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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, with nearly 600,000 new cases diagnosed annually [1]
While the development of cancer is presumed to be due to clonal expansion of tumor cells [7], studies suggest that continued acquisition of mutations in the clones, leads to a heterogeneous population of cells within the tumor resulting in the development of selective resistances to therapies through Darwinian selection [811]
Patient 2 with a recurrent oral tongue tumor was previously treated with cisplatin and radiation therapy
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, with nearly 600,000 new cases diagnosed annually [1]. Despite a vast array of research on HNSCC and development of new and less toxic treatment regimens, the survival rates of HNSCC have not dramatically changed over the last 50 years, with overall survival of approximately 50% [2] This somewhat guarded outcome is, in part due to the development of chemotherapy and radiation resistance following an initial response, leading to locoregional and distant failures. Widespread intratumor heterogeneity was reported in specimens from different regions of the primary tumor and corresponding metastatic lymph nodes from a single patient with HNSCC [3]. They reconstructed an evolution of these changes throughout the tumor clones evaluated, showing that the development of genetic alterations that were present in metastatic samples arose as late events. Intratumor heterogeneity appears to be an important factor in both treatment and prognosis for HNSCC
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