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Abstract
Anal squamous cell carcinoma (ASCC) is a rare, potentially fatal malignancy primarily caused by high-risk human papillomaviruses (HPV). The prognostic implication of programmed death-ligand 1 (PD-L1) expression remains controversial, and glucose transporter 1 (GLUT1) expression has never been examined in ASCC. Covalently closed circular RNAs have recently been shown to be widespread in cancers and are proposed to be biomarkers. We discovered HPV16 expresses a circular E7 RNA (circE7) which has not been assessed as a potential biomarker. A retrospective, translational case series at UT Southwestern was conducted to analyze PD-L1, GLUT1, HPV-ISH, and HPV circE7 in relation to the clinical features and overall survival of patients with ASCC. Twenty-two (22) subjects were included in the study. Improved overall survival was predicted by basaloid histology ( p = 0.013), PD-L1 expression ( p = 0.08), and HPV-ISH positivity ( p & 0.001), but not GLUT1 expression. High levels of circE7 by quantitative RT-PCR predicted improved overall survival in ASCC ( p = 0.023) and analysis of The Cancer Genome Atlas sequencing from HPV-positive head and neck cancer and cervical cancer suggested high circE7 marked improved survival in 875 subjects ( p = 0.074). While our study suggests that circE7 levels correlate with improved survival in ASCC, larger, prospective studies are necessary to confirm the potential role of circE7 as a biomarker.
Highlights
Anal Squamous Cell Carcinoma (ASCC) has 30,000 new cases diagnosed annually worldwide and the incidence is rising by 2% each year [1]
Lower overall survival rate could be predicted by male sex (hazard ratio (HR): 4.04, 95% confidence interval (CI): 1.2-13.5, p = 0.034), higher T stage (HR: 4.09, CI: 1.3-12.7, p = 0.046), and higher N stage (HR: 9.31, CI: 2.8-30.4, p = 0.008)
Decreased overall survival could be predicted by greater smoking pack-years (HR: 5.88, CI: 1.8-19.3, p = 0.01) and greater size of tumor (>5 cm dimension) upon presentation (HR: 3.59, CI:1.1-11.5, p = 0.03) (Table 2)
Summary
Anal Squamous Cell Carcinoma (ASCC) has 30,000 new cases diagnosed annually worldwide and the incidence is rising by 2% each year [1]. A major risk factor is immunosuppression, which may be iatrogenic (transplant patients) or secondary to infection with the Human Immunodeficiency Virus (HIV) [2]. Other risk factors for ASCC include male-to-male sex, a high-life time number of sexual partners, and cigarette smoking [3]. Infection by high-risk human papillomavirus (HPV) is causative, and, in many cases, is linked to immunosuppression. The most effective treatment for advanced locoregional or metastatic ASCC is Mitomycin C and 5-Fluorouracil or Cisplatin with concurrent radiotherapy, known as the Nigro Protocol. Over 40 years, the standard Nigro Protocol has shown a 5-year survival of ~60% in metastatic cases of ASCC [1, 5]
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