Genetic diagnosis of Down syndrome in an underserved community.

It is a matter of course that in high-income countries, infants born with features suggestive of Down syndrome (DS) are offered genetic testing for confirmation of a clinical diagnosis. Benefits of a definitive diagnosis include an end to the diagnostic odyssey, informed prognosis, opportunities for caregiver support, inclusion to social support networks, and more meaningful genetic counseling. The healthcare experience for families of children born with DS in low- and middle-income nations is in stark contrast with such a level of care.

Genome chaos: survival strategy during crisis.

Genome chaos, a process of complex, rapid genome re-organization, results in the formation of chaotic genomes, which is followed by the potential to establish stable genomes. It was initially detected through cytogenetic analyses, and recently confirmed by whole-genome sequencing efforts which identified multiple subtypes including "chromothripsis", "chromoplexy", "chromoanasynthesis", and "chromoanagenesis". Although genome chaos occurs commonly in tumors, both the mechanism and detailed aspects of the process are unknown due to the inability of observing its evolution over time in clinical samples.

Ovarian cancer evolution through stochastic genome alterations: defining the genomic role in ovarian cancer.

Ovarian cancer is the fifth leading cause of death among women worldwide. Characterized by complex etiology and multi-level heterogeneity, its origins are not well understood. Intense research efforts over the last decade have furthered our knowledge by identifying multiple risk factors that are associated with the disease.

Unstable genomes elevate transcriptome dynamics.

The challenge of identifying common expression signatures in cancer is well known, however the reason behind this is largely unclear. Traditionally variation in expression signatures has been attributed to technological problems, however recent evidence suggests that chromosome instability (CIN) and resultant karyotypic heterogeneity may be a large contributing factor. Using a well-defined model of immortalization, we systematically compared the pattern of genome alteration and expression dynamics during somatic evolution.

Single cell heterogeneity: why unstable genomes are incompatible with average profiles.

Multi-level heterogeneity is a fundamental but underappreciated feature of cancer. Most technical and analytical methods either completely ignore heterogeneity or do not fully account for it, as heterogeneity has been considered noise that needs to be eliminated. We have used single-cell and population-based assays to describe an instability-mediated mechanism where genome heterogeneity drastically affects cell growth and cannot be accurately measured using conventional averages.

Chromosomal instability (CIN): what it is and why it is crucial to cancer evolution.

Results of various cancer genome sequencing projects have "unexpectedly" challenged the framework of the current somatic gene mutation theory of cancer. The prevalence of diverse genetic heterogeneity observed in cancer questions the strategy of focusing on contributions of individual gene mutations. Much of the genetic heterogeneity in tumors is due to chromosomal instability (CIN), a predominant hallmark of cancer.

Chromosomal instability and transcriptome dynamics in cancer.

Whole transcriptome profiling has long been proposed as a method of identifying cancer-specific gene expression profiles. Indeed, a multitude of these studies have generated vast amounts of expression data for many types of cancer, and most have identified specific gene signatures associated with a given cancer. These studies however, often contradict with each other, and gene lists only rarely overlap, challenging clinical application of cancer gene signatures.

Genome constraint through sexual reproduction: application of 4D-Genomics in reproductive biology.

Assisted reproductive technologies have been used to achieve pregnancies since the first successful test tube baby was born in 1978. Infertile couples are at an increased risk for multiple miscarriages and the application of current protocols are associated with high first-trimester miscarriage rates. Among the contributing factors of these higher rates is a high incidence of fetal aneuploidy.

Why imatinib remains an exception of cancer research.

The archetype driving the drug targeting approach to cancer therapy is the success of imatinib against chronic phase chronic myeloid leukemia (CML-CP). Molecular targeting success of this magnitude has yet to be repeated for most solid tumors. To answer why imatinib remains an exception of cancer research, we summarize key features and patterns of evolution that contrast CML-CP from prostate cancer, an example of a solid tumor that also shares a signature fusion gene.

Evolutionary mechanisms and diversity in cancer.

The recently introduced genome theory of cancer evolution provides a new framework for evolutionary studies on cancer. In particular, the established relationship between the large number of individual molecular mechanisms and the general evolutionary mechanism of cancer calls upon a change in our strategies that have been based on the characterization of common cancer gene mutations and their defined pathways. To further explain the significance of the genome theory of cancer evolution, a brief review will be presented describing the various attempts to illustrate the evolutionary mechanism of cancer, followed by further analysis of some key components of somatic cell evolution, including the diversity of biological systems, the multiple levels of information systems and control systems, the two phases (the punctuated or discontinuous phase and gradual Darwinian stepwise phase) and dynamic patterns of somatic cell evolution where genome replacement is the driving force.

