukaemia were identified in 7 patients (14.9%). Additionally, one patient each developed ovarian cancer or small cell neuroendocrine carcinoma with liver metastases.The median age of patients with HMs was 22 years. All patients with HMs had a positive family history of XP and cancer, and six of the seven were born to consanguineous parents. Notably, each of these patients developed basal cell carcinoma prior to their HMs diagnosis.Notably, five of the seven HMs cases belonged to a single extended family and were homozygous for a novel germline pathogenic variant in the XPC gene (c.856A>T; p.R286*). Somatic TP53 mutations were detected in three of these patients, and complex karyotypes were observed in three cases. Interestingly, the same XPC variant was also found in a patient who did not develop HMs but was diagnosed with ovarian cancer.A deletion in the XPC protein (p.E34del) was also identified in another XP/HM patient who harbored also a JAK2 mutation. Another XP patient who developed basal cell carcinoma, ovarian high-grade serous carcinoma, and breast cancer harbored pathogenic variants in TP53, STAG2, BCOR, TET2, and ABL1, along with a complex karyotype; however, XPC gene status was not assessed in this individual due to the limitations of the testing panel.ConclusionOur findings highlight XP particularly in individuals harboring XPC variants, as a germline predisposition syndrome not only for skin cancers but also for HMs especially in populations with high rates of consanguinity. These results support the need for enhanced genetic surveillance and HMs screening in XP patients. Functional study is needed to confirm the deleterious effect of XPC c.856A>T (p.R286*) in the XP patients. Furthermore, our data provide a compelling rationale for considering XP, specifically XPC-related subtypes, among the WHO-classified germline predisposition syndromes to HMs.