Cancer initiation with epistatic interactions between driver and passenger mutations

We investigate the dynamics of cancer initiation in a mathematical model with one driver mutation and several passenger mutations. Our analysis is based on a multi type branching process: We model individual cells which can either divide or undergo apoptosis. In case of a cell division, the two daughter cells can mutate, which potentially confers a change in fitness to the cell. In contrast to previous models, the change in fitness induced by the driver mutation depends on the genetic context of the cell, in our case on the number of passenger mutations. The passenger mutations themselves have no or only a very small impact on the cell's fitness. While our model is not designed as a specific model for a particular cancer, the underlying idea is motivated by clinical and experimental observations in Burkitt Lymphoma. In this tumor, the hallmark mutation leads to deregulation of the MYC oncogene which increases the rate of apoptosis, but also the proliferation rate of cells. This increase in the rate of apoptosis hence needs to be overcome by mutations affecting apoptotic pathways, naturally leading to an epistatic fitness landscape. This model shows a very interesting dynamical behavior which is distinct from the dynamics of cancer initiation in the absence of epistasis. Since the driver mutation is deleterious to a cell with only a few passenger mutations, there is a period of stasis in the number of cells until a clone of cells with enough passenger mutations emerges. Only when the driver mutation occurs in one of those cells, the cell population starts to grow rapidly

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Auditing the Editor: A Review of Key Translational Issues in Epigenetic Editing

Currently, most advances in site-specific epigenetic editing for human use are concentrated in basic research, yet, there is considerable interest to translate this technology beyond the bench. This review highlights recent developments with epigenetic editing technology in comparison with the canonical CRISPR-Cas genome editing, as well as the epistemic and ethical considerations with preemptive translation of epigenetic editing into clinical or commercial use in humans. Key considerations in safety, equity, and access to epigenetic editing are highlighted, with a spotlight on the ethical, legal, and social issues of this technology in the context of global health equity

No significantly increased frequency of the inversion polymorphism at the WBS-critical region 7q11.23 in German parents of patients with Williams-Beuren syndrome as compared to a population control

<p>Abstract</p> <p>Background</p> <p>Typical Williams-Beuren syndrome (WBS) is commonly caused by a ~1.5 Mb - ~1.8 Mb heterozygous deletion of contiguous genes at chromosome region 7q11.23. The majority of WBS cases occurs sporadically but few familial cases of autosomal dominant inheritance have been reported. Recent data demonstrated the existence of the paracentric inversion polymorphism at the WBS critical region in 7q11.23 in some of the progenitors transmitting the chromosome which shows the deletion in the affected child. In parents having a child affected by WBS the prevalence of such a structural variant has been reported to be much higher (~25- ~30%) than in the general population (~1- ~6%). However, in these previously reported studies only a limited number of randomly selected patients and non transmitting parents of WBS patients were used as controls, but without specification of any clinical data. Therefore we have undertaken a German population-based molecular cytogenetic investigation. We evaluated the incidence of the paracentric inversion polymorphism at 7q11.23 analyzing interphase nuclei of lymphocytes using a three color fluorescence in situ hybridization (FISH) probe.</p> <p>Results</p> <p>FISH analysis was carried out on couples with a child affected by WBS as compared to a population sample composed of different normal individuals: Control group I: couples with two healthy children, control group II: couples with fertility problems, planning ICSI and control group III: couples with two healthy children and one child with a chromosome aberration, not involving region 7q11.23. The three color FISH assay showed that the frequency of the paracentric inversion polymorphism at 7q11.23 in couples with a child affected by WBS was 20.8% (5 out of 24 pairs) as compared to 8.3% (2 out of 24 pairs, control group I), 25% (4 out of 16 pairs, control group II) and 9.1% (1 out of 11 pairs, control group III), respectively (total 7 out of 51 pairs, 13.8%). The frequencies differed between the groups, but this was statistically not significant (p > 0.05, Fisher's test).</p> <p>Conclusion</p> <p>Our results do not support the hypothesis that the paracentric inversion polymorphism at 7q11.23 is a major predisposing factor for the WBS deletion.</p

Fast approach for clarification of chromosomal aberrations by using LM-PCR and FT-CGH in leukaemic sample

Chromosomal abnormalities, like deletions, amplifications, inversions or translocations, are recurrent features in haematological malignancies. However, the precise molecular breakpoints are frequently not determined. Here we describe a rapid analysis of genetic imbalances combining fine tiling comparative genomic hybridization (FT-CGH) and ligation-mediated PCR (LM-PCR). We clarified an inv(14)(q11q32) in a case of T cell acute lymphoblastic leukaemia with a breakpoint in the TRA/D in 68% of cells detected by fluorescence in situ hybridization. FT-CGH showed several mono- and biallelic losses within TRA/D. LM-PCR disclosed a TRA/D rearrangement on one allele. The other allele revealed an inv(14)(q11q32), joining TRDD2 at 21,977,000 of 14q11 together with the IGH locus at 105,948,000 and 3'-sequence of TRAC at 22,092,000 joined together with IGHV4-61 at 106,166,000. This sensitive approach can unravel complex chromosomal abnormalities in patient samples with a limited amount of aberrant cells and may lead to better diagnostic and therapeutic options

Lymphoma stem cells: enough evidence to support their existence?

