Genomic Analyses Reveal Mutational Signatures and Frequently Altered Genes in Esophageal Squamous Cell Carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets.

Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing

“…Mutations have been observed in the cell-cycle regulatory pathway genes TP53 (88%), CDKN2A (8%), and RB1 (2%) [35] . In addition, ESCC tumors show amplification of CCND1, which encodes for cyclin D1, and deletion of CDKN2A/ B, which encodes for p16 and p14.…”

“…Agrawal and colleagues published the first exome-sequencing study of esophageal cancer, sequencing 12 ESCCs and 11 EACs as well as matched non-neoplastic tissues from subjects in the United States [31] , and a handful of NGS studies in ESCC have been published over the last four years (summarized in Table 2) [31][32][33][34][35] . Genetic aberrations identified within these studies, including gene mutation, gene rearrangement, and gene amplification/deletion, increased the understanding of constitutive activation of oncogenes, or loss of function of tumor suppressors.…”

“…The oncogenic activity of this pathway has been observed in a number of hematopoietic cancers [55] . When we characterized the distribution of NOTCH1 somatic mutations obtained from the two studies [32,35] , most NOTCH1 mutations observed in ESCC affect the epidermal growth factor (EGF)-like ligand-binding domain (56%, 30 of 54) and are thought to lead to a loss of function. Inactivating mutations in these regions of the gene have also been observed in cutaneous, lung, head, and neck squamous cell carcinomas [56][57][58] .…”

“…NOTCH1 is the second most commonly mutated gene in ESCC, with a mutation rate of 8%-33% [31][32][33][34][35] . The [31] 92 (M) [34] 83 (M) [33] 60 (M)…”

Clinical significance of ZNF750 gene expression, a novel tumor suppressor gene, in esophageal squamous cell carcinoma

“…Previously, it was suggested that ZNF750 function was associated with epithelial differentiation (5)(6)(7)10,11). These data suggested that a low expression of ZNF750 is associated with tumor aggressiveness in ESCC.…”