title: 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  National Cancer Institute, American Cancer Society, Agency for Science, Technology and Research of Singapore, and Gilead Sciences Inc.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Hedberg
authors.forename: Gerald
authors.initials: G
authors.lastname: Goh
authors.forename: Simion I
authors.initials: SI
authors.lastname: Chiosea
authors.forename: Julie E
authors.initials: JE
authors.lastname: Bauman
authors.forename: Maria L
authors.initials: ML
authors.lastname: Freilino
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Brenda B
authors.initials: BB
authors.lastname: Diergaarde
authors.forename: William E
authors.initials: WE
authors.lastname: Gooding
authors.forename: Vivian W Y
authors.initials: VW
authors.lastname: Lui
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D000069439:Dasatinib / Q000627:therapeutic use; D000070818:Discoidin Domain Receptors; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D011975:Receptors, Mitogen / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: C506929:ITPR3 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D000069439:Dasatinib