Oral Squamous Cell Carcinoma in Young Patients Show Higher Rates of EGFR Amplification: Implications for Novel Personalized Therapy

Abstract

There is an increasing worldwide incidence of patients under 50 years of age presenting with oral squamous cell carcinoma (OSCC). The molecular mechanisms driving disease in this emerging cohort remain unclear, limiting impactful treatment options for these patients. To identify common clinically actionable targets in this cohort, we used whole genome and transcriptomic sequencing of OSCC patient samples from 26 individuals under 50 years of age. These molecular profiles were compared with those of OSCC patients over 50 years of age (n=11) available from TCGA. We show for the first time that a molecular signature comprising of EGFR amplification and increased EGFR RNA abundance is specific to the young subset of OSCC patients. Furthermore, through functional assays using patient tumor-derived cell lines, we reveal that this EGFR amplification results in increased activity of the EGFR pathway. Using a panel of clinically relevant EGFR inhibitors we determine that an EGFR-amplified patient-derived cell line is responsive to EGFR inhibition, suggesting EGFR amplification represents a valid therapeutic target in this subset of OSCC patients. In particular, we demonstrate sensitivity to the second-generation EGFR tyrosine kinase inhibitor afatinib, which offers a new and promising therapeutic avenue versus current EGFR-targeting approaches. We propose that testing for EGFR amplification could easily be integrated into current diagnostic workflows and such measures could lead to more personalized treatment approaches and improved outcomes for this younger cohort of OSCC patients.

Viral Integration Plays a Minor Role in the Development and Prognostication of Oral Squamous Cell Carcinoma

“…While the incidence of OSCC is rising in patients younger than 50 years, this is a relatively recent trend [ 14 ]. Of note, The Cancer Genome Atlas (TCGA) in its multi-institutional efforts includes only 10 patients younger of 50 years of age [ 65 ]. Additionally, WGS needs high quality tumour DNA requiring access to a functional biobank with streamlined protocols for collection of tissues immediately after resection.…”

Age-Related Cancer-Associated Microbiota Potentially Promotes Oral Squamous Cell Cancer Tumorigenesis by Distinct Mechanisms

“…Studies have shown that classic carcinogens, such as smoking, drinking and HPV infection, are not the main reasons for the rise in incidence as young subjects have short period of time to be exposed to those carcinogens (Sarode et al, 2021). The genomic studies showed that mutations in young and elderly OSCC patients were similar, which were mainly in the genes such as TP53, CDKN2A, NOTCH1, CASP8, FAT1, PIK3CA, and MLL2 (Kandoth et al, 2013;Pickering et al, 2014), but study also reported OSCC patients with younger age appeared to have an attenuated immune response due to lower load of mutations (Maroun et al, 2021), and EGFR was reported to have higher rate of amplification in young patients (Satgunaseelan et al, 2021). However, the mechanism underlying young OSCC incidence elevating cannot be merely explained by genomic alteration.…”