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.
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
(A) Top panel: distribution of SSNVs in each tumor pair; synchronous nodal metastases on the left, metachronous recurrences on the right. Lower panel: panels describing presence of SSNVs in select cancer driver genes in each tumor pair. SSNVs were identified as unique to primary tumor (dark blue), shared between paired tumors (light blue), or unique to metastasis or recurrent tumor (gold). (B) Differences in subclonal architecture in the primary and synchronous nodal metastatic tumors from patient PY-16. 44% of SSNVs were private to the metastatic tumor (clusters 4 and 5) and 25% private to the primary tumor (cluster 1). (C) SSNVs in the samples from patient PY-8 are unique to the primary tumor (cluster 1) or the recurrent tumor (cluster 2); shared SSNVs (clusters 3 and 4) are germline. VAF, variant allele frequency.