MATH, a novel measure of intratumor genetic heterogeneity, is high in poor-outcome classes of head and neck squamous cell carcinoma

Oral Oncol. 2013 Mar;49(3):211-5. doi: 10.1016/j.oraloncology.2012.09.007. Epub 2012 Oct 15.


Objectives: Differences among cancer cells within a tumor are important in tumorigenesis and treatment resistance, yet no measure of intratumor heterogeneity is suitable for routine application. We developed a quantitative measure of intratumor genetic heterogeneity, based on differences among mutated loci in the mutant-allele fractions determined by next-generation sequencing (NGS) of tumor DNA. We then evaluated the application of this measure to head and neck squamous cell carcinoma (HNSCC).

Materials and methods: We analyzed published electronically available NGS results for 74 HNSCC. For each tumor we calculated mutant-allele tumor heterogeneity (MATH) as the ratio of the width to the center of its distribution of mutant-allele fractions among tumor-specific mutated loci.

Results: Intratumor heterogeneity assessed by MATH was higher in three poor-outcome classes of HNSCC: tumors with disruptive mutations in the TP53 gene (versus wild-type TP53 or non-disruptive mutations), tumors negative versus positive for human papillomavirus (even when restricted to tumors having wild-type TP53), and HPV-negative tumors from smokers with more pack-years of cigarette exposure (with TP53 status taken into account).

Conclusion: The relation of this type of intratumor heterogeneity to HNSCC outcome classes supports its further evaluation as a prognostic biomarker. As NGS of tumor DNA becomes widespread in clinical research and practice, MATH should provide a simple, quantitative, and clinically practical biomarker to help evaluate relations of intratumor genetic heterogeneity to outcome in any type of cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Alphapapillomavirus / isolation & purification
  • Biomarkers, Tumor / genetics
  • Carcinoma, Squamous Cell / genetics*
  • Chromosome Mapping
  • DNA Copy Number Variations / genetics
  • DNA, Neoplasm / genetics*
  • Exome / genetics
  • Genes, p53 / genetics
  • Genetic Heterogeneity*
  • Head and Neck Neoplasms / genetics*
  • Humans
  • Mutagens / adverse effects
  • Mutation / genetics*
  • RNA Splice Sites / genetics
  • Sequence Analysis, DNA / methods
  • Smoking / genetics
  • Treatment Outcome


  • Biomarkers, Tumor
  • DNA, Neoplasm
  • Mutagens
  • RNA Splice Sites