The EGFR receptor protein has different domains that have different key roles in the signaling \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}.
In the nervous system, EGFR plays an important role in a variety of ways including the 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 in different ways to their interactions and cross-talk with other signaling components in the milieu. For example, there is a strong 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 the rest\cite{Spigel_2016}.
It can be thus seen that the predominance of domain-specific mutations of the same gene in different cancers is mainly a manifestation of the functions driven by those domains, the upstream and downstream signaling processes, and ligand interactions that are intertwined with such domains. When a similar pattern of mutations get reflected in another form of cancers like ESCC but not in other forms of cancers e.g. lung cancers, there is a possibility of similar interacting ligands or signaling interactions in EGRF.
There have been very few studies on presence and distribution of EGRF mutations and their relevance in the process of oncogenesis in ESCC. Either their presence is rare and insignificant \cite{Guo2016} OR their significance has been less studied. Either way, their copy number is directly related to poor prognosis\cite{Barsouk2019} and changes associated with them including copy number OR mutations is one of the changes associated with the development of ESCC\cite{Mandard2000}. Keeping these in the backdrop, we propose that the interacting partners that are unique to the mutation-specific domains of the EGFR gene in Glioblastoma possibly match up in functional aspects with those involved in Esophageal Squamous Cell Carcinoma. Given the predominance of ESCCs in the AA population it would be also interesting to study if the same population matches up in mortality rates in GBM, for the same EGFR mutation, as well.
Further investigations in a larger cohort of patient samples is required to validate the role of these mutations in ESCC tumorigenesis as well as their role AA population, given their increased predisposition and mortality rates. The identification of these EGFR mutations also opens the potential for targeted therapy in patients with ESCC harboring these rare mutations.
Given that the EGFRvIII mutation lacks the L1 and CR1 domains, which are critical for ligand binding, it becomes a key driver in tumor progression and is linked to poor prognosis. Therefore, exploring potential shared targets between GBM and ESCC with this mutation profile could lead to the development of effective therapies. Cetuximab, a monoclonal antibody targeting the extracellular domain of EGFR, has shown promising results in GBM and could potentially be used as an off-label treatment for ESCC with EGFRvIII amplification. Alternatively, the development of novel therapies that target EGFRvIII or its downstream signaling pathways could be considered for ESCC patients with this mutation profile. Further research and clinical trials are needed to validate these approaches, but they hold promise for improving outcomes for patients with ESCC and EGFRvIII amplification.