TY - JOUR
T1 - Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma
AU - Hedberg, Matthew L.
AU - Goh, Gerald
AU - Chiosea, Simion I.
AU - Bauman, Julie E.
AU - Freilino, Maria L.
AU - Zeng, Yan
AU - Wang, Lin
AU - Diergaarde, Brenda B.
AU - Gooding, William E.
AU - Lui, Vivian W.Y.
AU - Herbst, Roy S.
AU - Lifton, Richard P.
AU - Grandis, Jennifer R.
N1 - Funding Information: We would like to thank Theresa Whiteside for graciously providing the UPCI 15B cell line and Peter Hammerman for graciously providing the DDR2 retroviral expression construct. This work was supported by grants from the NCI (1F30CA180235-01A1 to M.L. Hedberg, and P50CA097190 to J.R. Grandis), the Agency for Science, Technology and Research of Singapore (fellowship to G. Goh), the American Cancer Society (CRP-08-229-01 to J.R. Grandis), and Gilead Sciences Inc. (research support to R.P. Lifton and R.S. Herbst).
PY - 2016/1/4
Y1 - 2016/1/4
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI82066
DO - 10.1172/JCI82066
M3 - Article
C2 - 26619122
SN - 0021-9738
VL - 126
SP - 169
EP - 180
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -