Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas

Abstract

BackgroundAlthough the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality.Methods and FindingsClinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity’s associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed.ConclusionsTo our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types.

Genomic heterogeneity meets cellular energetics: crosstalk between the mitochondria and the cell cycle

“…Sequencing of different regions within a tumor reveals equally staggering intra-tumor genomic heterogeneity [13][14][15][16][17] , which is dynamic over time [18][19][20][21][22] . Taken together, these results are consistent with models of rapid genomic evolution within tumors and intra-tumoral genomic heterogeneity increasing over time, correlating with tumor aggressiveness and decreased patient survival [23,24] . Genomic instability can be initiated by exogenous or endogenous agents.…”

The Role of Aneuploidy in Cancer Evolution

“…For similar reasons, known oncogenes might be potent CIN drivers because they moderately affect the expression and function of genes involved in genome maintenance. Nevertheless, CIN enables the exploration of a phenotypic landscape in a way that cannot be achieved with an increased mutation rate alone (Mroz et al 2015). A deep understanding of the underlying causes of CIN and the context enabling its propagation is still lacking and needs thorough longitudinal studies to fully understand its importance.…”

Positive expression of NANOG, mutant P53, and CD44 is directly associated with clinicopathological features and poor prognosis of oral squamous cell carcinoma

“…Heterogeneity denotes that tumors are composed of multiple clonal subpopulations of different characteristic cells, and thus, histological examination frequently reveals differences in cell morphology and properties, among cells in the same cancer specimen [20]. Enhanced intra-tumor heterogeneity was directly correlated with increased mortality; in particular, high heterogeneity and p53 mutation positivity were associated with higher mortality rates in a large cohort study of head and neck cancer [19]. In the present study, serial sections of tumor specimens frequently revealed the coexpression of NANOG, mutant p53, and CD44, which was associated with poorer prognosis.…”