Single Catastrophic Event Research Articles

Chromothripsis in cancer.

Chromothripsis is a mutational phenomenon in which a single catastrophic event generates extensive rearrangements of one or a few chromosomes. This extreme form of genome instability has been detected in 30-50% of cancers. Studies conducted in the past few years have uncovered insights into how chromothripsis arises and deciphered some of the cellular and molecular consequences of chromosome shattering. This Review discusses the defining features of chromothripsis and describes its prevalence across different cancer types as indicated by the manifestations of chromothripsis detected in human cancer samples. The different mechanistic models of chromothripsis, derived from in vitro systems that enable causal inference through experimental manipulation, are discussed in detail. The contribution of chromothripsis to cancer development, the selective advantages that cancer cells might gain from chromothripsis, the evolutionary trajectories of chromothriptic tumours, and the potential vulnerabilities and therapeutic opportunities presented by chromothriptic cells are also highlighted.

From Institutional Trauma to Institutional Healing

The societal struggles in American higher education have intensified in recent years, impacting various facets of academic life. Enrollment declines, rising costs, student debt, and emerging alternatives pose significant threats to colleges and universities. The COVID-19 pandemic further strained institutions, leading to deeper budget cuts and potential closures. Falling tuition revenue coupled with culture wars and political polarization have led to prolonged institutional trauma in higher education institutions. Conservative-leaning states have restricted faculty tenure, courses dealing with social and political inequity, and DEI initiatives, while progressives emphasize universities’ role in fostering critical thinking and truth. Organizational trauma can significantly impact an organization’s well-being. It can arise from a single catastrophic event or persistent issues such as workplace biases, discrimination, and poor communication. For many campuses, this manifests as chronic stress, apathy, and mental health challenges, leading to turnover of faculty and staff and low productivity. Understanding and addressing organizational trauma is crucial. Strategies include fostering resilience through supportive leadership, trust-building, and inclusive practices. Thoughtful solutions and collective efforts are needed to heal and strengthen American democracy. The 2024 elections remain uncertain, raising questions about the future of not only higher education, but American democracy. Addressing these challenges requires a concerted effort to bridge divides, promote critical thinking, and uphold the purpose of higher education. The path forward remains complex, but collective action is essential to repair and strengthen American civic health.

Social Memory, Public Memory, and Marginality: The Case of the “Death in Migration”

Memory is a source of ‘immunization’ for individuals (psycho-cognitive memory and biological immune system) and for communities (De Martino). We can consider culture as the memory of society. Particularly, the cultural memory of disasters plays a fundamental role. Ideally, it should help to reduce the vulnerability of societies to the risks of recurrence of natural/technological/social catastrophic events. However, memory is not an exact process, but a selective and reconstructive one (Bartlett). Furthermore, the memory of society is multiple and continuously exposed to the risk of distortions, interpretations, and manipulations. Social memory (Halbwachs) is the broader sphere of communicability that delimits the arena in which the different collective memories (of groups) compete for the relevance and plausibility of their own discourses. It will correspond, with good approximation, to the term “public memory”. In particular, the media and journalism play a very important function, as public memory is a memory of the public sphere (Habermas) and, somehow, the public sphere is itself memory (Jedlowski). This presentation aims to compare two social memories of a single catastrophic event in which a marginal social category was involved: migrants illegally crossing the Mediterranean Sea. The research focus concerns a watershed event of the recent migratory phenomenon: the Lampedusa shipwreck that took place on the 3<sup>rd</sup> October 2013. The goal is to show how collective and public memory contrast each other. We will discuss two cultural and communicative processes located along the oppositional materialization/dematerialization axis. In the article we will reinterpret the evidence collected in the research carried out in 2014 on the Lampedusa shipwreck that took place on 3 October 2013 in order to reflect on the dynamics between different types of memories in the framework of the memory of disasters. We assume that they can be deeply distortive as they promote interrelated memory bias.

