Levels Of Aneuploidy Research Articles

Cancer type-dependent correlations between TP53 mutations and antitumor immunity

Many studies have shown that TP53 mutations play a negative role in antitumor immunity. However, a few studies reported that TP53 mutations could promote antitumor immunity. To explain these contradictory findings, we analyzed five cancer cohorts from The Cancer Genome Atlas (TCGA) project. We found that TP53-mutated cancers had significantly higher levels of antitumor immune signatures than TP53-wildtype cancers in breast invasive carcinoma (BRCA) and lung adenocarcinoma (LUAD). In contrast, TP53-mutated cancers had significantly lower antitumor immune signature levels than TP53-wildtype cancers in stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC). Moreover, TP53-mutated cancers were more likely to have a higher tumor mutation burden (TMB) and tumor aneuploidy level (TAL) than TP53-wildtype cancers. However, the TMB differences were more marked between TP53-mutated and TP53-wildtype cancers than the TAL differences in BRCA and LUAD, and the TAL differences were more significant in STAD and COAD. Furthermore, we showed that TMB and TAL had a positive and a negative correlation with antitumor immunity and that TMB affected antitumor immunity more than TAL did in BRCA and LUAD while TAL affected antitumor immunity more strongly than TMB in STAD and HNSC. These findings indicate that the distinct correlations between TP53 mutations and antitumor immunity in different cancer types are a consequence of the joint effect of the altered TMB and TAL caused by TP53 mutations on tumor immunity. In addition, the deregulation of p53-mediated pathways, including cell cycle and apoptosis, may also contribute to the different correlations of TP53 mutations with antitumor immunity between different cancer cohorts. Furthermore, we demonstrated the different correlations of TP53 mutations with the response to immune checkpoint inhibitors between different cancer cohorts, suggesting that the TP53 mutation status could be a useful biomarker for predicting the response to cancer immunotherapy in different cancer types.

From tumorigenesis to cell death: the aneuploidy paradox

ABSTRACTAneuploidy, an abnormal chromosome number, is a hallmark of cancer. We recently showed that depletion of microtubule-associated protein ATIP3 (AT2 receptor-interacting protein 3) induces aneuploidy and sensitizes breast cancer cells to taxanes. Combining taxane treatment with ATIP3 depletion cooperates to reach a detrimental level of aneuploidy.

Is it forever? Genotoxicological impact of marine contaminants on Arabian/Persian Gulf bivalves: An experimental approach

A novel approach of combining manipulative field experiments and cytogenetic endpoints was used to assess the genotoxic impact of chemical contamination on a local model bivalve species, the pearl oyster -Pinctada imbricata radiata. Baseline levels of Polycyclic Aromatic Hydrocarbons (PAHs), Total Petroleum Hydrocarbons (TPHs) and trace metals were determined from surface sediments and pearl oyster tissue collected from 3 coastal locations in Qatar (Umm Bab, Dukhan and Al-Wakra). Initial aneuploidy –numerical chromosomal abnormality-level in oysters was also assessed during the baseline survey. The oysters’ ability to adapt to new sites, with distinct signatures in terms of chemical contamination, was assessed using a reciprocal transplantation experiment among the same 3 coastal locations, from February to April 2016. Significant differences in sediment contamination levels were detected among the 3 sites. TPHs were in higher concentrations at Umm Bab (western coast), while higher concentrations of metals and PAHs were found at Dukhan (western coast) and Al-Wakra (eastern coast), respectively. Oysters transplanted between locations showed lower levels of aneuploidy, relative to those kept in the original location (controls). Transplanted oysters, regardless of the contamination levels at the origin and destination, showed recovery from initial aneuploidy levels. Moreover, there was a larger percentage of aneuploid cells with chromosomal gain than with chromosomal loss in all treatments, which contrasts with the pattern usually observed in bivalves.

Relationship between age and blastocyst chromosomal ploidy analyzed by noninvasive preimplantation genetic testing for aneuploidies (niPGT-A).

