DITHER: an algorithm for Defining IntraTumor Heterogeneity based on EntRopy

Abstract

Intratumor heterogeneity (ITH) is associated with tumor development, prognosis, immune evasion and therapeutic effects. We proposed the Defining ITH based on EntRopy (DITHER) algorithm for evaluating ITH. We first evaluated the entropies of somatic mutation profiles and copy number alteration (CNA) profiles in a tumor, respectively, and defined their average as the ITH level for the tumor. Using DITHER, we analyzed 33 cancer types from The Cancer Genome Atlas (TCGA) program. We demonstrated that the ITH defined by DITHER had the typical properties of ITH, namely its strong correlations with tumor progression, unfavorable phenotype, genomic instability and immune evasion. Compared with two other ITH evaluation methods: MATH and PhyloWGS, the DITHER ITH had more prominent characteristics of ITH. Moreover, different from MATH and PhyloWGS, DITHER scores were positively correlated with tumor purity, suggesting that DITHER tends to capture the ITH between tumor cells. Interestingly, microsatellite instability (MSI)-high tumors had significantly lower DITHER scores than microsatellite stability (MSS)/MSI-low tumors, although the former had significantly higher tumor mutation loads than the latter. It suggests that the hypermutability of MSI is homogeneous between different cellular populations in bulk tumors. The DITHER ITH may provide novel insights into tumor biology and potential clinical applications.

Molecular classification of human papillomavirus-positive cervical cancers based on immune signature enrichment

“…This is consistent with our results that Immunity-H had higher TMB and lower levels of CNAs than Immunity-L. In addition, the markedly lower ITH in Immunity-H vs. Immunity-L supports the notion that ITH can contribute to tumor immune evasion (23,47).…”

“…The G-score represents the amplitude of the SCNA and the frequency of its occurrence across a class of samples ( 22 ). We utilized the DITHER algorithm ( 23 ) to score ITH, which measures ITH based on both somatic mutation and SCNA profiles. The ESTIMATE algorithm ( 24 ) was used to calculate immune scores, stromal scores, and tumor purity for bulk tumors, which represent immune infiltration levels, stromal contents, and proportions of tumor cells in bulk tumors.…”

Subtyping of Human Papillomavirus-Positive Cervical Cancers Based on the Expression Profiles of 50 Genes

“…Because tumor immune signatures, stemness, and ITH are associated with clinical outcomes in cancer (18,23,24) and had significantly different scores between the HPV+ cervical cancer subtypes, the survival difference between the subtypes could be impacted by these confounding variables. To explore the possibility, we performed multivariate (immune score, stemness score, ITH score, and subtype) survival analysis with the multivariate Cox proportional hazards model.…”

Classification of lung adenocarcinoma based on stemness scores in bulk and single cell transcriptomes

“…The G-score represents the amplitude of the CNA and the frequency of its occurrence across a group of samples [22] . We used the DITHER algorithm [6] to evaluate ITH levels, which scores ITH based on the entropies of somatic mutation profiles and SCNA profiles in the tumor.…”

“…Recently, with the advances in sequencing, genomics, and computational technologies, mounting large-scale multi-omics data for cancer have emerged, such as the Cancer Genome Atlas (TCGA, https://cancergenome.nih.gov ). These multi-omics data provide valuable resource for exploring cancer features, e.g., tumor stemness [1] , [4] , ITH [5] , [6] , and tumor immunity [7] . In fact, multi-omics data analyses have shown that tumor stemness is associated with dedifferentiated oncogenic phenotype, metastasis, ITH, and immunosuppression across various cancers [1] , [4] .…”