The Presence of Ring Chromosomes in Patients with Myeloid Neoplasms Is Predictive of a Poor Outcome

Cytogenomic analysis is an important tool in the risk stratification of patients with hematologic malignancies. Complex chromosomal alterations are associated with a poor prognosis (Döhner et al., Blood 2022). Ring chromosomes (RC) are circular chromosomal structures associated with loss or gain/amplification of genetic material and are associated with poor prognosis in acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) (Rosenbaum et al., Human Path 2017). Due to their rarity, the impact of RC on response to therapy has not yet been well characterized. We further examined the significance of RC in AML, MDS and myeloproliferative neoplasms (MPN) by retrospectively analyzing records of patients identified to have RC and myeloid neoplasms at our institution between 2017 and 2023 and collected demographic, diagnostic, treatment, molecular, cytogenomic, and outcomes data. We identified 27 cases with RC with clinical data available for 25. Demographic and treatment details are described in Table 1. The most common chromosomes involved were r(11) and r(7), 6 and 4 cases respectively, followed by r(6) and r(19) with 2 cases each. The most frequently observed diagnosis was AML in 12 patients (48%) followed by MDS with 9 cases (36%) and MPN in 4 cases (16%). In 17 cases (68%) the RC was cytogenetically detected at diagnosis and was not observed in the context of prior therapy. Remarkably, mutations in TP53 were present in 14 cases (56%) and accompanied by loss of 17p (bi-allelic) in 7 cases (28%). The next most commonly observed gene mutations were in DNMT3A (7 cases), TET2 (4 cases) and ASXL1 (3 cases). In 11 cases (44%) the alterations in TP53 were not associated with prior therapy for other malignancies. The median time from prior chemotherapy to detection of the RC was 5.1 years (range 0.6 to 13.5 years). Chromothripsis (a single DNA catastrophic event resulting in extensive genomic rearrangements of one or a few chromosomes) as detected by CGH+SNP array and homogenous staining regions (autonomously replicating extra-chromosomal elements that are frequently associated with gene amplification) were observed in 3 patients each. RC were the sole genetic abnormality in 5 patients. A Kaplan-Meier analysis of median overall survival (mOS) in patients with AML and MDS with RC at diagnosis revealed that patients who received supportive care had significantly shorter mOS than patients who received hypomethylating agents (HMA), HMA/Venetoclax(VEN), or anthracycline-based chemotherapy (log rank test, p = 0.001). A significant difference in mOS between patients who received HMA alone versus HMA/VEN versus chemotherapy was not observed (11.4 vs 3.1 vs 7.3 months, p = 0.8) (Figure 1). Patients who received any of the therapies outlined above likewise demonstrated a significantly longer progression free survival (log rank test, p = 0.001). There was no effect on mOS for any of the other tested prognostic parameters, including the presence of a complex karyotype, TP53 allele status, or therapy-related neoplasm, nor for pair-wise interactions between those categories and first-line therapies (p > 0.05 for all tested associations). These data represent a large single-institution cohort of patients with RC and is the first to investigate the impact of therapy and molecular profiles in this population. We observed a high prevalence of TP53 mutations and loss of 17p, however we lacked longitudinal data to make causal inferences regarding the relationship between these abnormalities and ring formation. Of note, 68% of patients did not have prior exposure to therapy, and 36% of all patients lacked TP53 mutations or chromosomal p53 loss, indicating a high rate of de novo ring formation. This is a novel finding perhaps suggesting that inherent chromosomal instability characterizes these patients. Comparing response to type of therapy and outcomes of patients, we conclude that the mOS in patients with RC without therapy is significantly shortened compared with any of the therapeutic options described above, and that the addition of VEN to HMA did not positively influence mOS or PFS compared to HMA alone or chemotherapy in our cohort. Furthermore, the presence of a complex karyotype or a mutation and/or deletion of TP53 with a RC was not independently associated with inferior mOS, suggesting that the presence of a ring chromosome alone may be an important adverse risk factor in myeloid malignancies.

50,000 yr of recurrent volcaniclastic megabed deposition in the Marsili Basin, Tyrrhenian Sea

Abstract Megabeds are exceptionally large submarine deposits interpreted to originate from single catastrophic events. Megabeds are significant components of deep-water basins and are critical for understanding geohazards. We discovered a succession of four megabeds within the upper 70 m of the western Marsili Basin, Tyrrhenian Sea, deposited within the past 50 k.y. The megabeds were imaged as distinctive acoustically transparent units with ponded geometries, 10–25 m thick, separated by parallel-bedded strata. Cores from Site 650 of Ocean Drilling Program Leg 107 revealed that three of the four megabeds are made of alternating volcaniclastic sand and mud, and one is a volcaniclastic debris flow. Abundant shallow-water benthic foraminifera within the megabeds suggest that they were not sourced locally from the active Marsili Seamount, but most likely originated from the Campanian volcanic province to the north. The time interval during which the megabeds were deposited includes the 39.8 ka Campanian ignimbrite supereruption of the Campi Flegrei caldera, Italy, which is among the largest known eruptions on Earth, and the 14.9 ka Neapolitan Yellow Tuff supereruption. Volume (minimum) estimates range from 1.3 to 13.3 km3. However, similar megabeds observed in the neighboring Vavilov Basin to the west suggest that the megabeds in both basins may be correlative, and thus volumes could be much larger. The newly discovered megabeds of the Marsili Basin reveal significant geohazard events for the circum–Tyrrhenian Sea coastlines with a recurrence interval on the order of ~10–15 k.y.

