Amplification of EGFR mutations, vIII and vIVa, in two patients with Esophageal Squamous Cell Carcinoma, with similarities to Glioblastoma Multiforme, hints at common binding targets.

Esophageal cancer has a strikingly low survival rate, mainly due to the lack of diagnostic markers for early detection and effective therapies. In the U.S., 75% of individuals diagnosed with esophageal squamous cell carcinoma (ESCC) are African Americans (A.A.). AA ESCC is particularly aggressive, and its biological underpinnings remain poorly understood. Recently, whole-genome sequencing was carried out in matched tumor and normal tissues from 10 A.A. patients to identify tumor-specific genomic abnormalities\cite{Erkizan2021}. Two interesting mutations were identified in the EGFR gene that is typically found in the Ectodomains of the EGFR gene for Glioblastoma Multiforme (GBM), EGFRvIII, and EGFRvIVa. These findings represent a rare, novel, and clinically significant finding in patients with ESCC. Esophageal cancer is recognized to have significant differences in incidence based on geographical location, race, ethnicity, and gender. In the United States, the incidence rate of esophageal cancer is over two times higher in African Americans compared to whites. In comparison, whites have a higher incidence rate than Hispanics, Asian Americans, and Native Americans\cite{Brown2000}. EGFR plays an essential role in the nervous system in various ways, including 1) Maintenance of the neural stem cells pool, 2) Maturation and functions of astrocytes, 3) Oligodendrogenesis, and 4) neurite outgrowth in the CNS. They also play a role in PNS development\cite{Romano2020}. As a result, alterations in EGFR, like GBM, possibly have their causes rooted in the appropriate mutations. In lung cancers, the ramifications of mutations in kinase domains get expressed differently to their interactions and cross-talk with other signaling components in the milieu. For example, there is a substantial cross-talk and interplay between other tyrosine kinase mediators like Vascular Endothelial Growth Factor (VEGF) and Interferon-Gamma(IFNg)\cite{Attili2018}\cite{Passaro2020}. Further, the mutational burden conferred by EGFR is generally considered lower compared to the rest \cite{Spigel_2016}. Compared to the EGFR gene, the EGFRvIII variant has missing L1 and CR1 domains due to the deletion of exons 2-7. This truncation results in the inability of the receptor to bind to any ligand, thus becoming an important driver in tumor progression and a marker of poor prognosis\cite{Gan2013}. There are two variations of EGFR vIV, namely EGFR-vIVa and EGFR-vIVb, which contain deletions of exons 25-27 and 25-26, respectively \cite{Pines2010}. The EGFR receptor protein has different domains with different key signaling roles \cite{Ferguson2008}. As a result, mutations in the gene expressing them also manifest uniquely in different cancers. For example, mutations in the tyrosine kinase domain are unique to lung cancers \cite{Purba2017}\cite{Lee2010} while brain tumors show mutations in the autoregulatory domains and the ectodomains of the same gene \cite{Wong1987}\cite{Binder2018}.