Intratumor heterogeneity inferred from targeted deep sequencing as a prognostic indicator

Bo Young Oh,Hyun-Tae Shin,Seong Hyeon Yun,Young-Hyuck Im,Joon Seol Bae,Jeeyun Lee,Yoon Ah Park,Je-Gun Joung,Kyu-Tae Kim,Jinho Kim,Yeon Hee Park,Woong-Yang Park,Woo Yong Lee,Jae Won Yun,Yong Beom Cho,Hee Cheol Kim

doi:10.1038/s41598-019-41098-0

Abstract

Tumor genetic heterogeneity may underlie poor clinical outcomes because diverse subclones could be comprised of metastatic and drug resistant cells. Targeted deep sequencing has been used widely as a diagnostic tool to identify actionable mutations in cancer patients. In this study, we evaluated the clinical utility of estimating tumor heterogeneity using targeted panel sequencing data. We investigated the prognostic impact of a tumor heterogeneity (TH) index on clinical outcomes, using mutational profiles from targeted deep sequencing data acquired from 1,352 patients across 8 cancer types. The TH index tended to be increased in high pathological stage disease in several cancer types, indicating clonal expansion of cancer cells as tumor progression proceeds. In colorectal cancer patients, TH index values also correlated significantly with clinical prognosis. Integration of the TH index with genomic and clinical features could improve the power of risk prediction for clinical outcomes. In conclusion, deep sequencing to determine the TH index could serve as a promising prognostic indicator in cancer patients.

Highlights

Tumor genetic heterogeneity may underlie poor clinical outcomes because diverse subclones could be comprised of metastatic and drug resistant cells
We examined whether the heterogeneity of this cohort of Colorectal cancer (CRC) patients was associated with clinical outcome
In this study, using a cancer panel designed to cover the genomic regions of frequently mutated loci, we demonstrated the clinical utility of measuring tumor heterogeneity (TH), for CRC

Summary

Introduction

Tumor genetic heterogeneity may underlie poor clinical outcomes because diverse subclones could be comprised of metastatic and drug resistant cells. We investigated the prognostic impact of a tumor heterogeneity (TH) index on clinical outcomes, using mutational profiles from targeted deep sequencing data acquired from 1,352 patients across 8 cancer types. With the recent advances in precision medicine using next-generation sequencing, characterization of ITH can allow for a better understanding of tumorigenesis and the development of personalized therapeutic strategies for cancer patients. Sequencing from bulk tissue yields only an average of the mixed subpopulations of cells[16] Despite this limitation, subclones can be identified by diverse computational approaches using WES of bulk tissue[17]

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Conclusion