Abstract
Intratumor heterogeneity (ITH) is a biomarker of tumor progression, metastasis, and immune evasion. Previous studies evaluated ITH mostly based on DNA alterations. Here, we developed a new algorithm (DEPTH) for quantifying ITH based on mRNA alterations in the tumor. DEPTH scores displayed significant correlations with ITH-associated features (genomic instability, tumor advancement, unfavorable prognosis, immunosuppression, and drug response). Compared to DNA-based ITH scores (EXPANDS, PhyloWGS, MATH, and ABSOLUTE), DEPTH scores had stronger correlations with antitumor immune signatures, cell proliferation, stemness, tumor advancement, survival prognosis, and drug response. Compared to two other mRNA-based ITH scores (tITH and sITH), DEPTH scores showed stronger and more consistent associations with genomic instability, unfavorable tumor phenotypes and clinical features, and drug response. We further validated the reliability and robustness of DEPTH in 50 other datasets. In conclusion, DEPTH may provide new insights into tumor biology and potential clinical implications for cancer prognosis and treatment.
Highlights
Intratumor heterogeneity (ITH) is a biomarker of tumor progression, metastasis, and immune evasion
We found that the developed a new algorithm (DEPTH) scores had a strong positive correlation with the numbers of different cancer types the cell lines originate from in the simulated tumor samples (ρ = 0.999, 0.999, 1, 1, 0.999, 0.999, 1, 1, 0.999, and 1 for m = 62, 49, 46, 42, 35, 32, 31, 30, 29, and 27, respectively) (Fig. 1b)
We explored the correlation between ITH scores defined by seven different methods (DEPTH, tITH24, sITH26, PhyloWGS6, EXPANDS4,5, ABSOLUTE2, and MATH3) in The Cancer Genome Atlas (TCGA) pan-cancer and individual cancer types
Summary
Intratumor heterogeneity (ITH) is a biomarker of tumor progression, metastasis, and immune evasion. Compared to DNA-based ITH scores (EXPANDS, PhyloWGS, MATH, and ABSOLUTE), DEPTH scores had stronger correlations with antitumor immune signatures, cell proliferation, stemness, tumor advancement, survival prognosis, and drug response. Cancer.gov/about-nci/organization/ccg/research/structuralgenomics/tcga), we demonstrated that the ITH defined by DEPTH had the common features of ITH characterized in previous studies, such as its negative correlation with tumor prognosis and antitumor immunity[5,9,12] and positive correlation with drug resistance[25]. We further validated these features of ITH evaluated by DEPTH in more than 10,000 tumor samples apart from TCGA. Our data showed that DEPTH is an effective and robust method for evaluating ITH, and its performance is superior to or comparable to that of the other methods
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