Oncotarget

Research Papers:

The degree of intratumor mutational heterogeneity varies by primary tumor sub-site

Levi G. Ledgerwood, Dhruv Kumar, Agda Karina Eterovic, Jo Wick, Ken Chen, Hao Zhao, Loubna Tazi, Pradip Manna, Spencer Kerley, Radhika Joshi, Lin Wang, Simion I. Chiosea, James David Garnett, Terance Ted Tsue, Jeremy Chien, Gordon B. Mills, Jennifer Rubin Grandis and Sufi Mary Thomas _

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Oncotarget. 2016; 7:27185-27198. https://doi.org/10.18632/oncotarget.8448

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Abstract

Levi G. Ledgerwood1,*, Dhruv Kumar1,*, Agda Karina Eterovic2, Jo Wick3, Ken Chen4, Hao Zhao4, Loubna Tazi5, Pradip Manna6, Spencer Kerley6, Radhika Joshi1, Lin Wang7, Simion I. Chiosea7, James David Garnett1, Terance Ted Tsue1, Jeremy Chien8,9, Gordon B. Mills2, Jennifer Rubin Grandis10,11 and Sufi Mary Thomas1,9,12

1 Department of Otolaryngology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA

2 Department of Systems Biology and Bioinformatics, MD Anderson Cancer Center, Houston, TX, USA

3 Department of Biostatistics, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA

4 Department of Computational Biology, MD Anderson Cancer Center, Houston, TX, USA

5 Division of Biology, Kansas State University, Manhattan, KS, USA

6 Physicians Reference Laboratory, Kansas City, MO, USA

7 Department of Pathology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

8 Department of Pathology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA

9 Department of Cancer Biology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA

10 Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

11 Department of Pharmacology and Chemical Biology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

12 Department of Anatomy and Cell Biology, University of Kansas Medical Center, and University of Kansas Cancer Center, Kansas City, MO, USA

* These authors have contributed equally to this work

Correspondence to:

Sufi Mary Thomas, email:

Keywords: HNSCC, HPV, intratumor heterogeneity, mutation, deep sequencing

Received: March 03, 2016 Accepted: March 23, 2016 Published: March 28, 2016

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.


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