Objective:To assess the relationship between human blastocyst chromosomal ploidy established by niPGT-A and increasing age.Methods:This is a prospective multicenter study carried out by ten assisted reproduction centers after their embryologists acquired training and validated their results with the previous use of niPGT-A. A total of 94 couples with indication for niPGT-A due to increase maternal age, male factor, repeated implantation failures, recurrent abortion or because they requested niPGT-A were included in this study. The couples had no karyotype abnormalities. After ICSI, the embryos were cultured until blastocyst stage using one or two step culture systems, single or sequential media respectively, at 37ºC in an atmosphere of 6-7% CO2 and 5-20% O2 incubators. On day 3, we re-evaluated cleavage embryos to complete cumulus cells removal. The embryos were then cultured in individual well, with 20µl of medium under oil until they reached blastocyst stage. The blastocysts were vitrified and stored in liquid nitrogen. After that, the spent blastocyst culture medium (20µl) was transferred to a PCR tube and sent for analysis in the genetic laboratory, where it was stored at -80ºC until sequencing. A total of 243 samples of spent blastocyst culture medium were collected on the 5th/6th day. Cell-free DNA secreted on culture medium was amplified using NICS Sample Preparation Kit (Yikon Genomics), based on the MALBAC technology. After whole genome amplification, the DNA was measured using a Qubit 2.0 fluorometer and subjected to next generation sequencing (NGS) using Illumina MiSeq® platform. The data were analyzed using the ChromGo® software (Yikon Genomics).Results:The mean age of the patients was 38±4.08 years with an interval of 20-44 years. The euploid was diagnosed in 36.4% (80/220) of cases, aneuploidy in 31.3% (69/220), and mosaicism in 32.3% (71/220; with ≥60% aneuploidy) of blastocysts. Mosaic values ranged from 29.8% to 33.8% in different age groups. Individually, the most frequent chromosomal abnormality was XXY (Klinefelter Syndrome) occurring in 18 cases, followed by chromosome 21 (trisomy/monosomy) in 8 cases. The niPGT-A data showed a ≥60% incidence of aneuploid cells in all cases of chromosomal mosaicism (n=71).Conclusion:A high degree of mosaicism with aneuploidy cells was detected, and some hypotheses were suggested for this data (niPGT-A sensitivity in detecting the self-correction of chromosomal abnormalities phenomenon). However, it did not vary remarkably with age. On the other hand, euploidy levels had a negative correlation with age and aneuploidy levels had a positive relationship. This is the first report in the literature to relate chromosomal ploidy in blastocysts using niPGT-A and increasing patient age.

Zygotic Autopolyploidization of Rye (Secale cereale L.)

The paper presents the results of zygotic autopolyploidization by the nitrous oxide (N2O) of diploid cultivars and F1 hybrids of winter rye. It has been shown that the method of creating zygotic rye tetraploids by the nitrous oxide (N2O) is effective and allows obtaining up to 86.0% of tetraploids. The average yield of tetraploids was 51.0%. Nine new rye tetraploids were created with this method. The created tetraploids are characterized by chromosomal balance and low levels of aneuploidy (up to 9.7%). Meiosis in rye zygotic tetraploids occurs with significantly more defections (P ≤ 0.05) than in the original diploids. It has been established that part of the nuclear DNA is eliminated in the created tetraploids to the C6–C7 generations. On the basis of the obtained tetraploid Yubileinaya, a new variety of winter tetraploid rye Camea 16 was created.

15.IMPACT OF MATERNAL AGE IN THE INCIDENCE OF UNIFORM AND MOSAIC ANEUPLOIDIES

Introduction Female fertility decreases with age and increases the incidence of aneuploidies mostly due to meiotic errors. The incidence of aneuploid embryos turn around 60% confirming the high abortion rates observed by the presence of chromosomal aneuploidies. Next generation sequencing (NGS) proved to be the most appropriate technology for aneuploidy testing in trophectoderm biopsies, with accurate results, high throughput and cost efficiency. However, the rates and levels of embryonic mosaicism are still a subject of discussion. It is known that they can lead to miscarriage and birth defects but the data linking advanced maternal age and mosaicism is limited. Thus, this study aims to assess the differences between the incidence of different levels of mosaicism and uniform aneuploidies in blastocyst biopsies according to maternal age to verify if they follow a similar pattern. Material & methods A total of 34,387 blastocyst biopsies were sent for PGT-A analysis between October and December 2018 from private assisted reproduction centers to our laboratory. NGS technology (ThermoFisher platform) combined with diagnosis a proprietary validated algorithm was used to optimize results. Patients were stratified by age in seven groups: 50% - 30% - Results 33,341 biopsies were informative with 6% (n=1997) of total mosaicism, 47% uniform aneuploidy (n= 15.670) and 47% euploid biopsies (n=15.674). Regarding the mosaicism rates, 65.3 % (n= 1305) were low mosaic degree, and 34.6% (n=692) were high mosaic degree. A significant decrease (p Conclusions The rate of euploid embryos decreased with advanced maternal age and aneuploidies increased, corroborating previous data from other studies. Regarding mosaicism different trends were observed for low mosaic degree, with a trend towards a decrease of low mosaic degree with maternal age, and high mosaic degree without an effect of maternal age.