Coupling and complexity at the global scale: flows, networks, interconnectedness and synchronicity (e.g. Covid-19)

The argument of this paper is that the notions of coupling and complexity introduced by Perrow to discuss high-risk technologies need to be scaled up from their original scope to a wider, global one considering the evolution of the operational landscape of safety–critical systems. One value of Perrow in the 1980 s was to trigger core debates, contributing to a new form of causal reasoning. It provided a way of thinking about causality within a context of expanding sociotechnical systems such as nuclear power plants, civil commercial aviation or petroleum infrastructures. In the 2020 s, high-risk technologies do not only represent potential for single catastrophic events anymore but are also the sources of wider problems associated with globalised flows (systemic risks) and ecological degradation known as anthropocene (leading to existential risks). In this context, the scope, scale and timeframe of high-risk systems is extended in comparison to Perrow’s original work. In these new circumstances, coupling and complexity categories apply to a much wider spectrum of issues than initially conceived by Perrow and notions such as flows, nodes, networks, interconnectedness, and synchronicity should be incorporated to illustrate a move to the global stage. After a presentation and discussion of Perrow’s coupling and interaction, the “global turn” in research is discussed, using sociology and history as examples. It is followed by the contribution by Guillén on the “architecture of collapse” characterising our contemporary era. Its implications for safety science research are then explored using Covid-19 as an example.

Familial transmission of chromoanagenesis leads to unpredictable unbalanced rearrangements through meiotic recombination.

Chromoanagenesis is a cellular mechanism that leads to complex chromosomal rearrangements (CCR) during a single catastrophic event. It may result in loss and/or gain of genetic material and may be responsible for various phenotypes. These rearrangements are usually sporadic. However, some familial cases have been reported. Here, we studied six families in whom an asymptomatic or paucisymptomatic parent transmitted a CCR to its offspring in an unbalanced manner. The rearrangements were characterized by karyotyping, fluorescent in situ hybridization, chromosomal microarray (CMA) and/or whole genome sequencing (WGS) in the carrier parents and offspring. We then hypothesized meiosis-pairing figures between normal and abnormal parental chromosomes that may have led to the formation of new unbalanced rearrangements through meiotic recombination. Our work indicates that chromoanagenesis might be associated with a normal phenotype and normal fertility, even in males, and that WGS may be the only way to identify these events when there is no imbalance. Subsequently, the CCR can be transmitted to the next generation in an unbalanced and unpredictable manner following meiotic recombination. Thereby, prenatal diagnosis using CMA should be proposed to these families to detect any pathogenic imbalances in the offspring.

Long runout distance of a block breccia density flow along a half-graben axis: latest Jurassic rift climax in East Greenland

A basinally isolated breccia–pebbly sandstone couplet occurs in the axial part of the latest Jurassic rift-climax half-graben in Wollaston Forland, East Greenland. Synrift breccias are otherwise restricted to a narrow zone along the scarp of the basin-margin Dombjerg Fault. Towards the north the Dombjerg Fault sidesteps en echelon towards the east where it continues in the Thomsen Land Fault. The breccia part of the couplet was transported by a noncohesive debris flow and the pebbly sandstone by a high-density turbidity flow. The couplet is located about 15 km east of the Dombjerg scarp and flowed southwards along the half-graben axis. It is interpreted to have been derived from the southern end of the Thomsen Land Fault. This gives a runout distance of at least 25 km. Other isolated breccias have been reported towards the south along the half-graben axis, giving a runout distance of up to 40 km along the roughly horizontal half-graben axis. The angularity of the clasts is remarkable and reflects derivation directly from the fault scarp during a single catastrophic event. The occurrence of breccias thus cannot be taken as evidence of short transport and deposition at the foot of a scarp or steep slope.

