Multiregional Tumor Trees Are Not Phylogenies

Area of Science:

• Cancer Biology
• Evolutionary Biology
• Genomics

Background:

• Tumor samples frequently contain diverse cell lineages, a phenomenon known as intratumor heterogeneity.
• Current phylogenetic methods analyzing bulk mutational data often overlook this cellular mixture.

Purpose of the Study:

• To identify potential inaccuracies in evolutionary inferences derived from multiregional tumor phylogenetics.
• To highlight the impact of unaddressed intratumor heterogeneity on somatic mutation timing and metastasis chronology.

Main Methods:

• Review of existing phylogenetic tree construction methods for cancer.
• Analysis of simulated and real-world tumor mutation data with varying degrees of heterogeneity.

Main Results:

• Multiregional phylogenetic trees can lead to biased somatic mutation timing.
• Failure to account for cellular heterogeneity may result in spurious parallel mutation events.
• Incorrect chronological ordering of metastatic events is a potential consequence of ignoring tumor composition.

Conclusions:

• Intratumor heterogeneity significantly complicates accurate tumor evolutionary modeling.
• Future phylogenetic approaches must incorporate methods to address cellular mixtures for reliable inferences.