Chromosome instability (CIN) is the most common form of genome instability and is a hallmark of cancer. CIN invariably leads to aneuploidy, a state of karyotype imbalance. Here, we show that ...aneuploidy can also trigger CIN. We found that aneuploid cells experience DNA replication stress in their first S-phase and precipitate in a state of continuous CIN. This generates a repertoire of genetically diverse cells with structural chromosomal abnormalities that can either continue proliferating or stop dividing. Cycling aneuploid cells display lower karyotype complexity compared to the arrested ones and increased expression of DNA repair signatures. Interestingly, the same signatures are upregulated in highly-proliferative cancer cells, which might enable them to proliferate despite the disadvantage conferred by aneuploidy-induced CIN. Altogether, our study reveals the short-term origins of CIN following aneuploidy and indicates the aneuploid state of cancer cells as a point mutation-independent source of genome instability, providing an explanation for aneuploidy occurrence in tumors.
...alterations range in scale from small tweaks to the DNA sequence, called point mutations, to changes in the number or structure of whole chromosomes (termed aneuploidy), and even to doubling of ...the entire genetic content of the nucleus - a phenomenon called whole-genome doubling. ...the high degree of DNA damage was mostly associated with S phase and the process of DNA replication. ...treatment of tetraploid cells with drugs that inhibited DNA replication caused a marked decrease in signs of DNA damage. ...the authors carried out single-cell DNA sequencing, and observed abnormal chromosome compositions (called karyotypes) in tetraploid cells after a single S phase, even before mitosis began.
Aneuploidy is a hallmark of cancer with tissue-specific prevalence patterns that suggest it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to ...tumorigenesis depends on both cellular and genomic contexts. Whole-genome duplication (WGD) is a common macroevolutionary event that occurs in more than 30% of human tumors early in tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy, it remains unknown whether WGD also affects aneuploidy prevalence patterns. Here we analyzed clinical tumor samples from 5,586 WGD- tumors and 3,435 WGD+ tumors across 22 tumor types and found distinct patterns of aneuploidy in WGD- and WGD+ tumors. WGD+ tumors were characterized by more promiscuous aneuploidy patterns, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD- and WGD+ tumors, giving rise to distinct cooccurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy compared with arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Finally, induction of WGD and assessment of aneuploidy in isogenic WGD-/WGD+ human colon cancer cell lines under standard or selective conditions validated key findings from the clinical tumor analysis, supporting a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors and propose that this interaction contributes to tumor evolution.
These findings suggest that the interactions between whole-genome duplication and aneuploidy are important for tumor evolution, highlighting the need to consider genome status in the analysis and modeling of cancer aneuploidy.
Germline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified ...based on the spectrum of response to platinum/PARP inhibition: (i) refractory overall survival (OS) <6 months, (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti-PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions.
glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development. This article is highlighted in the In This Issue feature, p. 1749.
A proton beam with a velocity of the order of 109 cm/s is generated to interact with a charge neutral hydrogen-boron medium such as H3B. The created charged particles are confined by magnetic fields. ...This concept was the basis for a novel non-thermal fusion reactor, published recently in Laser and Particle Beams 1. The fusion is initiated by protons followed by a process of chain reactions in a neutral medium density of the order of 1019 cm−3, heated by the pB11 fusion created alphas up to a temperature of about one electron volt. In this system, the radiation losses by bremsstrahlung are negligible and the plasma thermal pressure is low. The ionization of the gaseous medium is caused by the alpha elastic nuclear collisions with the hydrogen atoms and their thermal heating and it is < 10−4. An external electric field is applied to avoid the energy losses of the protons particles by friction, due to their interaction with the electrons of the medium, to keep the proton-boron fusion at the maximum cross section of about 600 keV at the center of mass frame of reference. The alphas created in the pB11 fusion undergo nuclear elastic collisions with the hydrogen protons of the medium and causing a pB11 chain reaction. In this paper the equation of motion of these proton and alphas are solved numerically for the one-dimensional (1D) case, and their possible solutions are analyzed and discussed. Specifically, it is shown how the electric field can mitigate the stopping power for the proton11-proton nuclear fusion. Our results show that starting from a bunch of 1013 protons in our volume, an alpha number of particles of 6 × 1016 was accepted after a 5 ms cycle of applying our specially designed electric field. Consequently, the medium temperature was raised to 1.3 eV. The aim of this paper is to present a new concept by addressing only the main physical processes and not to present a complete engineering design. The configuration for mitigating the stopping power and the numerical solution in this paper is novel and promises few applications with a viable proton-boron11 fusion reactions.
Familial Mediterranean fever (FMF) is an autoinflammatory disorder with episodic and persistent inflammation, which is only partially suppressed by continuous colchicine treatment. While chronic ...inflammation is considered an important cardiovascular risk factor in many inflammatory disorders, its impact in FMF is still disputed. We measured arterial stiffness, a marker of atherosclerotic cardiovascular disease, in a group of FMF patients, in order to evaluate the cardiovascular consequences of inflammation in FMF and the role of colchicine in their development.
Eighty colchicine treated FMF patients, without known traditional cardiovascular risk factors, were randomly enrolled in the study. Demographic, genetic, clinical and laboratory data were retrieved from patient files and examinations. Arterial stiffness was measured using pulse wave velocity (PWV). The recorded values of PWV were compared with those of an age and blood pressure adjusted normal population, using internationally endorsed values.
FMF patients displayed normal PWV values, with an even smaller than expected proportion of patients deviating from the 90th percentile of the reference population (5% vs. 10%, p=0.02). The lowest PWV values were recorded in patients receiving the highest dose of colchicine (≥2 mg vs. 0-1 mg, p=0.038), and in patients of North African Jewish origin, whose disease was typically more severe than that of patients of other ethnicities; both observations supporting an ameliorating colchicine effect (p=0.043).
Though subjected to chronic inflammation, colchicine treated FMF patients have normal PWV. Our findings provide direct evidence for a cardiovascular protective role of colchicine in FMF.
PDF
