Abstract
Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy of the eyelid and ocular adnexa that frequently recurs and metastasizes, and effective therapies beyond surgical excision are lacking. There remains a critical need to define the molecular-genetic drivers of the disease to understand carcinomagenesis and progression and to devise novel treatment strategies. We present next-generation sequencing of a targeted panel of cancer-associated genes in 42 and whole transcriptome RNA sequencing from eight OA sebaceous carcinomas from 29 patients. We delineate two potentially distinct molecular-genetic subtypes of OA sebaceous carcinoma. The first is defined by somatic mutations impacting TP53 and/or RB1 [20/29 (70%) patients, including 10 patients whose primary tumors contained coexisting TP53 and RB1 mutations] with frequent concomitant mutations affecting NOTCH genes. These tumors arise in older patients and show frequent local recurrence. The second subtype [9/29 (31%) patients] lacks mutations affecting TP53, RB1, or NOTCH family members, but in 44% (4/9) of these tumors, RNA sequencing and in situ hybridization studies confirm transcriptionally active high-risk human papillomavirus. These tumors arise in younger patients and have not shown local recurrence. Together, our findings establish a potential molecular-genetic framework by which to understand the development and progression of OA sebaceous carcinoma and provide key molecular-genetic insights to direct the design of novel therapeutic interventions.
Highlights
Ocular adnexal (OA) sebaceous carcinoma is an aggressive cancer that accounts for $5% of malignant epithelial eyelid tumors [1,2,3,4,5]
OA sebaceous carcinoma has a high propensity for multifocal intraepithelial and locally infiltrative growth that each contribute to frequent local recurrence
We identified patients with OA sebaceous carcinoma diagnosed at our institution during 2007 to 2017 for whom sufficient tissue was available for molecular studies
Summary
Ocular adnexal (OA) sebaceous carcinoma is an aggressive cancer that accounts for $5% of malignant epithelial eyelid tumors [1,2,3,4,5]. Aggressive surgery is often required but may produce appreciable functional and aesthetic morbidity, and orbital exenteration is necessary to achieve local control of disease in 13% to 23% of patients [5, 7, 8]. Systemic therapies for OA sebaceous carcinoma remain largely ineffective [10]. These properties underscore a critical need to define the complete set of molecular-genetic alterations driving the development and progression of OA sebaceous carcinoma to possibly improve patient outcomes through the application of rationally designed therapeutic strategies in patients with metastatic
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