Chromosomal Rearrangements and Chromothripsis: The Alternative End Generation Model

Chromothripsis defines a genetic phenomenon where up to hundreds of clustered chromosomal rearrangements can arise in a single catastrophic event. The phenomenon is associated with cancer and congenital diseases. Most current models on the origin of chromothripsis suggest that prior to chromatin reshuffling numerous DNA double-strand breaks (DSBs) have to exist, i.e., chromosomal shattering precedes rearrangements. However, the preference of a DNA end to rearrange in a proximal accessible region led us to propose chromothripsis as the reaction product of successive chromatin rearrangements. We previously coined this process Alternative End Generation (AEG), where a single DSB with a repair-blocking end initiates a domino effect of rearrangements. Accordingly, chromothripsis is the end product of this domino reaction taking place in a single catastrophic event.

Abstract 3795: Early seeding of Richter transformation in chronic lymphocytic leukemia

Abstract Introduction: Clonal evolution drives cancer development due to the emergence and/or selection of proliferatively advantageous subclones. Its understanding may facilitate the design of anticipation-based management strategies. Richter transformation (RT) is a paradigmatic tumor evolution in which chronic lymphocytic leukemia (CLL), an indolent neoplasia of mature B-cells, transforms into a high-grade lymphoma, usually diffuse large B-cell lymphoma (DLBCL), conferring a dismal prognosis. The evolutionary trajectories of RT and its driving (epi)genomic mechanisms remain largely unknown. Aims: To reconstruct the evolutionary history of RT and to reveal the molecular processes underlying this transformation. Methods: We characterized the whole genome (WGS), epigenome (DNA methylation, H3K27ac, ATAC-seq), and transcriptome (RNA-seq), combined with single-cell DNA and RNA sequencing analyses, of 19 CLL patients developing RT before (n=3) or after treatment with chemoimmunotherapy (n=6) and targeted therapies (BCR or BCL2 inhibitors, n=10). We analyzed 54 longitudinal samples covering up to 19 years of disease course. Results: Our WGS analyses uncovered that RT is characterized by a remarkable structural complexity. We also identified a novel treatment-independent RT-specific mutational process, which we named SBS-RT. The genetic driver landscape of RT is a compendium of alterations in genes involved in cell cycle, MYC, and NF-κB pathways, frequently targeted in single catastrophic events including chromothripsis and chromoplexy. The WGS-based phylogenic reconstruction and single-cell DNA/RNA-seq analyses identified a very early diversification of CLL leading to emergence of RT-cells carrying specific genetic drivers and transcriptomic profiles of RT already at CLL diagnosis. These small subclones were dormant for 6-19 years until rapid expansion associated with the clinical transformation. While the DNA methylome kept track of the cell of origin and proliferative history of RT cells, their chromatin configuration and transcriptional program converged into the overexpression of cell cycle regulators, Toll-like receptors, MYC, MTORC1, and OXPHOS related transcripts, as well as downregulation of BCR pathway. This phenotypic shift was related to de novo activation of key transcription factors. In vitro experiments confirmed that RT cells have a 4-fold higher oxygen consumption at routine respiration and electron transfer system capacity compared to CLL. The resistance of RT to BCR inhibition is consistent with its high OXPHOS and low BCR signaling, which mimics de novo DLBCL-OXPHOS insensitive to BCR inhibition. This OXPHOShigh-BCRlow transcriptional axis of RT can be exploited therapeutically. Conclusions: These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover therapeutic targets for the, once expanded, lethal Richter transformation. Citation Format: Ferran Nadeu, Romina Royo, Ramon Massoni-Badosa, Beatriz Garcia-Torre, Martí Duran-Ferrer, Kevin J. Dawson, Marta Kulis, Ander Diaz-Navarro, Neus Villamor, Juan L. Melero, Vicente Chapaprieta, Ana Dueso-Barroso, Julio Delgado, Riccardo Moia, Sara Ruiz-Gil, Domenica Marchese, Núria Verdaguer-Dot, Mónica Romo, Maria Rozman, Gerard Frigola, Alfredo Rivas-Delgado, Tycho Baumann, Miguel Alcoceba, Marcos González, Fina Climent, Pau Abrisqueta, Josep Castellví, Francesc Bosch, Marta Aymerich, Anna Enjuanes, Sílvia Ruiz-Gaspà, Armando López-Guillermo, Pedro Jares, Sílvia Beà, Dolors Colomer, Núria López-Bigas, Josep LlGelpí, David Torrents, Peter J. Campbell, Ivo Gut, Pablo M. Garcia-Roves, Davide Rossi, Gianluca Gaidano, Xose S. Puente, Holger Heyn, Francesco Maura, José I. Martín-Subero, Elías Campo. Early seeding of Richter transformation in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3795.

Chromoanagenesis Landscape in 10,000 TCGA Patients.

Simple SummaryChromoanagenesis is a single catastrophic event in which one or few chromosomes are shattered and disorderly reassembled. Chromoanagenesis is common in many types of cancers. In this study, we utilize data from The Pan-Cancer Analysis of Whole Genome (PCAWG) to build a machine learning algorithm that detects chromoanagenesis with high accuracy. We applied the algorithm on ~10,000 samples from The Cancer Genome Atlas (TCGA), thereby providing, for the first time, chromoanagenesis status labels for the complete data set. An in-depth analysis of somatic and clinical chromoanagenesis features is presented for 20 cancer types. Mutual exclusivity patterns between genes impaired in chromoanagenesis versus non-chromoanagenesis cases might imply at distinct pathways involved in chromoanagenesis-driven tumorigenesis.During the past decade, whole-genome sequencing of tumor biopsies and individuals with congenital disorders highlighted the phenomenon of chromoanagenesis, a single chaotic event of chromosomal rearrangement. Chromoanagenesis was shown to be frequent in many types of cancers, to occur in early stages of cancer development, and significantly impact the tumor’s nature. However, an in-depth, cancer-type dependent analysis has been somewhat incomplete due to the shortage in whole genome sequencing of cancerous samples. In this study, we extracted data from The Pan-Cancer Analysis of Whole Genome (PCAWG) and The Cancer Genome Atlas (TCGA) to construct and test a machine learning algorithm that can detect chromoanagenesis with high accuracy (86%). The algorithm was applied to ~10,000 unlabeled TCGA cancer patients. We utilize the chromoanagenesis assignment results, to analyze cancer-type specific chromoanagenesis characteristics in 20 TCGA cancer types. Our results unveil prominent genes affected in either chromoanagenesis or non-chromoanagenesis tumorigenesis. The analysis reveals a mutual exclusivity relationship between the genes impaired in chromoanagenesis versus non-chromoanagenesis cases. We offer the discovered characteristics as possible targets for cancer diagnostic and therapeutic purposes.

Slope Failure in a Period of Increased Landslide Activity: Sennwald Rock Avalanche, Switzerland

The Säntis nappe is a complex fold-and-thrust structure in eastern Switzerland, consisting of numerous tectonic discontinuities and a range of hillslopes prone to landsliding and large slope failures that modify the topography irreversibly. A slope failure, namely the Sennwald rock avalanche, occurred in the southeast wall of this fold-and-thrust structure due to the rock failure of Lower Cretaceous Helvetic limestones along the Rhine River valley. In this research, this palaeolandslide is examined in a multidisciplinary approach for the first time with detection and mapping of avalanche deposits, dynamic run-out modelling and cosmogenic nuclide dating. During the rock failure, the avalanche deposits were transported down the hillslope in a spreading-deck fashion, roughly preserving the original stratigraphic sequence. The distribution of landslide deposits and surface exposure age of the rock failure support the hypothesis that the landslide was a single catastrophic event. The 36Cl surface exposure age of avalanche deposits indicates an age of 4.3 ± 0.5 ka. This time coincides with a notably wet climate period, noted as a conditioning factor for landslides across the Alps in the mid-Holocene. The contemporaneity of our event at its location in the Eastern Alps provide additional support for the contention of increased regional seismic activity in mid-Holocene.

Subterranean freshwater gastropod biodiversity and conservation in the United States and Mexico

