NGS Analysis Confirms Common TP53 and RB1 Mutations, and Suggests MYC Amplification in Ocular Adnexal Sebaceous Carcinomas.

Cornelia Peterson,Robert Moore,Angelo M De Marzo,Ashley A Campbell,Charles G Eberhart,Jessica L Hicks,Laura A Morsberger,Ying Zou

doi:10.3390/ijms22168454

Abstract

Ocular adnexal (OA) sebaceous carcinomas generally demonstrate more aggressive clinical and histopathological phenotypes than extraocular cases, but the molecular drivers implicated in their oncogenesis remain poorly defined. A retrospective review of surgical and ocular pathology archives identified eleven primary resection specimens of OA sebaceous carcinomas with adequate tissue for molecular analysis; two extraocular cases were also examined. Next-generation sequencing was used to evaluate mutations and copy number changes in a large panel of cancer-associated genes. Fluorescence in situ hybridization (FISH) confirmed MYC copy number gain in select cases, and immunohistochemistry to evaluate MYC protein expression. The commonest mutations occurred in TP53 (10/13) and RB1 (7/13). Additional mutations in clinically actionable genes, or mutations with a frequency of at least 25%, included the NF1 (3/12), PMS2 (4/12), ROS1 (3/12), KMT2C (4/12), MNX1 (6/12), NOTCH1 (4/12), PCLO (3/12), and PTPRT (3/12) loci. Low level copy number gain suggestive of amplification of the MYC locus was seen in two cases, and confirmed using FISH. MYC protein expression, as assessed by immunohistochemistry, was present in almost all sebaceous carcinoma cases. Our findings support the concept that alterations in TP53 and RB1 are the commonest alterations in sebaceous carcinoma, and suggest that MYC may contribute to the oncogenesis of these tumors.

Highlights

40% of sebaceous carcinomas arise from the sebaceous glands of the periocular region, where they represent approximately 5% of all epithelial eyelid malignancies [1,2,3,4]
Eleven primary sebaceous carcinoma specimens from ocular adnexal (OA) sites with enough tissue for Next-generation sequencing (NGS) analysis were identified from retrospective review, along with 2 from extraocular sites
Staging was performed according to the American Joint Committee on Cancer (AJCC) TNM staging system for eyelid carcinoma, 8th edition guidelines

Summary

Introduction

40% of sebaceous carcinomas arise from the sebaceous glands of the periocular region, where they represent approximately 5% of all epithelial eyelid malignancies [1,2,3,4] These ocular adnexal (OA) sebaceous carcinomas can have variable presentations, including cases resembling benign inflammatory lesions, such as blepharoconjunctivitis or chalazion, or other types of malignancy, often leading to a delay in diagnosis and surgical intervention [3,5,6]. Sebaceous carcinomas in this region are relatively aggressive, and tumor recurrence has been demonstrated in 18% of cases, metastasis in 7–21%, and mortality in 6–20% [4,7,8]. Intraepithelial or pagetoid spread, in the conjunctiva, occurs in approximately 50% of OA sebaceous carcinomas, and is thought to contribute to a more aggressive phenotype than that seen in extraocular tumors [7]

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