title: Tumor evolution and intratumor heterogeneity of an oropharyngeal squamous cell carcinoma revealed by whole-genome sequencing.
abstract: Head and neck squamous cell carcinoma (HNSCC) is characterized by significant genomic instability that could lead to clonal diversity. Intratumor clonal heterogeneity has been proposed as a major attribute underlying tumor evolution, progression, and resistance to chemotherapy and radiation. Understanding genetic heterogeneity could lead to treatments specific to resistant and metastatic tumor cells. To characterize the degree of intratumor genetic heterogeneity within a single tumor, we performed whole-genome sequencing on three separate regions of an human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma and two separate regions from one corresponding cervical lymph node metastasis. This approach achieved coverage of approximately 97.9% of the genome across all samples. In total, 5701 somatic point mutations (SPMs) and 4347 small somatic insertions and deletions (indels)were detected in at least one sample. Ninety-two percent of SPMs and 77% of indels were validated in a second set of samples adjacent to the discovery set. All five tumor samples shared 41% of SPMs, 57% of the 1805 genes with SPMs, and 34 of 55 cancer genes. The distribution of SPMs allowed phylogenetic reconstruction of this tumor's evolutionary pathway and showed that the metastatic samples arose as a late event. The degree of intratumor heterogeneity showed that a single biopsy may not represent the entire mutational landscape of HNSCC tumors. This approach may be used to further characterize intratumor heterogeneity in more patients, and their sample-to-sample variations could reveal the evolutionary process of cancer cells, facilitate our understanding of tumorigenesis, and enable the development of novel targeted therapies.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Xinyi Cindy
authors.initials: XC
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Seattle, WA ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Chang
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Seattle, WA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Mitchell
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Derek
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Wenhong
authors.initials: W
authors.lastname: Fan
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Seattle, WA.
authors.forename: Luisa Angelica
authors.initials: LA
authors.lastname: Lerma
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle, WA.
authors.forename: Melissa P
authors.initials: MP
authors.lastname: Upton
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Hay
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Seattle, WA ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA ; Surgery and Perioperative Care Service, VA Puget Sound Health Care System, Seattle, WA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Méndez
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA ; Department of Biostatistics, University of Washington School of Public Health, Seattle, WA.
authors.forename: Lue Ping
authors.initials: LP
authors.lastname: Zhao
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000556:secondary; D004252:DNA Mutational Analysis; D052138:Genes, Neoplasm; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation; D008207:Lymphatic Metastasis; D008297:Male; D058977:Molecular Sequence Annotation; D016366:Open Reading Frames; D009959:Oropharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology