Translational Cancer Mechanisms and Therapy Distinct Biological Types of Ocular Adnexal Sebaceous Carcinoma: HPV-Driven and Virus- Negative Tumors Arise through Nonoverlapping Molecular-Genetic Alterations Michael T. Tetzlaff 1,2 , Jonathan L. Curry 1,3 , Jing Ning 4 , Oded Sagiv 5 , Thomas L. Kandl 5 , Bo Peng 4 , Diana Bell 1 , Mark Routbort 6 , Courtney W. Hudgens 2 , Doina Ivan 1,3 , Tae-Boom Kim 4 , Ken Chen 4 , Agda Karina Eterovic 7,8 , Kenna Shaw 7 , Victor G. Prieto 1,3 , Anna Yemelyanova 1 , and Bita Esmaeli 5 Abstract Purpose: 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. Experimental Design: We present next-generation sequenc- ing of a targeted panel of cancer-associated genes in 42 and whole transcriptome RNA sequencing from eight OA seba- ceous carcinomas from 29 patients. Results: 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 sequenc- ing and in situ hybridization studies confirm transcription- ally active high-risk human papillomavirus. These tumors arise in younger patients and have not shown local recurrence. Conclusions: 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. Introduction Ocular adnexal (OA) sebaceous carcinoma is an aggressive cancer that accounts for 5% of malignant epithelial eyelid tumors (1–5). Surgical excision remains the principal treat- ment modality. However, OA sebaceous carcinoma has a high propensity for multifocal intraepithelial and locally infiltra- tive growth that each contribute to frequent local recurrence. Given the tumor's delicate anatomic location on the surface of the eye or eyelid, these characteristics make this a chal- lenging tumor to treat (1, 6, 7). Aggressive surgery is often required but may produce appreciable functional and aes- thetic morbidity, and orbital exenteration is necessary to achieve local control of disease in 13% to 23% of patients (5, 7, 8). Further, regional nodal or distant metastasis occurs in 8% to 22% of patients, and up to 22% of patients diagnosed with OA sebaceous carcinoma die of the disease (7–9). Nevertheless, systemic therapies for OA sebaceous car- cinoma remain largely ineffective (10). Collectively, 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 1 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 2 Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 3 Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 4 Department of Bioinformatics and Computational Biology, The Univer- sity of Texas MD Anderson Cancer Center, Houston, Texas. 5 Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. 6 Department of Hema- topathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 7 Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. 8 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Authors: Michael T. Tetzlaff, University of Texas MD Anderson Cancer Center, Department of Pathology and Translational and Molecular Pathology, 1515 Holcombe Blvd, Unit 0085, Houston, TX 77030. Phone: 7137922585; Fax: 7137450778; E-mail: mtetzlaff@mdanderson.org; and Bita Esmaeli, MD, FACS Orbital Oncology and Ophthalmic Plastic Surgery, Depart- ment of Plastic Surgery, The University of Texas MD Anderson Cancer Center 1515 Holcombe Blvd, Unit 1488, Houston, Texas 77030. Phone: 713-792-4457; Fax: 713-794-4662; E-mail: besmaeli@mdanderson.org doi: 10.1158/1078-0432.CCR-18-1688 Ó2018 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 25(4) February 15, 2019 1280 on July 4, 2020. © 2019 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst November 12, 2018; DOI: 10.1158/1078-0432.CCR-18-1688