Distinct biological types of ocular adnexal sebaceous carcinoma: HPV-driven and virus-negative tumors arise through nonoverlapping molecular-genetic alterations

Purpose: Ocular adnexal (OA) sebaceous carcinoma is an tumors contained coexisting TP53 and RB1 mutations] with aggressive malignancy of the eyelid and ocular adnexa that frequent concomitant mutations affecting NOTCH genes. frequently recurs and metastasizes, and effective therapies These tumors arise in older patients and show frequent beyond surgical excision are lacking. There remains a critical local recurrence. The second subtype [9/29 (31%) patients] need to define the molecular-genetic drivers of the disease to lacks mutations affecting TP53, RB1, or NOTCH family understand carcinomagenesis and progression and to devise members, but in 44% (4/9) of these tumors, RNA sequenc-novel treatment strategies. ing and in situ hybridization studies confirm transcription-Experimental Design: We present next-generation sequencally active high-risk human papillomavirus. These tumors ing of a targeted panel of cancer-associated genes in 42 and arise in younger patients and have not shown local whole transcriptome RNA sequencing from eight OA seba-recurrence. ceous carcinomas from 29 patients. Conclusions: Together, our findings establish a potential Results: We delineate two potentially distinct molecular-molecular-genetic framework by which to understand the genetic subtypes of OA sebaceous carcinoma. The first is development and progression of OA sebaceous carcinoma defined by somatic mutations impacting TP53 and/or RB1 and provide key molecular-genetic insights to direct the design [20/29 (70%) patients, including 10 patients whose primary of novel therapeutic interventions.