Metastatic malignant cylindroma arising on a background of digenic inheritance of BRCA2 and CYLD pathogenic variants targeted with PARP inhibition.

Background: CYLD cutaneous syndrome (CCS) is caused by germline heterozygous pathogenic variants in CYLD and results in the progressive formation of cylindromas, spiradenomas or trichoepitheliomas. Malignant cylindroma is a rare skin adnexal tumour occurring in CCS, which can metastasize with lethal outcomes and has limited genomic characterization. BRCA2 loss in CCS is not described and may modulate the cutaneous cancer risk of CCS.

Objectives: To establish whether BRCA deficiency drives metastatic malignant cylindroma and to report the phenotype of three siblings with digenic inheritance of CYLD and BRCA2 pathogenic variants (PVs), one of whom developed metastatic cylindroma at 28 years old.

Methods: A kindred study reporting seven members of a family with CCS was conducted in a tertiary hospital setting within the United Kingdom from April 2021 to February 2023. Clinical phenotype, pathological, radiological and genetic findings and treatment data were -collected. Whole-genome sequencing of the primary malignant cylindroma occurring in one patient was performed to identify targetable driver mutations and signatures.

Results: Malignant cylindroma arose in one (proband) of the two male siblings with digenic inheritance of BRCA2 (c.5158insT) and CYLD (c.2689-2A>G) pathogenic variants. A further female sibling with digenic inheritance of the same BRCA2 and CYLD PVs developed early breast cancer. Whole-genome sequencing of the primary malignant cylindroma in the affected patient showed loss of heterozygosity of both BRCA2 and CYLD. Bioinformatic analysis confirmed homologous repair deficiency (HRD). These data supported the use of the PARP [poly(ADP-ribose) polymerase] inhibitor rucaparib to target HRD in a non-canonical BRCA-deficient skin cancer.

Conclusions: Digenic inheritance of pathogenic variants in cancer-predisposing genes should prompt clinicians to be vigilant for atypical malignant presentations. We demonstrate that rapid whole-genome sequencing can inform the treatment of metastatic malignant cylindroma and identify novel systemic therapies.