Novel genomic alteration in superficial esophageal squamous cell neoplasms in non-smoker non-drinker females

Yusuke Onozato,Yoshiyuki Ueno,Yu Sasaki,Takayuki Sakai,Yasuhiko Abe,Naoko Mizumoto,Makoto Yagi,Matsuki Umehara,Ayumi Koseki,Hidenori Sato,Minami Ito,Takashi Kon

doi:10.1038/s41598-021-99790-z

Yusuke Onozato, Yoshiyuki Ueno + Show 10 more

Open Access

https://doi.org/10.1038/s41598-021-99790-z

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Abstract

Alcohol consumption and smoking pose a significant risk for esophageal squamous cell neoplasia (ESCN) development in males; however, ESCN is often diagnosed in non-drinking and non-smoking females. The mechanisms underlying these differences remain elusive, and understanding them can potentially identify novel pathways involved in ESCN development. We performed short-read sequencing to identify somatic variants on a cancer panel targeting 409 genes using DNA extracted from the superficial squamous cell carcinoma (ESCC) tissues and adjacent non-neoplastic epithelium (NE), and immunohistochemical staining of the protein encoded by the target gene. All male patients (n = 117) were drinkers or smokers, whereas 45% of the female patients (n = 33) were not. Somatic variants were compared among three age-matched groups: 13 female ESCC patients with smoking and drinking habits (known-risk group, F-KR), 13 female ESCC patients without these habits (unknown-risk group, F-UR), and 27 males with ESCC and smoking and drinking habits (M-KR). In the NE, the frequencies of CDKN2A variants were significantly higher in F-UR than in F-KR and M-KR. In both ESCC and NE, p14ARF was significantly overexpressed in F-UR than in the other groups. In conclusion, CDKN2A might be important in ESCC development, independent of known risk factors.

Highlights

Alcohol consumption and smoking pose a significant risk for esophageal squamous cell neoplasia (ESCN) development in males; ESCN is often diagnosed in non-drinking and non-smoking females
All male patients had a history of drinking or smoking, whereas 15 (45%) of the female patients had no history of Scientific Reports | (2021) 11:20150 |
We showed for the first time that in female patients with extracted from the superficial squamous cell carcinoma (ESCC) without drinking and smoking habits, which are considered risk factors for ESCC, there are distinctive genetic alterations in the esophageal epithelium, a high frequency of cyclin-dependent kinase inhibitor 2A (CDKN2A) gene variants in adjacent non-neoplastic epithelium and high p14 alter‐ nate reading frame (p14ARF) expression in neoplastic and adjacent non-neoplastic epithelium

Summary

Introduction

Alcohol consumption and smoking pose a significant risk for esophageal squamous cell neoplasia (ESCN) development in males; ESCN is often diagnosed in non-drinking and non-smoking females. The mechanisms underlying these differences remain elusive, and understanding them can potentially identify novel pathways involved in ESCN development. To clarify the molecular mechanisms underlying the development of ESCC in females without known risk factors such as alcohol consumption and smoking, we investigated the clinical characteristics and genomic alterations of the esophageal epithelium in patients with superficial ESCC with respect to risk factors

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