Whole-exome sequencing reveals novel mutations and epigenetic regulation in hypopharyngeal carcinoma

Abstract

Hypopharyngeal cancer (HPC) frequently presents at an advanced stage, resulting in poor prognosis. Although combined surgical therapy and chemoradiotherapy have improved the survival for patients with HPC over the past 3 decades, the mortality rate in late-stage diagnosis of HPC is unsatisfactory. In this study, we performed whole-exome sequencing (WES) of 23 hypopharyngeal tumor and paired adjacent normal tissue to identify novel candidate driver genes associated with hypopharyngeal carcinoma. We identified several copy number variants (CNVs) and 15 somatic mutation genes that were associated with hypopharyngeal carcinoma. Mutations in nine new genes (PRB4, NSD1, REC8, ZNF772, ZNF69, EI24, CYFIP2, NEFH, KRTAP4-5) were also indentified. PRB4 and NSD1 expression were significantly upregulated in hypopharyngeal carcinoma, which was confirmed in an independent cohort using IHC. There was a positive relationship between PRB4 and NSD1. Downregulation of PRB4 by siRNA could inhibit cell growth, colony formation and cell invasion. Notably, we here demonstrate that NSD1 could bind to the promoter regions of PRB4 and activate promoter activity by reducing the binding of H3K27me2 and increasing the binding of H3K36me2 on PRB4 promoter. In summary, we pinpoint the predominant mutations in hypopharyngeal carcinoma by WES, highlighting the substantial genetic alterations contributing to hypopharyngeal carcinoma tumorigenesis. We also indentify a novel epigenetically regulatory between PRB4 and NSD1 that contribute to hypopharyngeal carcinoma tumorigenesis. They may become potential prognostic biomarkers and therapeutic target for hypopharyngeal carcinoma treatment.

The ectopic expression of meiCT genes promotes meiomitosis and may facilitate carcinogenesis

“…To further support the tumor suppressor role of this gene, induced overexpression of REC8 in gastric cancer inhibited proliferation, invasion and migration of gastric cancer cells, while the knockdown of REC8 reversed these effects in vitro [147]. Not surprisingly, studies revealed that REC8 is epigenetically downregulated in gastric cancer [148], thyroid cancer [149] and gastrointestinal stromal tumors [150] and mutated in hypopharyngeal [151], and ovarian carcinomas [152].…”

<p>Prognostic Significance of PD-L1 Expression and Its Tumor-Intrinsic Functions in Hypopharyngeal Squamous Cell Carcinoma</p>

“…3 One important reason is that after the treatments up to 30% of patients with HSCC die within a year as a result of distant metastasis, which makes it a particularly devastating disease. 4 Although there have been some studies on the pathogenesis of HSCC, [5][6][7] investigations of new potential mechanisms related to the development and progression of HSCC are still urgent.…”

Overlapping variants in the blood, tissues and cell lines for patients with intracranial meningiomas are predominant in stem cell-related genes

“…Most variants were detected in chromosomes 1, 17 and 19, which are consistent with regional changes detected previously in meningiomas [ 11 , 31 ]. Similar to other tumours, the most common variants here were missense mutations, with a C > T transversion in the exomic regions [ 32 , 33 , 34 ]. Tri-homozygosity among variants detected in the BTCs were very rare, and only 16 variants showed a heterozygous pattern in the blood, along with a homozygous change in the tumour or cell line.…”