Molecular Profiles of Matched Primary and Metastatic Tumor Samples Support a Linear Evolutionary Model of Breast Cancer

Abstract

The interpretation of accumulating genomic data with respect to tumor evolution and cancer progression requires integrated models. We developed a computational approach that enables the construction of disease progression models using static sample data. Application to breast cancer data revealed a linear, branching evolutionary model with two distinct trajectories for malignant progression. Here, we used the progression model as a foundation to investigate the relationships between matched primary and metastasis breast tumor samples. Mapping paired data onto the model confirmed that molecular breast cancer subtypes can shift during progression and supported directional tumor evolution through luminal subtypes to increasingly malignant states. Cancer progression modeling through the analysis of available static samples represents a promising breakthrough. Further refinement of a roadmap of breast cancer progression will facilitate the development of improved cancer diagnostics, prognostics, and targeted therapeutics. SIGNIFICANCE: Analysis of matched primary and metastatic tumor samples supports a unidirectional, linear cancer evolution process and sheds light on longstanding issues regarding the origins of molecular subtypes and their progression relationships.

Figure 1:

Breast cancer progression modeling analysis performed on METABRIC gene expression data. (A) Data visualization analysis provides a general view of sample distribution. The dataset contains 144 normal breast tissue samples, which we used as the baseline to represent the origin of cancer progression. To help with visualization and to put the result into context by referring to previous classification systems, each sample was color-coded based on its PAM50 subtype label. (B) A progression model of breast cancer. Each node represents an identified cluster, and the pie chart in each node depicts the percentage of the samples in the node belonging to one of the five PAM50 subtypes. The analysis revealed four major progression paths, referred to as N-B (normal to basal), N-H (normal through luminal A/B to HER2+), N-LB (normal through luminal A to luminal B side-branch), and N-LA (normal to luminal A side-branch). The model was modified from Sun et al. [7].

Figure 2.

Progression analysis of 89 pairs of matched primary and metastasis (P/M) tumor samples. (A) Sankey diagram showing the subtype changes of matched tumor pairs. (B) Data visualization of the P/M cohort mapped onto the METABRIC model. Two examples (9P/9M, 48P/48M) were shown that underwent evident disease progression from luminal A to the HER2+ subtype. (C) Comparison of progression distances of matched primary and metastasis tumors. A total of 16 and 1 pairs were identified with significant positive and negative disease progression (i.e., samples outside of the shaded region. FDR ≤ 0.1), respectively. d_m: progression distance of a metastasis tumor, d_p: progression distance of a primary tumor.