CPC12 Coinheritance of BRCA2 and CYLD germline pathogenic variants associated with targetable metastatic malignant cylindroma

Abstract

Abstract CYLD cutaneous syndrome (CCS) presents during puberty with the development of hair follicle tumours, including cylindromas, spiradenomas or trichoepitheliomas, and is associated with pathogenic variants in the tumour suppressor gene CYLD. Germline pathogenic variants of BRCA2 are associated with an increased risk of breast, ovarian, pancreatic and prostate cancer. Coinheritance of pathogenic variants in both genes has not been previously reported, and here, we present a 29-year-old man with metastatic malignant cylindroma, where knowledge of the germline variants has targetable therapeutic implications. The proband presented with cylindromas on his scalp from the age of 8 years, inherited from his mother who had CCS. The proband’s father and paternal grandmother both had early-onset breast cancer. The proband’s 33-year-old sister had been diagnosed with breast cancer and CCS; genetic testing revealed germline pathogenic variants in both BRCA2 and CYLD. Aged 28 years, the proband presented with a growing, ulcerated cylindroma on the scalp. Histology revealed a biphasic neoplasm, showing malignant cylindroma with high-grade features arising within a pre-existing benign cylindroma. The malignant epithelioid component of the tumour showed brisk mitotic activity (25 mitoses per mm2) and large infiltrative nests with central comedo-type necrosis. Immunohistochemistry showed positivity for epithelial membrane antigen, CK7, p63 and patches of CK5/6, whereas carcinoembryonic antigen, S100 and human melanoma black-45 were negative. Several weeks after excision of the malignant scalp cylindroma, a lump presented on the left side of the patient’s neck; biopsy revealed histology consistent with the malignant scalp cylindroma. Radiological imaging revealed metastatic deposits of malignant cylindroma in the right axilla, both lungs and the brain. Genetic testing of the proband revealed germline pathogenic variants in both BRCA2 and CYLD, as seen in his sister. The patient received radiotherapy for the tumour in his neck, with partial resolution of symptoms and gamma-knife ablation of brain metastases. DNA extracted from the patient’s tumour was analysed using a high-resolution single-nucleotide polymorphism array, which demonstrated loss of heterozygosity including the BRCA2 and CYLD loci. The germline and somatic pathogenic variants in this patient support the use of unlicensed therapeutics that target BRCA deficiency, such as poly-ADP ribose polymerase inhibitors, which have not previously been used to treat malignant cylindroma. This case emphasizes the importance of recognizing coinheritance of tumour suppressor genes in rare genetic conditions, as this can provide novel management options and improve patient outcomes.