ARID1A Mutations Are Associated with Increased Immune Activity in Gastrointestinal Cancer.

Because traditional treatment strategies for advanced gastrointestinal (GI) cancers often have a limited therapeutic effect, immunotherapy could be a viable approach for the therapy of advanced GI cancers, considering the recent success of immunotherapy in treating various refractory malignancies, including the DNA mismatch repair-deficient GI cancers. However, only a subset of cancer patients currently respond to immunotherapy. Thus, it is important to identify useful biomarkers for predicting cancer immunotherapy response. The tumor suppressor gene ARID1A has a high mutation rate in GI cancers and its deficiency is correlated with the microsatellite instability (MSI) genomic feature of cancer. We investigated the correlation between ARID1A mutations and tumor immunity using three GI cancer genomics datasets by the bioinformatic approach, and found that diverse antitumor immune signatures were more highly enriched in ARID1A-mutated GI cancers than in ARID1A-wildtype GI cancers. The elevated immune activity in ARID1A-mutated GI cancers was associated with the higher tumor mutation burden and lower tumor aneuploidy level, as well as a higher proportion of MSI cancers in this GI cancer subtype. Moreover, we found that ARID1A-mutated GI cancers more highly expressed PD-L1 than ARID1A-wildtype GI cancers. The elevated antitumor immune signatures and PD-L1 expression could contribute to the more active immunotherapeutic responsiveness and better survival prognosis in ARID1A-mutated GI cancers than in ARID1A-wildtype GI cancers in the immunotherapy setting, as evidenced in three cancer cohorts receiving immunotherapy. Thus, the ARID1A mutation could be a useful biomarker for identifying GI cancer patients responsive to immunotherapy.

Abstract 2736: A molecular and histopathologic map of cancer metastasis

Abstract Metastatic disease is responsible for the vast majority of cancer-related deaths. Patterns of metastatic spread and colonization are, however, not random: routes of metastatic dissemination are cancer-type specific, and different cancer types exhibit varying levels of affinity for specific organs as metastatic target sites. We analyzed a cohort of more than 30,000 patients that were treated at Memorial Sloan Kettering Cancer Center (MSK) and had their tumors sequenced using the clinical MSK-IMPACT test, a targeted next-generation sequencing assay that identifies mutations, copy number changes and structural rearrangements in 468 genes. By querying the electronic medical record, we catalogued all metastatic events in the clinical history of these patients and mapped them to a set of 32 tissue sites. The primary diagnoses spanned 30 different cancer types, which were further stratified into >50 relevant molecular subtypes, based on a combination of molecular and histopathological features. Observed patterns of metastatic dissemination were cancer type specific and, in some cases, exhibited strong differences across molecular subtypes of the same cancer type. For example, HER2+ subtypes of breast cancer exhibited increased rates of brain (34% vs. 18%, p<0.0001) and lung (31% vs. 19%, p=0.006) metastasis when compared to HER2- subtypes. The median number of organs affected by metastatic disease per patient was 4 (range 1-14). The number of affected organs exhibited a strong positive correlation with the overall level of aneuploidy, as measured by the total fraction of genome altered by copy number changes (P<0.0001, Spearman correlation), but not with overall mutational burden. We identified genomic alterations that were significantly enriched in tumors from patients with metastasis to specific organs in a cancer-type dependent manner. For example, 244/556 (44%) of lung adenocarcinoma patients with EGFR amplification or activating mutations presented bone metastasis at some point of their clinical history, as opposed to only 400/1,124 (36%) of EGFR wild type patients (p=0.001, Fisher’s exact test). In the case of HR+/ER- breast adenocarcinoma patients, bone metastases were reported in 22/30 (73%) of patients with NF1 inactivated tumors, as opposed to only 330/745 (44%) of patients with NF1 wild-type (p=0.002, Fisher’s exact test). We present the first pan-cancer study that combines molecular and histopathological features to draw a comprehensive atlas of tumor metastasis. Our results provide novel insights into the biology of metastatic tumors and can have a direct impact on patient management and care by optimizing the use and frequency of specific imaging studies for metastasis surveillance. Citation Format: Francisco Sanchez-Vega, Christopher Fong, Walid Chatila, Philip Jonsson, Alexander V. Penson, Renzo G. DiNatale, Michael F. Berger, Ahmet Zehir, Ed Reznik, Jianjiong Gao, Karuna Ganesh, Barry S. Taylor, Nikolaus Schultz. A molecular and histopathologic map of cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2736.