While leukemia-originating stem cells are critical in the initiation and maintenance of leukemias, the existence of similar cell populations that may generate B-cell lymphoma upon mutation remains uncertain. Here we propose that committed lymphoid progenitor/precursor cells with an active V-D-J recombination program are the initiating cells of follicular lymphoma and mantle cell lymphoma when targeted by immunoglobulin (IG)- gene translocations in the bone marrow. However, these pre-malignant lymphoma-initiating cells cannot drive complete malignant transformation, requiring additional cooperating mutations in specific stem-cell programs to be converted into the lymphoma-originating cells able to generate and sustain lymphoma development. Conversely, diffuse large B-cell lymphoma and sporadic Burkitt’s lymphoma derive from B lymphocytes that acquire translocations through IG-hyper-mutation or class-switching errors within the germinal center. Although secondary reprogramming mutations are generally required, some cells such as centroblasts or memory B cells that have certain stem cell-like features, or lymphocytes with MYC rearrangements that deregulate self-renewal pathways, may bypass this need and directly function as the lymphoma-originating cells. An alternative model supports an aberrant epigenetic modification of gene sets as the first occurring hit, which either leads to retaining stem-cell features in hematopoietic stem or progenitor cells, or reprograms stemness into more committed lymphocytes, followed by secondary chromosomal translocations that eventually drive lymphoma development. Isolation and characterization of the cells that are at the origin of the different B-cell non-Hodgkin’s lymphomas will provide critical insights into the disease pathogenesis and will represent a step towards the development of more effective therapies

Current and emerging therapeutic approaches for extracranial malignant rhabdoid tumors

Extracranial malignant rhabdoid tumors (extracranial MRT) are rare, highly aggressive malignancies affecting mainly infants and children younger than 3 years. Common anatomic sites comprise the kidneys (RTK – rhabdoid tumor of kidney) and other soft tissues (eMRT – extracranial, extrarenal malignant rhabdoid tumor). The genetic origin of these diseases is linked to biallelic pathogenic variants in the genes SMARCB1, or rarely SMARCA4, encoding subunits of the SWI/SNF chromatin-remodeling complex. Even if extracranial MRT seem to be quite homogeneous, recent epigenome analyses reveal a certain degree of epigenetic heterogeneity. Use of intensified therapies has modestly improved survival for extracranial MRT. Patients at standard risk profit from conventional therapies; most high-risk patients still experience a dismal course and often therapy resistance. Discoveries of clinical and molecular hallmarks and the exploration of experimental therapeutic approaches open exciting perspectives for clinical and molecularly stratified experimental treatment approaches. To ultimately improve the outcome of patients with extracranial MRTs, they need to be characterized and stratified clinically and molecularly. High-risk patients need novel therapeutic approaches including selective experimental agents in phase I/II clinical trials

The BCR-ABL1 Kinase Bypasses Selection for the Expression of a Pre–B Cell Receptor in Pre–B Acute Lymphoblastic Leukemia Cells

The BCR-ABL1 kinase expressed in acute lymphoblastic leukemia (ALL) drives malignant transformation of human pre–B cells. Comparing genome-wide gene expression profiles of BCR-ABL1+ pre–B ALL and normal bone marrow pre–B cells by serial analysis of gene expression, many genes involved in pre–B cell receptor signaling are silenced in the leukemia cells. Although normal pre–B cells are selected for the expression of a functional pre–B cell receptor, BCR-ABL1+ ALL cells mostly do not harbor a productively rearranged IGH allele. In these cases, we identified traces of secondary VH gene rearrangements, which may have rendered an initially productive VH region gene nonfunctional. Even BCR-ABL1+ ALL cells harboring a functional VH region gene are unresponsive to pre–B cell receptor engagement and exhibit autonomous oscillatory Ca2+ signaling activity. Conversely, leukemia subclones surviving inhibition of BCR-ABL1 by STI571 restore responsiveness to antigen receptor engagement and differentiate into immature B cells expressing immunoglobulin light chains. BCR-ABL1 kinase activity is linked to defective pre–B cell receptor signaling and the expression of a truncated isoform of the pre–B cell receptor–associated linker molecule SLP65. Also in primary leukemia cells, truncated SLP65 is expressed before but not after treatment of the patients with STI571. We conclude that inhibition of BCR-ABL1 reconstitutes selection for leukemia cells expressing a functional (pre–) B cell receptor

Conflicting results of prenatal FISH with different probes for Down's Syndrome critical regions associated with mosaicism for a de novo del(21)(q22) characterised by molecular karyotyping: Case report

For the rapid detection of common aneuploidies either PCR or Fluorescence in situ hybridisation (FISH) on uncultured amniotic fluid cells are widely used. There are different commercial suppliers providing FISH assays for the detection of trisomies affecting the Down's syndrome critical regions (DSCR) in 21q22. We present a case in which rapid FISH screening with different commercial probes for the DSCR yielded conflicting results. Chromosome analysis revealed a deletion of one chromosome 21 in q22 which explained the findings. Prenatally an additional small supernumerary marker chromosome (sSMC) was discovered as well, which could not be characterised. Postnatal chromosome analysis in lymphocytes of the infant revealed complex mosaicism with four cell lines. By arrayCGH the sSMC was provisionally described as derivative chromosome 21 which was confirmed by targeted FISH experiments