Decoding the genome beyond sequencing: the new phase of genomic research.

While our understanding of gene-based biology has greatly improved, it is clear that the function of the genome and most diseases cannot be fully explained by genes and other regulatory elements. Genes and the genome represent distinct levels of genetic organization with their own coding systems; Genes code parts like protein and RNA, but the genome codes the structure of genetic networks, which are defined by the whole set of genes, chromosomes and their topological interactions within a cell. Accordingly, the genetic code of DNA offers limited understanding of genome functions.

Comparison of mitotic cell death by chromosome fragmentation to premature chromosome condensation.

Mitotic cell death is an important form of cell death, particularly in cancer. Chromosome fragmentation is a major form of mitotic cell death which is identifiable during common cytogenetic analysis by its unique phenotype of progressively degraded chromosomes. This morphology however, can appear similar to the morphology of premature chromosome condensation (PCC) and thus, PCC has been at times confused with chromosome fragmentation.

The evolutionary mechanism of cancer.

Identification of the general molecular mechanism of cancer is the Holy Grail of cancer research. Since cancer is believed to be caused by a sequential accumulation of cancer gene mutations, the identification, characterization, and targeting of common genetic alterations and their defined pathways have dominated the field for decades. Despite the impressive data accumulated from studies of gene mutations, epigenetic dysregulation, and pathway alterations, an overwhelming amount of diverse molecular information has offered limited understanding of the general mechanisms of cancer.

Genetic and epigenetic heterogeneity in cancer: a genome-centric perspective.

Genetic and epigenetic heterogeneity (the main form of non-genetic heterogeneity) are key elements in cancer progression and drug resistance, as they provide needed population diversity, complexity, and robustness. Despite drastically increased evidence of multiple levels of heterogeneity in cancer, the general approach has been to eliminate the "noise" of heterogeneity to establish genetic and epigenetic patterns. In particular, the appreciation of new types of epigenetic regulation like non-coding RNA, have led to the hope of solving the mystery of cancer that the current genetic theories seem to be unable to achieve.

Genome based cell population heterogeneity promotes tumorigenicity: the evolutionary mechanism of cancer.

Cancer progression represents an evolutionary process where overall genome level changes reflect system instability and serve as a driving force for evolving new systems. To illustrate this principle it must be demonstrated that karyotypic heterogeneity (population diversity) directly contributes to tumorigenicity. Five well characterized in vitro tumor progression models representing various types of cancers were selected for such an analysis.

Mitotic cell death by chromosome fragmentation.

Cell death plays a key role for both cancer progression and treatment. In this report, we characterize chromosome fragmentation, a new type of cell death that takes place during metaphase where condensed chromosomes are progressively degraded. It occurs spontaneously without any treatment in instances such as inherited status of genomic instability, or it can be induced by treatment with chemotherapeutics.

Stochastic cancer progression driven by non-clonal chromosome aberrations.

Cancer research has previously focused on the identification of specific genes and pathways responsible for cancer initiation and progression based on the prevailing viewpoint that cancer is caused by a stepwise accumulation of genetic aberrations. This viewpoint, however, is not consistent with the clinical finding that tumors display high levels of genetic heterogeneity and distinctive karyotypes. We show that chromosomal instability primarily generates stochastic karyotypic changes leading to the random progression of cancer.

Chromatin loops are selectively anchored using scaffold/matrix-attachment regions.

The biological significance of nuclear scaffold/matrix-attachment regions (S/MARs) remains a topic of long-standing interest. The key to understanding S/MAR behavior relies on determining the physical attributes of in vivo S/MARs and whether they serve as rigid or flexible chromatin loop anchors. To analyze S/MAR behavior, single and multiple copies of the S/MAR-containing constructs were introduced into various host genomes of transgenic mice and transfected cell lines.

Imaging genome abnormalities in cancer research.

Increasing attention is focusing on chromosomal and genome structure in cancer research due to the fact that genomic instability plays a principal role in cancer initiation, progression and response to chemotherapeutic agents. The integrity of the genome (including structural, behavioral and functional aspects) of normal and cancer cells can be monitored with direct visualization by using a variety of cutting edge molecular cytogenetic technologies that are now available in the field of cancer research. Examples are presented in this review by grouping these methodologies into four categories visualizing different yet closely related major levels of genome structures.