Many taxonomic groups successfully exploit groundwater environments and have adapted to a subterranean (stygobiotic) existence. Among these groups are freshwater gastropods (stygosnails), which represent a widespread and taxonomically diverse component of groundwater ecosystems in North America. However, owing to sampling difficulty and lack of targeted study, stygosnails remain among the most understudied of all subterranean groups. We conducted a literature review to assess the biodiversity and geographic associations of stygosnails, along with the threats, management activities, and policy considerations related to the groundwater systems they inhabit. We identified 39 stygosnail species known to occur in a range of groundwater habitats from karst regions in the United States and Mexico. Most stygosnails exhibit extreme narrow-range endemism, resulting in a high risk of extinction from a single catastrophic event. We found that anthropogenically driven changes to surface environments have led to changes in local hydrology and degradation of groundwater systems inhabited by stygosnails such as increased sedimentation, introduction of invasive species, groundwater extraction, or physical collapse of water-bearing passages. Consequently, 32 of the 39 described stygosnail species in the United States and Mexico have been assessed as imperiled under NatureServe criteria, and 10 species have been assessed as threatened under International Union for Conservation of Nature criteria. Compared with surface species of freshwater snails, stygosnail conservation is uniquely hindered by difficulties associated with accessing subterranean habitats for monitoring and management. Furthermore, only three species were found to have federal protection in either the United States or Mexico, and current laws regulating wildlife and water pollution at the state and federal level may be inadequate for protecting stygosnail habitats. As groundwater systems continue to be manipulated and relied on by humans, groundwater-restricted fauna such as stygosnails should be studied so unique biodiversity can be protected.

47. CRISPR Cas9-mediated targeted sequencing on nanopore: a powerful technology to map complex structural chromosome abnormalities

Complex structural chromosome abnormalities are common in cancer cells. Besides the well-known mechanism of gradual accumulation of mutations to prefer cell duplication/survival in cancer cells, complex and massive chromosomal and genomic alterations can also be generated by a chromoanagenesis event, which is characterized by the simultaneous occurrence of multiple structural alterations through a single catastrophic cellular event. Despite improvements in genomics technology, the detection of complex structural chromosome abnormalities from short-read sequencing still poses challenges.

Mechanical properties of 2D aggregates of oil droplets as model mono-crystals.

We investigate the elastic and yielding properties of two dimensional defect-free mono-crystals made of highly monodisperse droplets. Crystals are compressed between two parallel boundaries of which one acts as a force sensor. As the available space between boundaries is reduced, the crystal goes through successive row-reduction transitions. For small compression forces, the crystal responds elastically until a critical force is reached and the assembly fractures in a single catastrophic global event. Correspondingly there is a peak in the force measurement associated with each row-reduction. The elastic properties of ideal mono-crystal samples are fully captured by a simple analytical model consisting of an assembly of individual capillary springs. The yielding properties of the crystal are captured with a minimal bond breaking model.

Chromothripsis in Human Breast Cancer.

Chromothripsis is a form of genome instability by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosomes. Widely assumed to be an early event in tumor development, this phenomenon plays a prominent role in tumor onset. In this study, an analysis of chromothripsis in 252 human breast cancers from two patient cohorts (149 metastatic breast cancers, 63 untreated primary tumors, 29 local relapses, and 11 longitudinal pairs) using whole-genome and whole-exome sequencing reveals that chromothripsis affects a substantial proportion of human breast cancers, with a prevalence over 60% in a cohort of metastatic cases and 25% in a cohort comprising predominantly luminal breast cancers. In the vast majority of cases, multiple chromosomes per tumor were affected, with most chromothriptic events on chromosomes 11 and 17 including, among other significantly altered drivers, CCND1, ERBB2, CDK12, and BRCA1. Importantly, chromothripsis generated recurrent fusions that drove tumor development. Chromothripsis-related rearrangements were linked with univocal mutational signatures, with clusters of point mutations due to kataegis in close proximity to the genomic breakpoints and with the activation of specific signaling pathways. Analyzing the temporal order of events in tumors with and without chromothripsis as well as longitudinal analysis of chromothriptic patterns in tumor pairs offered important insights into the role of chromothriptic chromosomes in tumor evolution. SIGNIFICANCE: These findings identify chromothripsis as a major driving event in human breast cancer.

The Impact of Chromothripsis on the Clinical Outcomes of Acute Myeloid Leukemia (AML): A Meta-Analysis

Introduction: Chromothripsis is a single genomic catastrophic event that can involve one or several chromosomes resulting in chromosomal fragmentation. Genomic instability leading to loss of chromosomes and complex karyotype is known to be associated with resistance to chemotherapy and poor prognosis in AML. While chromothripsis is associated with aggressive clinical course in various cancers, its impact on AML clinical outcomes has not been consistently conclusive. The purpose of this meta-analysis is to evaluate the pooled effect of chromothripsis on the response rates and overall survival of patients with AML. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of AML diagnosis, English language, and studies reporting OS with hazard ratios (HR) or Kaplan-Meier curves that compared AML outcomes with and without chromothripsis. A meta-analysis using an inverse variance method with a random-effects model was conducted. Results: Two comparative studies with a total of 444 patients were included in this meta-analysis. In the presence of chromothripsis OS was adversely impacted (HR 1.78, 95%CI: 1.05-3.01, p=0.03) with a heterogeneity estimate, I2=40%. Moreover, response rates were significantly lower in AML cases with chromothripsis versus those without (19% vs. 62%, p<0.05). Conclusions: This meta-analysis confirms the adverse impact of chromothripsis on response rates and OS of patients with AML. Disclosures No relevant conflicts of interest to declare.