The Immune Subtypes and Landscape of Squamous Cell Carcinoma.

To identify immune subtypes and investigate the immune landscape of squamous cell carcinomas (SCC), which share common etiology and histologic features. Based on the immune gene expression profiles of 1,368 patients with SCC in the Cancer Genome Atlas (TCGA), we used consensus clustering to identify robust clusters of patients and assessed their reproducibility in an independent pan-SCC cohort of 938 patients. We further applied graph structure learning-based dimensionality reduction to the immune profiles to visualize the distribution of individual patients. We identified and independently validated six reproducible immune subtypes associated with distinct molecular characteristics and clinical outcomes. An immune-cold subtype had the least amount of lymphocyte infiltration and a high level of aneuploidy, and these patients had the worst prognosis. By contrast, an immune-hot subtype demonstrated the highest infiltration of CD8+ T cells, activated NK cells, and elevated IFNγ response. Accordingly, these patients had the best prognosis. A third subtype was dominated by M2-polarized macrophages with potent immune-suppressive factors such as TGFβ signaling and reactive stroma, and these patients had relatively inferior prognosis. Other subtypes showed more diverse immunologic features with intermediate prognoses. Finally, our analysis revealed a complex immune landscape consisting of both discrete clusters and continuous spectrum. This study provides a conceptual framework to understand the tumor immune microenvironment of SCCs. Future work is needed to evaluate its relevance in the design of combination treatment strategies and guiding optimal selection of patients for immunotherapy.

Role of aneuploidy in the carcinogenic process: Part 3 of the report of the 2017 IWGT workgroup on assessing the risk of aneugens for carcinogenesis and hereditary diseases

Aneuploidy is regarded as a hallmark of cancer, however, its role is complex with both pro- and anti-carcinogenic effects evident. In this IWGT review, we consider the role of aneuploidy in cancer biology; cancer risk associated with constitutive aneuploidy; rodent carcinogenesis with known chemical aneugens; and chemotherapy-related malignant neoplasms.Aneuploidy is seen at various stages in carcinogenesis. However, the relationship between induced aneuploidy occurring after exposure and clonal aneuploidy present in tumours is not clear. Recent evidence indicates that the induction of chromosomal instability (CIN), may be more important than aneuploidy per se, in the carcinogenic process.Down Syndrome, trisomy 21, is associated with altered hematopoiesis in utero which, in combination with subsequent mutations, results in an increased risk for acute megakaryoblastic and lymphoblastic leukemias. In contrast, there is reduced cancer risk for most solid tumours in Down Syndrome. Mouse models with high levels of aneuploidy are also associated with increased cancer risk for particular tumours with long latencies, but paradoxically other types of tumour often show decreased incidence.The aneugens reviewed that induce cancer in humans and animals all possess other carcinogenic properties, such as mutagenicity, clastogenicity, cytotoxicity, organ toxicities, hormonal and epigenetic changes which likely account for, or interact with aneuploidy, to cause carcinogenesis. Although the role that aneuploidy plays in carcinogenesis has not been fully established, in many cases, it may not play a primary causative role. Tubulin-disrupting aneugens that do not possess other properties linked to carcinogenesis, were not carcinogenic in rodents. Similarly, in humans, for the tubulin-disrupting aneugens colchicine and albendazole, there is no reported association with increased cancer risk. There is a need for further mechanistic studies on agents that induce aneuploidy, particularly by mechanisms other than tubulin disruption and to determine the role of aneuploidy in pre-neoplastic events and in early and late stage neoplasia.

Physiological, hyaluronan-selected intracytoplasmic sperm injection for infertility treatment (HABSelect): a parallel, two-group, randomised trial

