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 5

HNSCC cells harboring an endogenous DDR2(D590G) mutation are sensitive to dasatinib.

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HNSCC cells harboring an endogenous DDR2(D590G) mutation are sensitive t...
6.5 × 103 BICR 18 (DDR2 mutant), PE/CA-PJ34, and UPCI 15B (both DDR2 WT) cells were plated in triplicate in a 48-well plate, treated with half-log doses of dasatinib from 10 nM to 30 μM for 48 hours, and assessed by MTT. Pooled data from 3 replicate experiments are shown (A) and demonstrate exquisite sensitivity to dasatinib in the case of BICR 18. PE/CA-PJ34 and UPCI 15B cells are 1 and 2 orders of magnitude less sensitive, respectively, to treatment with dasatinib. 2.0 × 104 BICR 18 cells were placed in migration (uncoated) chambers or invasion (Matrigel coated) chambers and treated in duplicate with DMSO or in triplicate with the indicated doses of dasatinib for 24 hours. Cells were counted and averaged from 4 photomicrographs (×20) of each membrane, and the invasion/migration ratios were calculated. Pooled data from 3 replicate experiments are shown (B) along with representative images of the membranes (C). The invasion of BICR 18 cells in Matrigel invasion assays is inhibited by dasatinib in a dose-dependent manner. Growth curves and statistics (extra sum of the squares F test and unpaired, 2-tailed t test with Welch’s correction) are described in Methods.