Tumor heterogeneity in neoplasms of breast, colon, and skin

Abstract

Background: Different cell subpopulations in a single tumor may show diverse capacities for growth, differentiation, metastasis formation, and sensitivity to treatments. Thus, heterogeneity is an important feature of tumors. However, due to limitations in experimental and analytical techniques, tumor heterogeneity has rarely been studied in detail.

Presentation of the hypothesis: Different tumor types have different heterogeneity patterns, thus heterogeneity could be a characteristic feature of a particular tumor type.

Testing the hypothesis: We applied our previously published mathematical heterogeneity model to decipher tumor heterogeneity through the analysis of genetic copy number aberrations revealed by array CGH data for tumors of three different tissues: breast, colon, and skin. The model estimates the number of subpopulations present in each tumor. The analysis confirms that different tumor types have different heterogeneity patterns. Computationally derived genomic copy number profiles from each subpopulation have also been analyzed and discussed with reference to the multiple hypothetical relationships between subpopulations in origin-related samples.

Implications of the hypothesis: Our observations imply that tumor heterogeneity could be seen as an independent parameter for determining the characteristics of tumors. In the context of more comprehensive usage of array CGH or genome sequencing in a clinical setting our study provides a new way to realize the full potential of tumor genetic analysis.

Figure 1

The development of P0 P1, P1 P2, and P2 P3 subpopulations. The developments of copy number profiles are divided into three groups if available. From top to bottom, the change of P0 P1 subpopulations, P1 P2 subpopulations, and P2 P3 subpopulations for breast (left), colon (center), and SCC (right) tumor samples. The heights of the vertical lines represent the percentage of samples in which the corresponding clones have DNA copy number alterations. The index of clone is given at the bottom and ordered by genomic position (x-axis). The solid vertical bars demarcate the chromosomes. The different copy number alterations were represented by colors in the lower right corner.

Figure 2

The relationship between subpopulations in origin-related samples. Twenty-nine pairs of breast primary tumors (T), lymph node metastases (M) and four "normal" breast tissue samples (N) were analyzed by unsupervised clustering. The similarity of genomic profiles of subpopulations between samples is displayed by clustering (right). The corresponding hypothetical models are shown in the left. The subpopulations presenting the same color denotes they have a close relationship. For more explanations see the text.