title: The degree of intratumor mutational heterogeneity varies by primary tumor sub-site.
abstract: In an era where mutational profiles inform treatment options, it is critical to know the extent to which tumor biopsies represent the molecular profile of the primary and metastatic tumor. Head and neck squamous cell carcinoma (HNSCC) arise primarily in the mucosal lining of oral cavity and oropharynx. Despite aggressive therapy the 5-year survival rate is at 50%. The primary objective of this study is to characterize the degree of intratumor mutational heterogeneity in HNSCC. We used multi-region sequencing of paired primary and metastatic tumor DNA of 24 spatially distinct samples from seven patients with HNSCC of larynx, floor of the mouth (FOM) or oral tongue. Full length, in-depth sequencing of 202 genes implicated in cancer was carried out. Larynx and FOM tumors had more than 69.2% unique SNVs between the paired primary and metastatic lesions. In contrast, the oral tongue HNSCC had only 33.3% unique SNVs across multiple sites. In addition, HNSCC of the oral tongue had fewer mutations than larynx and FOM tumors. These findings were validated on the Affymetrix whole genome 6.0 array platform and were consistent with data from The Cancer Genome Atlas (TCGA). This is the first report demonstrating differences in mutational heterogeneity varying by subsite in HNSCC. The heterogeneity within laryngeal tumor specimens may lead to an underestimation of the genetic abnormalities within tumors and may foster resistance to standard treatment protocols. These findings are relevant to investigators and clinicians developing personalized cancer treatments based on identification of specific mutations in tumor biopsies.
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA.
authors.forename: Levi G
authors.initials: LG
authors.lastname: Ledgerwood
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Department of Systems Biology and Bioinformatics, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Agda Karina
authors.initials: AK
authors.lastname: Eterovic
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA.
authors.forename: Jo
authors.initials: J
authors.lastname: Wick
authors.affiliation: Department of Computational Biology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Computational Biology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Division of Biology, Kansas State University, Manhattan, KS, USA.
authors.forename: Loubna
authors.initials: L
authors.lastname: Tazi
authors.affiliation: Physicians Reference Laboratory, Kansas City, MO, USA.
authors.forename: Pradip
authors.initials: P
authors.lastname: Manna
authors.affiliation: Physicians Reference Laboratory, Kansas City, MO, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Kerley
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Joshi
authors.affiliation: Department of Pathology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Simion I
authors.initials: SI
authors.lastname: Chiosea
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA.
authors.forename: James David
authors.initials: JD
authors.lastname: Garnett
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA.
authors.forename: Terance Ted
authors.initials: TT
authors.lastname: Tsue
authors.affiliation: Department of Pathology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA.|Department of Cancer Biology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
authors.affiliation: Department of Systems Biology and Bioinformatics, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Jennifer Rubin
authors.initials: JR
authors.lastname: Grandis
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA.|Department of Cancer Biology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA.|Department of Anatomy and Cell Biology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA.
authors.forename: Sufi Mary
authors.initials: SM
authors.lastname: Thomas
mesh_terms: D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D005260:Female; D018740:Genetic Heterogeneity; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007822:Laryngeal Neoplasms / Q000235:genetics / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics / Q000473:pathology; D009154:Mutation; D014062:Tongue Neoplasms / Q000235:genetics / Q000473:pathology
keywords: HNSCC; HPV; deep sequencing; intratumor heterogeneity; mutation