Prenatal chromosomal diversification of leukemia in monozygotic twins

Previous studies on concordant acute lymphoblastic leukemia (ALL) in identical twins have identified the leukemia as monoclonal with MLL or ETV6-RUNX1 gene fusion as early or initiating events in utero. In the latter case, postnatal latency is associated with secondary genetic events such as ETV6 deletion. We describe here a pair of infant twins with concordant acute monoblastic leukemia (AML). They are a unique pair in that their leukemia blasts display extensive intraclonal chromosomal diversity. Comparison of the leukemic cells between the two twins by karyotype and fluorescence in situ hybridization identifies a common or shared stem line and extensive subclonal diversity for which the twins\u27 leukemic populations are divergent. This case of leukemia illustrates in utero initiation with early imposition of chromosomal instability, the progressively divergent evolution of which can be mapped in the twins into pre- and postnatal periods

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Molecular cytogenetics in childhood leukemia

In the last decade molecular cytogenetics, or fluorescence in situ hybridization (FISH), has become an important complementary procedure to routine chromosomal analysis. The most significant consequence from cytogenetic studies in childhood leukemia has been the association of specific chromosomal abnormalities with different patient subgroups, particularly in relation to prognosis. In childhood acute myeloid leukemia (AML), the rearrangements t(8;21)(q22;q22), t(15;17)(q22;q12), and inv(16)(p13q22) are associated with a good outcome. Conversely, deletions of the long arm of chromosome 5, monosomy 5 or 7, in association with a complex karyotype, are related to a poor prognosis. Karyotypes with a favorable outcome in childhood acute lymphoblastic leukemia (ALL) include high hyperdiploidy (51-65 chromosomes) and the translocation, t(12;21)(p13;q22). The Philadelphia translocation, t(9;22)(q34;q11), rearrangements involving the MLL gene and near haploidy (23-29 chromosomes) are associated with a short overall survival (2). Metaphase and interphase FISH are increasingly being used to screen routinely for such chromosomal abnormalities in childhood leukemia. Metaphase FISH also plays a role in the identification of new nonrandom chromosomal changes of prognostic significance.<br/

Informed choice in bowel cancer screening: a qualitative study to explore how adults with lower education use decision aids

Background: Offering informed choice in screening is increasingly advocated, but little is known about how evidence-based information about the benefits and harms of screening influences understanding and participation in screening. Objective:?We aimed to explore how a bowel cancer screening decision aid influenced decision making and screening behaviour among adults with lower education and literacy. Methods: Twenty-one men and women aged 55-64 years with lower education levels were interviewed about using a decision aid to make their screening decision. Participants were purposively selected to include those who had and had not made an informed choice. Results: Understanding the purpose of the decision aid was an important factor in whether participants made an informed choice about screening. Participants varied in how they understood and integrated quantitative risk information about the benefits and harms of screening into their decision making; some read it carefully and used it to justify their screening decision, whereas others dismissed it because they were sceptical of it or lacked confidence in their own numeracy ability. Participants' prior knowledge and beliefs about screening influenced how they made sense of the information. Discussion and conclusions:?Participants valued information that offered them a choice in a non-directive way, but were concerned that it would deter people from screening. Healthcare providers need to be aware that people respond to screening information in diverse ways involving a range of literacy skills and cognitive processes

Genetic and Functional Diversity of Propagating Cells in Glioblastoma

Summary: Glioblastoma (GBM) is a lethal malignancy whose clinical intransigence has been linked to extensive intraclonal genetic and phenotypic diversity and the common emergence of therapeutic resistance. This interpretation embodies the implicit assumption that cancer stem cells or tumor-propagating cells are themselves genetically and functionally diverse. To test this, we screened primary GBM tumors by SNP array to identify copy number alterations (a minimum of three) that could be visualized in single cells by multicolor fluorescence in situ hybridization. Interrogation of neurosphere-derived cells (from four patients) and cells derived from secondary transplants of these same cells in NOD-SCID mice allowed us to infer the clonal and phylogenetic architectures. Whole-exome sequencing and single-cell genetic analysis in one case revealed a more complex clonal structure. This proof-of-principle experiment revealed that subclones in each GBM had variable regenerative or stem cell activity, and highlighted genetic alterations associated with more competitive propagating activity in vivo. : In this article, Greaves and colleagues show that tumor-propagating cells in glioblastoma are genetically and functionally heterogeneous. When used in in vivo experiments, these cells show a variable competitive capacity for tumor propagation and further genetic diversification, suggesting that glioblastoma evolves through complex dynamics of subclonal fitness advantage and acquisition of mutations and copy number alterations