T-lymphoblastic lymphoma (T-LBL) is a rare and aggressive form of non-Hodgkin’s lymphoma and little is known about their molecular background. However, complex karyotypes were already related to this group of malignancy and associated with poor outcome. Here, we describe a 17-year-old female being diagnosed with T-LBL and a normal karyotype after standard G-banding with trypsin-Giemsa (GTG)-banding. However, further analyses including high-resolution molecular approaches, array-comparative genomic hybridization (aCGH), multiplex ligation-dependent probe amplification, fluorescence in situ hybridization and multicolor chromosome banding revealed a cryptic complex karyotype, NUP214-ABL1 gene fusion, episomes and intra-tumor genetic heterogeneity. In addition, homozygous loss of CDKN2A, as well as amplification of oncogene TLX1 (HOX11) were detected. Actually, NUP214-ABL1 fusion gene replicated autonomously in this case as episomes. Overall, highly amplification of NUP214-ABL1 fusion gene defines possibly a new subgroup of T-LBL patients which accordingly could benefit from treatment with tyrosine kinase inhibitors. As episomes are missed in standard karyotyping aCGH should be performed routinely in T-LBL to possibly detect more of such cases.

The intratumoral heterogeneity orchestrated by the tumor intrinsic and extrinsic mechanisms enable cancers to persist and spread notwithstanding the use of aggressive interventional therapies. The heterogeneity is revealed at multiple levels - at the level of individual tumor cells, in the cellular composition of tumor infiltrates and in the chemical microenvironment in which the cells reside. Deconvoluting the complex nature of the cell types present in the tumor, along with the homo and heterotypic interactions between different cell types can produce novel insights of biological and clinical relevance. However, most techniques analyze tumors at a gross level missing key inter-cell-type genotypic and phenotypic differences. The advent of single-cell sequencing has given an unprecedented opportunity to analyze the tumor at a resolution that not only captures the diversity of the cellular composition of a tumor but also provides information on the genetic, epigenetic and functional states of different cell types. In this review, we summarize the genesis of tumor heterogeneity, its impact on tumor growth and progression and their clinical consequences. We present an overview of the currently available platforms for isolation and sequencing of single tumor cells and provide evidence of its utility in precision medicine and personalized therapy.

Centrosomes serve as the major microtubule organizing centers in cells and thereby contribute to cell shape, polarity, and motility. Also, centrosomes ensure equal chromosome segregation during mitosis. Centrosome aberrations arise when the centrosome cycle is deregulated, or as a result of cytokinesis failure. A long-standing postulate is that centrosome aberrations are involved in the initiation and progression of cancer. However, this notion has been a subject of controversy because until recently the relationship has been correlative. Recently, it was shown that numerical or structural centrosome aberrations can initiate tumors in certain tissues in mice, as well as invasion. Particularly, we will focus on centrosome amplification and chromosome instability as drivers of intra-tumor heterogeneity and their consequences in cancer. We will also discuss briefly the controversies surrounding this theory to highlight the fact that the role of both centrosome amplification and chromosome instability in cancer is highly context-dependent. Further, we will discuss single-cell sequencing as a novel technique to understand intra-tumor heterogeneity and some therapeutic approaches to target chromosome instability.

Changes in cellular energetics and genomic instability are two characteristics of cancers that have been studied independently. Evidence of cross-talk between mitochondria function and nuclear function has started to emerge, suggesting that these pathways can influence one another. Here we review recent evidence that links the mitochondria and the cell cycle. This evidence indicates bidirectional cross-talk where mitochondria function can regulate the cell cycle and induce genomic instability, and conversely, the cell cycle machinery regulates mitochondria function. Implications for this cross-talk in the development of cancer are discussed.

Aim: Current cancer treatments are challenged by the plasticity of cancer cells, largely influenced by chromosomal instability (CIN) leading to variations in karyotype known as tumor-specific aneuploidy, which in turn, leads to intra-tumor cellular heterogeneity (TH). Cells with certain chromosomal defects often survive treatment and the growth-associated states of TH persist in recurrent tumors. Modulation of the CIN rate seems to reside within the tumor itself. In an attempt to develop a therapy targeting cancer plasticity, we studied the possible extracellular control of CIN rate in Chr7-defined TH in gliomas.

Methods: Chr7-fluorescence in situ hybridization was applied on various grades of gliomas, in vitro cultures and intracranial xenografts of two syngeneic glioma lines (U251 and U251-NS) derived from various cell-inoculating densities, with or without EFEMP1 overexpression.

Results: A grade-dependent increase of trisomy-7 population and Chr7-defined cell diversity was shown in gliomas. A negative association between Chr7-MS rate and initial cell-inoculating density was observed which was prevented by EFEMP1 overexpression.

Conclusion: Our data demonstrate that CIN is a major driver for cancer cell plasticity and suggest that CIN can be controlled by extracellular factors derived from normal and tumor cells, and EFEMP1 is one of these factors.

Aim: Present cancer hypotheses are almost all based on the concept that accumulation of specific driver gene mutations cause carcinogenesis. The discovery of intra-tumor genetic heterogeneity (ITGH), has resulted in this hypothesis being modified by assuming that most of these ITGH mutations are in passenger genes. In addition, accumulating ITGH data on driver gene mutations have revealed considerable genotype/phenotype disconnects. This study proposes to investigate this disconnect by examining the nature and degree of ITGH in breast tumors.

Methods: ITGH was examined in tumors using next generation sequencing of up to 68,000 reads and analysis tools that allowed for identification of distinct minority variants within single genes, i.e., complex single gene variance (CSGV).

Results: CSGV was identified in the androgen receptor genes in all breast tumors examined.

Conclusion: Evidence of CSGV suggests that a selection - as opposed to a mutation - centric hypothesis could better explain carcinogenesis. Our hypothesis proposes that tumors develop by the selection of preexisting de novo mutations rather than just the accumulation of de novo mutations. Thus, the role of selection pressures, such as changes in tissue microenvironments will likely be critical to our understanding of tumor resistance as well as the development of more effective treatment protocols.