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.

Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations

“…This observation from our two primary/recurrent tumour pairs (cases HKNPC001 and HKNPC012) seems to concur with our recent findings in primary/recurrent HNSCC. In paired primary/recurrent HNSCC samples, we also found that TP53 was the only shared annotated mutated cancer gene as defined by the Cancer Gene Census, COSMIC17. For these NPC patients, the recurrent or metastatic lesion appeared to show a single-nucleotide variant (SNV) clonality distribution different from that of the primary tumour, supportive of emerging new subclone(s) in recurrences.…”

The subclonal structure and genomic evolution of oral squamous cell carcinoma revealed by ultra-deep sequencing

“…In 3 of 5 cases, we did not observe new mutations in the metastasis which could indicate that no new mutations are needed for survival and colonization. The latter is supported by a recent HNSCC study of nodal metastasis that shows a low degree of metastasis specific mutations [11]. However, low tumor content in patient 2, 4 and 5′s lymph node metastases lowers the resolution and ability to identify unique metastasis specific mutations by whole-exome sequencing in these patients.…”

“…More than 90% of tumors are head and neck squamous cell carcinomas (HNSCC). Recent studies suggest that they are very heterogeneous between patients [1–11]. Oral squamous cell carcinoma (OSCC), a subgroup of HNSCC, is primarily attributed to alcohol consumption and tobacco use.…”

Targeting calcium signaling in cancer therapy

“…High expression of IP 3 R3 is associated with aggressiveness of colorectal carcinoma since it is related with decreased 5-year survival. A mutation in IP 3 R3 encoding gene ITPR3 was identified in genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma 27 . Similarly like IP 3 R1 and IP 3 R3, the dysregulation of IP 3 R2 was observed in chronic lymphocytic leukemia cells 28 .…”