Distribution-based measures of tumor heterogeneity are sensitive to mutation calling and lack strong clinical predictive power

Javad Noorbakhsh, Hyunsoo Kim, Sandeep Namburi, Jeffrey H. Chuang

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Mutant allele frequency distributions in cancer samples have been used to estimate intratumoral heterogeneity and its implications for patient survival. However, mutation calls are sensitive to the calling algorithm. It remains unknown whether the relationship of heterogeneity and clinical outcome is robust to these variations. To resolve this question, we studied the robustness of allele frequency distributions to the mutation callers MuTect, SomaticSniper, and VarScan in 4722 cancer samples from The Cancer Genome Atlas. We observed discrepancies among the results, particularly a pronounced difference between allele frequency distributions called by VarScan and SomaticSniper. Survival analysis showed little robust predictive power for heterogeneity as measured by Mutant-Allele Tumor Heterogeneity (MATH) score, with the exception of uterine corpus endometrial carcinoma. However, we found that variations in mutant allele frequencies were mediated by variations in copy number. Our results indicate that the clinical predictions associated with MATH score are primarily caused by copy number aberrations that alter mutant allele frequencies. Finally, we present a mathematical model of linear tumor evolution demonstrating why MATH score is insufficient for distinguishing different scenarios of tumor growth. Our findings elucidate the importance of allele frequency distributions as a measure for tumor heterogeneity and their prognostic role.

Original languageEnglish (US)
Article number11445
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

Bibliographical note

Funding Information:
JN would like to thank Joshy George, Francesca Menghi, and Ziming Zhao for helpful comments, Luc Morris for useful discussion and sharing of his previous results, Anna Lisa Lucido for manuscript edits, and Jane Cha for graphics design. JN and SN would like to thank Gaurav Kaushik for instructions on the Cancer Genome Cloud platform. JHC was supported by the National Cancer Institute of the National Institutes of Health under awards [R21CA191848], [R01 CA230031-01] and supplement [R21CA191848-01A1S1]. Research was also partially supported by the National Cancer Institute under award [P30CA034196].

Publisher Copyright:
© 2018, The Author(s).

Fingerprint

Dive into the research topics of 'Distribution-based measures of tumor heterogeneity are sensitive to mutation calling and lack strong clinical predictive power'. Together they form a unique fingerprint.

Cite this