Interphase Cytogenetic Analysis of G0 Lymphocytes Exposed to α-Particles, C-Ions, and Protons Reveals their Enhanced Effectiveness for Localized Chromosome Shattering—A Critical Risk for Chromothripsis

For precision cancer radiotherapy, high linear energy transfer (LET) particle irradiation offers a substantial advantage over photon-based irradiation. In contrast to the sparse deposition of low-density energy by χ- or γ-rays, particle irradiation causes focal DNA damage through high-density energy deposition along the particle tracks. This is characterized by the formation of multiple damage sites, comprising localized clustered patterns of DNA single- and double-strand breaks as well as base damage. These clustered DNA lesions are key determinants of the enhanced relative biological effectiveness (RBE) of energetic nuclei. However, the search for a fingerprint of particle exposure remains open, while the mechanisms underlying the induction of chromothripsis-like chromosomal rearrangements by high-LET radiation (resembling chromothripsis in tumors) await to be elucidated. In this work, we investigate the transformation of clustered DNA lesions into chromosome fragmentation, as indicated by the induction and post-irradiation repair of chromosomal damage under the dynamics of premature chromosome condensation in G0 human lymphocytes. Specifically, this study provides, for the first time, experimental evidence that particle irradiation induces localized shattering of targeted chromosome domains. Yields of chromosome fragments and shattered domains are compared with those generated by γ-rays; and the RBE values obtained are up to 28.6 for α-particles (92 keV/μm), 10.5 for C-ions (295 keV/μm), and 4.9 for protons (28.5 keV/μm). Furthermore, we test the hypothesis that particle radiation-induced persistent clustered DNA lesions and chromatin decompaction at damage sites evolve into localized chromosome shattering by subsequent chromatin condensation in a single catastrophic event—posing a critical risk for random rejoining, chromothripsis, and carcinogenesis. Consistent with this hypothesis, our results highlight the potential use of shattered chromosome domains as a fingerprint of high-LET exposure, while conforming to the new model we propose for the mechanistic origin of chromothripsis-like rearrangements.

Dramatic change in the diet of a late Pleistocene Elasmotherium population during its last days of life: Implications for its catastrophic mortality in the Saratov region of Russia

The late Pleistocene site of Irgiz 1 (Saratov Region, Russia) has yielded an accumulation of giant rhinoceros (Elasmotherium sibiricum) within the deposits of an oxbow lake. Irgiz 1 is one of the few sites in the world with a significant amount of elasmothere individuals of different age groups. Tooth mesowear and microwear are used to characterize the dietary traits of the giant rhinoceros on two temporal scales, the annual average diet and the diet at the time of death, respectively. Tooth mesowear, analyzed on 20 specimens, suggests a highly abrasive diet similar to that of extant grazers (similar to the extant white rhinoceros). Tooth microwear analyzed on 16 specimens, conversely, indicates that E. sibiricum was a browser (feeding on leaves from shrubs and trees) at the time of death. The strong discrepancy between the results from the two dietary proxies and the very low variability of the microwear signal suggest that these animals may have died in an event of short duration. The elasmotheres from the area around Irgiz 1 were grazers, but a catastrophic event, perhaps related to the significant accumulation of snow and/or ice coating (‘dzud’), limited the availability of grass and forced them to shift toward shrub/tree foliage that was still accessible. The combination of the two proxies, mesowear and microwear, allows the reconstruction of the dietary traits of E. sibiricum, but also to propose a hypothesis for death. This first study of tooth meso- and microwear on elasmotheres provided unique data which allows us to broaden our knowledge about the diet of these animals. The findings indicate that the Irgiz 1 population of elasmotheres died in a single catastrophic event and that the fossil assemblage is not time-averaged.

The landscape of chromothripsis across adult cancer types

Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. Here we analyse chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals insights in the clonal evolution of tumours with chromothripsis.