TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.

Chromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including FAT1, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that FAT1 alterations are positively selected before genome doubling and associated with HR deficiency.

Disentangling the roles of aneuploidy, chromosomal instability and tumour heterogeneity in developing resistance to cancer therapies.

Aneuploidy is defined as the cellular state of having a number of chromosomes that deviates from a multiple of the normal haploid chromosome number of a given organism. Aneuploidy can be present in a static state: Down syndrome individuals stably maintain an extra copy of chromosome 21 in their cells. In cancer cells, however, aneuploidy is usually present in combination with chromosomal instability (CIN) which leads to a continual generation of new chromosomal alterations and the development of intratumour heterogeneity (ITH).

Replication stress generates distinctive landscapes of DNA copy number alterations and chromosome scale losses.

Background: A major driver of cancer chromosomal instability is replication stress, the slowing or stalling of DNA replication. How replication stress and genomic instability are connected is not known. Aphidicolin-induced replication stress induces breakages at common fragile sites, but the exact causes of fragility are debated, and acute genomic consequences of replication stress are not fully explored.

The multifaceted role of micronuclei in tumour progression: A whole organism perspective.

Within most tumour types, cancerous cells exist in a state of aneuploidy, an incorrect chromosome number or structure. Additionally, tumour cells frequently exhibit chromosomal instability; the ongoing loss or gain of whole or parts of chromosomes during cell division. Chromosomal instability results in a high rate of chromosome segregation defects, and a constantly changing genomic landscape.

Cells on lockdown: long-term consequences of CDK4/6 inhibition.

Inhibition of cyclin-dependent kinases Cdk4/6 is emerging as a useful anti-proliferative chemotherapy, but it remains unclear how durable inhibition of cancer cell proliferation is achieved to promote a long-lasting response in patients, or how toxicity is limited to cancer cells with minimal side effects. Two recent papers in The EMBO Journal investigating senescence induction following prolonged Cdk4/6 inhibitor treatment now reveal important insights into ways to increase anti-tumour effects of Cdk4/6 inhibition and to reduce therapy-induced side effects of senescence induction.

Diversity in chromosome numbers promotes resistance to chemotherapeutics.

In this issue of Developmental Cell, papers from Ippolito et al. and from Lukow et al. show that increasing the range of aneuploidy states in cells increases their chance of developing resistance when they are subjected to chemotherapy.

Trends in antimicrobial resistance legislation 2011-2019: A review of the US policy response to the antimicrobial resistance threat and its public health Impact.

Background: Antimicrobial resistance is a continued global threat to public health. In recognition of this threat, the executive branch of the United States government consolidated guidelines through the President's Council of Advisors on Science and Technology and Executive Order 13676.

Methods: An analysis was conducted to assess the US government's response to this growing threat.

Specific Mechanisms of Chromosomal Instability Indicate Therapeutic Sensitivities in High-Grade Serous Ovarian Carcinoma.

Chromosomal instability (CIN) comprises continual gain and loss of chromosomes or parts of chromosomes and occurs in the majority of cancers, often conferring poor prognosis. Because of a scarcity of functional studies and poor understanding of how genetic or gene expression landscapes connect to specific CIN mechanisms, causes of CIN in most cancer types remain unknown. High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynecologic malignancy in the Western world, with chemotherapy resistance developing in almost all patients.

Towards restoring proper chromosome segregation and preventing ageing.

The natural progressive dysfunction of most living organisms-ageing-has captured the attention of several studies, with the intention to develop rejuvenation strategies. Evidence is emerging of a positive correlation between natural ageing and chromosomal instability (CIN). In this issue of EMBO Reports, Barroso-Vilares et al [1] now show a link between ageing and the erroneous assembly of the apparatus required for a proper cellular division.

Virtual reconstruction of unilateral pelvic fractures by using pelvic symmetry.

Purpose: Pelvic fractures are known to be one of the most difficult injuries to treat. The objective of this study is to introduce a novel technique for virtual unilateral pelvic fracture reconstruction. Since the pelvis exhibits remarkable left-right symmetry, the contralateral hemipelvis can be used as a template for rebuilding the fractured hemipelvis.

Human chromosome-specific aneuploidy is influenced by DNA-dependent centromeric features.

Intrinsic genomic features of individual chromosomes can contribute to chromosome-specific aneuploidy. Centromeres are key elements for the maintenance of chromosome segregation fidelity via a specialized chromatin marked by CENP-A wrapped by repetitive DNA. These long stretches of repetitive DNA vary in length among human chromosomes.

The emerging links between chromosomal instability (CIN), metastasis, inflammation and tumour immunity.

Many cancers possess an incorrect number of chromosomes, a state described as aneuploidy. Aneuploidy is often caused by Chromosomal Instability (CIN), a process of continuous chromosome mis-segregation. CIN is believed to endow tumours with enhanced evolutionary capabilities due to increased intratumour heterogeneity, and facilitating adaptive resistance to therapies.

Single-cell approaches to understand genome organisation throughout the cell cycle.

Mammalian genomes are ordered at several scales, ranging from nucleosomes (beads on a string), to topologically associated domains (TADs), laminar associated domains (LADs), and chromosome territories. These are described briefly below and we refer the reader to some recent comprehensive reviews on genome architecture summarising the current state of knowledge of the organisational principles of the nucleus [1,2]. Biological observations from populations of millions of individual cells can reveal consensus behaviour.

Impaired CENP-E Function Renders Large Chromosomes More Vulnerable to Congression Failure.

It has recently emerged that human chromosomes vary between one another in terms of features that impact their behaviour during impaired chromosome segregation, leading to non-random aneuploidy in the daughter cell population. During the process of chromosome congression to the metaphase plate, chromosome movement is guided by kinesin-like proteins, among which centromere-associated protein E (CENP-E) is important to transport chromosomes along the microtubules of the mitotic spindle. It is known that the inhibition of CENP-E notably impairs alignment for a subset of chromosomes, particularly those positioned close to the centrosome at nuclear envelope breakdown ('polar chromosomes'); it is, however, not clear whether chromosome identity could influence this process.

Non-random Mis-segregation of Human Chromosomes.

A common assumption is that human chromosomes carry equal chances of mis-segregation during compromised cell division. Human chromosomes vary in multiple parameters that might generate bias, but technological limitations have precluded a comprehensive analysis of chromosome-specific aneuploidy. Here, by imaging specific centromeres coupled with high-throughput single-cell analysis as well as single-cell sequencing, we show that aneuploidy occurs non-randomly following common treatments to elevate chromosome mis-segregation.

Role of chromosomal instability in cancer progression.

Cancer cells often display (CIN), a defect that involves loss or rearrangement of the cell's genetic material - chromosomes - during cell division. This process results in the generation of aneuploidy, a deviation from the haploid number of chromosomes, and structural alterations of chromosomes in over 90% of solid tumours and many haematological cancers. This trait is unique to cancer cells as normal cells in the body generally strictly maintain the correct number and structure of chromosomes.