Rare internal malignancies in xeroderma pigmentosum: A report of two cases from Tunisia and analysis of driver mutations

Xeroderma pigmentosum (XP)-associated internal malignancies are characterized by their rarity, early onset, atypical histological presentations, and poorly defined genomic landscape. In this study, we report the clinical, pathological, and molecular features of two rare XP-associated internal malignancies, focusing on their somatic mutational landscapes. These tumors represented highly uncommon histological variants in their respective anatomical sites: an ovarian high-grade sex cord-stromal tumor (HG-SCST) with heterologous rhabdomyosarcomatous differentiation diagnosed in an 18-year-old female, harboring a homozygous XP Complementation Group C ( XPC ): NM_004628.5:c.1643_1644delTG (p.Val548Alafs*25) mutation and a renal leiomyosarcoma diagnosed in a 14-year-old male carrying a homozygous XPC : NM_004628.5:c.850G>T (p.Glu284*) mutation. Neither patient had a documented history of cutaneous malignancies. The patient with the ovarian tumor exhibited no response to chemotherapy and succumbed six months after diagnosis, whereas the patient with the renal leiomyosarcoma initially achieved a complete response but subsequently relapsed and died after 5 years and eight months of follow-up. The literature review identified only one previously reported case of renal leiomyosarcoma in a patient with XP and seven cases of XP-associated malignant ovarian tumors, including four SCSTs. In this study, targeted next-generation sequencing using the AmpliSeq for Illumina Cancer HotSpot Panel identified pathogenic mutations in canonical cancer driver genes: tumor protein p53 ( TP53 ) NM_000546.6:c.730G>T (p.Gly244Cys) and platelet-derived growth factor receptor alpha ( PDGFRA ) NM_006206.6:c.2525A>T (p.Asp842Val) mutations in renal leiomyosarcoma and NRAS proto-oncogene, GTPase ( NRAS ) NM_002524.5:c.35G>T (p.Gly12Val) mutation in the ovarian tumor. These findings suggest a potential benefit of personalized therapies for XP patients with internal malignancies. • Uncommon tumors in two Tunisian xeroderma pigmentosum complementation group C patients: a high-grade ovarian sex cord-stromal tumor and a renal leiomyosarcoma. • These tumors exhibit early onset and display atypical histological features compared with their sporadic counterparts. • Tumor protein p53 ( TP53) p.G244C and platelet-derived growth factor receptor alpha ( PDGFRA ) p.D842Val mutations were detected in the renal leiomyosarcoma. • NRAS proto-oncogene, GTPase ( NRAS ) p.Gly12Val mutation was identified in the ovarian high-grade sex cord-stromal tumor • Although neither patient developed skin cancer, both succumbed to internal tumors, underscoring the importance of screening for such malignancies.