Intratumor Heterogeneity: Novel Approaches for Resolving Genomic Architecture and Clonal Evolution

Abstract

High-throughput genomic technologies have revealed a remarkably complex portrait of intratumor heterogeneity in cancer and have shown that tumors evolve through a reiterative process of genetic diversification and clonal selection. This discovery has challenged the classical paradigm of clonal dominance and brought attention to subclonal tumor cell populations that contribute to the cancer phenotype. Dynamic evolutionary models may explain how these populations grow within the ecosystem of tissues, including linear, branching, neutral, and punctuated patterns. Recent evidence in breast cancer favors branching and punctuated evolution driven by genome instability as well as nongenetic sources of heterogeneity, such as epigenetic variation, hierarchal tumor cell organization, and subclonal cell-cell interactions. Resolution of the full mutational landscape of tumors could help reconstruct their phylogenetic trees and trace the subclonal origins of therapeutic resistance, relapsed disease, and distant metastases, the major causes of cancer-related mortality. Real-time assessment of the tumor subclonal architecture, however, remains limited by the high rate of errors produced by most genome-wide sequencing methods as well as the practical difficulties associated with serial tumor genotyping in patients. This review focuses on novel approaches to mitigate these challenges using bulk tumor, liquid biopsies, single-cell analysis, and deep sequencing techniques. The origins of intratumor heterogeneity and the clinical, diagnostic, and therapeutic consequences in breast cancer are also explored. .

Intratumoral heterogeneity of Notch1 expression in small cell lung cancer

“…During the tumorigenesis processes, cancer cells exhibit genetic and epigenetic changes, hierarchal tumor cell organization, and subclonal cell-cell interaction, which may cause more heterogeneous cancers (1,2). The heterogeneity can also be modified by therapies and microenvironments including hypoxia, acidity, inflammation, immunological responses, and extracellular matrix components (1,3).…”

“…The heterogeneity can also be modified by therapies and microenvironments including hypoxia, acidity, inflammation, immunological responses, and extracellular matrix components (1,3). Analysis of tumor heterogeneity may help to resolve the subclonal origins of therapeutic resistance, relapsed diseases, and distant metastases, and mechanistic study and accurate assessment of tumor heterogeneity is crucial for effective therapies (1,2). Small cell lung cancer (SCLC) is a highly malignant neoplasm characterized by neuroendocrine differentiation, rapid tumor growth, high vascularity, early metastatic potential, high chemosensitivity at the first therapeutic trial, acquisition of chemoresistance, mutation of both TP53 and Rb1, and genome instability (4-6).…”

Chromosome Instability; Implications in Cancer Development, Progression, and Clinical Outcomes

“…For example, many of these factors increase cell-to-cell heterogeneity by modulating intracellular signaling pathways or by exerting selective pressures that influence cellular proliferation and/or viability; therefore, these factors can direct clonal evolution [146]. In this regard, numerous research teams have begun to map and study the specific pathogenic events and their temporal order of appearance by creating ancestral 'trees' to describe a tumor's evolution, in much the same manner that classical phylogenetic trees describe species evolution [147]. In keeping with the 'tree' analogy ( Figure 2), early pathogenic events are commonly referred to as 'trunk' or truncal alterations, whilst late occurring alterations (e.g., driving metastatic changes) are referred to as 'branch' alterations (see also [148]), both of which have implications for treatment strategies and outcomes.…”

“…Perhaps most importantly, various genetic assessments, including single cell DNA sequencing, copy number alterations, and the myriad of CIN-based analyses may provide additional and critical clinical information. For example, CTCs isolated from liquid biopsies are more readily amenable to sequential sampling than traditional tumor biopsies, and they can provide 'real-time' insight into tumor genetics, CIN, and intratumoral heterogeneity that may prove useful in monitoring disease progression, treatment responses [160], and/or modifying treatment decisions [147]. .…”

Basal-like Breast Cancers: From Pathology to Biology and Back Again

“…The fact that molecular analyses are becoming applicable to single cells to resolve the heterogeneity of cellular genomes within and between breast cancers is also of great interest (Brady et al., 2017, Casasent et al., 2018, Gao et al., 2017, Gupta and Somer, 2017). Analysis of circulating DNA is likewise an important emerging technology to address the same issue (Cheng et al., 2018, Zivanovic Bujak and Dawson, 2018).…”