DITHER

DITHER quantifies intratumor heterogeneity by computing entropies of somatic mutation and copy number alteration (CNA) profiles and defining the tumor ITH level as the average of these entropies.

Key Features:

• Entropy-Based Evaluation: Calculates the entropies of somatic mutation profiles and copy number alteration (CNA) profiles and defines the ITH level as the average of these entropies.
• Correlation with Tumor Characteristics: Demonstrates correlations between DITHER-defined ITH levels and tumor progression, unfavorable phenotypes, genomic instability, and immune evasion.
• Comparison with Existing Methods: Compared to MATH and PhyloWGS, DITHER exhibits more pronounced ITH characteristics and produces scores that are positively correlated with tumor purity, indicating measurement of heterogeneity specifically between tumor cells.
• Insights into Microsatellite Instability: Observes that microsatellite instability-high (MSI-H) tumors have significantly lower ITH scores than microsatellite stable (MSS)/MSI-low tumors despite higher mutation loads, suggesting a homogeneous distribution of hypermutability across cellular populations.

Scientific Applications:

• ITH quantification: Provides a quantitative measure of intratumor heterogeneity for studies of tumor biology.
• Prognostic assessment: Supports analyses linking ITH levels to prognosis and unfavorable tumor phenotypes.
• Therapeutic research: Informs investigations of therapeutic response and strategies related to tumor heterogeneity and immune evasion.
• Personalized medicine: Enables characterization of tumor cell diversity to guide research on personalized treatment approaches.

Methodology:

Calculates entropies of somatic mutation and CNA profiles, averages these entropies to define an ITH level per tumor, and was applied to The Cancer Genome Atlas (TCGA) data across 33 cancer types with comparisons to MATH, PhyloWGS, tumor purity, and MSI status.