Intratumoral heterogeneity in recurrent metastatic squamous cell carcinoma of the oral cavity: New perspectives afforded by multiregion DNA sequencing and mtDNA analysis

Publication date: Available online 20 September 2018

Source: Journal of Oral and Maxillofacial Surgery

Author(s): Andrea Gabusi, Davide Bartolomeo Gissi, Achille Tarsitano, Sofia Asioli, Claudio Marchetti, Lucio Montebugnoli, Maria Pia Foschini, Luca Morandi

Abstract

Purpose

Improvements in sequencing technologies have revealed that genetic differences among neoplastic cells may reflect clonal expansion. Intratumor heterogeneity (ITH) has been suggested to explain differences in prognosis and treatment response, indicating that personalized medicine is the goal of the future. Here, we evaluated ITH in five patients with recurrent metastatic oral squamous cell carcinoma (OSCC) and tracked the evolution from non-neoplastic tissue to neoplastic events developing after primary tumor formation.

Patients and Methods

Representative regions were macrodissected from specimens obtained from patients with OSCC of the tongue (n=4) and mouth floor (n=1). ITH and tumor evolution were explored by analyzing DNA mutations revealed by next-generation sequencing of specific driver genes combined with changes in the mtDNA D-loop hypervariable region. Phylogenetic trees were generated employing MAFFT tool with UPGMA/Jukes-Cantor serving as the substitute model.

Results

High levels of heterogeneity were observed within and among tumors. ITH emerged as metastatic/recurrent events progressed, but the evolutionary patterns differed. In some patients, specific subclones persisted during tumor relapse. Neighboring tissue was also heterogeneous at the pre-malignant level.

Conclusions

A multiregion approach yielded more representative data than did single samples when tumors were subjected to molecular investigation. Persistent mutations that might be targeted by individualized medicine were thus unveiled. mtDNA is a useful adjunct tool when studying the phylogenetic evolution of subclones. The clinical implications of "field" heterogeneity should be studied in depth.

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