Breast cancer intra-tumor heterogeneity - PubMed (original) (raw)

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Breast cancer intra-tumor heterogeneity

Luciano G Martelotto et al. Breast Cancer Res. 2014.

Abstract

In recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. Burgeoning genetic, epigenetic and phenomenological data support the existence of intra-tumor genetic heterogeneity in breast cancers; however, its basis is yet to be fully defined. Two of the most widely evoked concepts to explain the origin of heterogeneity within tumors are the cancer stem cell hypothesis and the clonal evolution model. Although the cancer stem cell model appeared to provide an explanation for the variability among the neoplastic cells within a given cancer, advances in massively parallel sequencing have provided several lines of evidence to suggest that intra-tumor genetic heterogeneity likely plays a fundamental role in the phenotypic heterogeneity observed in cancers. Many challenges remain, however, in the interpretation of the next generation sequencing results obtained so far. Here we review the models that explain tumor heterogeneity, the causes of intra-tumor genetic diversity and their impact on our understanding and management of breast cancer, methods to study intra-tumor heterogeneity and the assessment of intra-tumor genetic heterogeneity in the clinic.

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Figures

Figure 1

Figure 1

Spatial and temporal heterogeneity. Heterogeneity may be present within a given tumor, such that the different regions of the tumor harbor different repertoires of genetic aberrations (spatial heterogeneity), or during the course of disease progression (temporal heterogeneity).

Figure 2

Figure 2

Approaches to characterize heterogeneity. Tumor bulk sequencing: massively parallel sequencing of millions of tumor cells can be employed to assess the allele frequencies of mutations. Using statistical methods, the clonal frequencies of these mutations can be inferred. Detection of ultra-rare mutations: mutations that are present in rare populations of cancer cells (that is, comprise <1% of the tumor cell population) can be identified using high-fidelity sequencing, such as allele-specific tagging of DNA molecules, such that only alterations found on both strands are defined as mutations. Single-molecule sequencing: DNA is extracted from tumor cells and sequenced on a single-molecule sequencing platform (for instance, the Pacific Bioscience RS system). Single-cell sequencing: tumors are dissociated into single cells. DNA from single cells is amplified and sequenced using massively parallel sequencing to genotype individual cells. In situ topological genotyping: DNA or mRNA is amplified in situ on histological sections of the tumor, allowing for the genotyping of the cancer cells within the tumor without losing anatomical and histological information.

Figure 3

Figure 3

Circulating tumor cells and circulating cell free DNA. Circulating tumor cells and cell free DNA, which is at least in part derived from tumor cells, are obtained through serial collection of blood samples. Genetic analysis of these samples may provide information about the genetic heterogeneity of a cancer, and enable monitoring of its response to therapeutic interventions, the progression of the disease, and the emergence of resistant clones.

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