Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma
Matthew L. Hedberg, … , Richard P. Lifton, Jennifer R. Grandis
Matthew L. Hedberg, … , Richard P. Lifton, Jennifer R. Grandis
Published November 30, 2015
Citation Information: J Clin Invest. 2016;126(1):169-180. https://doi.org/10.1172/JCI82066.
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Clinical Research and Public Health Genetics Oncology

Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma

Abstract

BACKGROUND. Recurrence and/or metastasis occurs in more than half of patients with head and neck squamous cell carcinoma (HNSCC), and these events pose the greatest threats to long-term survival. We set out to identify genetic alterations that underlie recurrent/metastatic HNSCC.

METHODS. Whole-exome sequencing (WES) was performed on genomic DNA extracted from fresh-frozen whole blood and patient-matched tumor pairs from 13 HNSCC patients with synchronous lymph node metastases and 10 patients with metachronous recurrent tumors. Mutational concordance within and between tumor pairs was used to analyze the spatiotemporal evolution of HNSCC in individual patients and to identify potential therapeutic targets for functional evaluation.

RESULTS. Approximately 86% and 60% of single somatic nucleotide variants (SSNVs) identified in synchronous nodal metastases and metachronous recurrent tumors, respectively, were transmitted from the primary index tumor. Genes that were mutated in more than one metastatic or recurrent tumor, but not in the respective primary tumors, include C17orf104, inositol 1,4,5-trisphosphate receptor, type 3 (ITPR3), and discoidin domain receptor tyrosine kinase 2 (DDR2). Select DDR2 mutations have been shown to confer enhanced sensitivity to SRC-family kinase (SFK) inhibitors in other malignancies. Similarly, HNSCC cell lines harboring endogenous and engineered DDR2 mutations were more sensitive to the SFK inhibitor dasatinib than those with WT DDR2.

CONCLUSION. In this WES study of patient-matched tumor pairs in HNSCC, we found synchronous lymph node metastases to be genetically more similar to their paired index primary tumors than metachronous recurrent tumors. This study outlines a compendium of somatic mutations in primary, metastatic, and/or recurrent HNSCC cancers, with potential implications for precision medicine approaches.

FUNDING. National Cancer Institute, American Cancer Society, Agency for Science, Technology and Research of Singapore, and Gilead Sciences Inc.

Authors

Matthew L. Hedberg, Gerald Goh, Simion I. Chiosea, Julie E. Bauman, Maria L. Freilino, Yan Zeng, Lin Wang, Brenda B. Diergaarde, William E. Gooding, Vivian W.Y. Lui, Roy S. Herbst, Richard P. Lifton, Jennifer R. Grandis

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Figure 4

Spatial and temporal evolution of disease in patients harboring newly arisen DDR2 mutations in their recurrent tumors.

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Spatial and temporal evolution of disease in patients harboring newly ar...
The clinical histories of patient PY-3 (A) and patient PY-8 (B) are shown. Index primary and metachronous recurrent tumors assessed via WES are outlined and presented with CT imaging of the respective tumors. Treatments between cancer events are illustrated on the time line, and the time to recurrence between sequenced tumors is indicated in months. Below each time line is the mutational burden of each sequenced tumor for PY-3 and PY-8, respectively. SSNVs are defined as germline/unknown (black), unique to index primary tumor (dark blue), shared between paired tumors (light blue), or unique to metachronous recurrent tumor (gold). XRT, radiation therapy; chemo, chemotherapy.