SummaryBackgroundSperm selection strategies aimed at improving success rates of intracytoplasmic sperm injection (ICSI) include binding to hyaluronic acid (herein termed hyaluronan). Hyaluronan-selected sperm have reduced levels of DNA damage and aneuploidy. Use of hyaluronan-based sperm selection for ICSI (so-called physiological ICSI [PICSI]) is reported to reduce the proportion of pregnancies that end in miscarriage. However, the effect of PICSI on livebirth rates is uncertain. We aimed to investigate the efficacy of PICSI versus standard ICSI for improving livebirth rates among couples undergoing fertility treatment.MethodsThis parallel, two-group, randomised trial included couples undergoing an ICSI procedure with fresh embryo transfer at 16 assisted conception units in the UK. Eligible women (aged 18–43 years) had a body-mass index of 19–35 kg/m2 and a follicle-stimulating hormone (FSH) concentration of 3·0–20·0 mIU/mL or, if no FSH measurement was available, an anti-müllerian hormone concentration of at least 1·5 pmol/L. Eligible men (aged 18–55 years) had not had a vasovasostomy or been treated for cancer in the 24 months before recruitment and were able, after at least 3 days of sexual abstinence, to produce freshly ejaculated sperm for the treatment cycle. Couples were randomly assigned (1:1) with an online system to receive either PICSI or a standard ICSI procedure. The primary outcome was full-term (≥37 weeks' gestational age) livebirth, which was assessed in all eligible couples who completed follow-up. This trial is registered, number ISRCTN99214271.FindingsBetween Feb 1, 2014, and Aug 31, 2016, 2772 couples were randomly assigned to receive PICSI (n=1387) or ICSI (n=1385), of whom 2752 (1381 in the PICSI group and 1371 in the ICSI group) were included in the primary analysis. The term livebirth rate did not differ significantly between PICSI (27·4% [379/1381]) and ICSI (25·2% [346/1371]) groups (odds ratio 1·12, 95% CI 0·95–1·34; p=0·18). There were 56 serious adverse events in total, including 31 in the PICSI group and 25 in the ICSI group; most were congenital abnormalities and none were attributed to treatment.InterpretationCompared with ICSI, PICSI does not significantly improve term livebirth rates. The wider use of PICSI, therefore, is not recommended at present.FundingNational Institute for Health Research Efficacy and Mechanism Evaluation Programme.

Gene expression profiles in genome instability-based classes of colorectal cancer

BackgroundBroad copy number aberrations (BCNAs) represent a common form of genome instability in colorectal cancer (CRC). CRCs show large variations in their level of aneuploidy: microsatellite-instable (MSI) tumors are known to have a near-diploid karyotype while microsatellite-stable (MSS) tumors show high level of chromosomal instability. However, MSS tumors have great heterogeneity in the number of BCNAs, with a minor percentage of samples showing an almost normal karyotype. In the present work we subdivided MSS CRCs according to a “BCNA score” and characterized their transcriptome profiles, considered as a proxy to their phenotypic features.MethodsMicrosatellite testing, genome-wide DNA copy number and whole-transcript expression analysis (HTA) were performed on 33 tumor samples and 25 normal colonic tissue samples from 32 CRC patients. 15.1% of the samples were MSI tumors (n = 5), whereas 84.9% were MSS tumors (n = 28). Gene expression data of 34 additional MSI tumors was retrieved from a public functional genomics data repository.ResultsUsing as a threshold the first quartile of the BCNA score distribution, MSS samples were classified as low-BCNA (LB, n = 7) or high-BCNA (HB, n = 21). LB tumors were enriched for mucinous CRCs and their gene-expression profile resembled that of MSI samples for what concerns a subset of genes involved in secretory processes, mucosal protection, and extracellular matrix remodeling. HB tumors were predominantly non-mucinous adenocarcinomas and showed overexpression of a subset of genes typical of surface colonocytes and EGF signaling. A large percentage of unclassified samples according to the consensus molecular subtypes (CMS) classifier was found in the LB group (43%), whereas 76% HB tumors belonged to CMS2.ConclusionsA classification of colorectal tumors based on the number of BCNAs identifies two groups of MSS tumors which differ for histopathology and gene expression profile. Such information can be exploited for its translational relevance in different aspects of CRC clinical management.

In vivo haploid induction leads to increased frequency of twin-embryo and abnormal fertilization in maize

BackgroundIn vivo haploid induction (HI) based on Stock6-derived inducer lines has been the most prevalent means of producing haploids. Nevertheless, the biological mechanism of HI is not fully understood, the twin-embryo kernels had been found during haploid induction, which may provide potential evidence for the abnormal double fertilization during HI.ResultsWe investigated twin-embryo frequency in progenies of different haploid inducers. Results reveal that increasing the HI potential significantly improved the frequency of twin-embryo kernels. Compared with the average twin-embryo kernel frequency (average frequency = 0.07%) among progenies pollinated by the haploid inducer line CAUHOI, the frequency of twin-embryo was improved to 0.16% in progenies pollinated by the haploid inducer line CAU5. This result was further confirmed by pollinating single hybrid ND5598 with four haploid inducers possessing differentiated HIRs, where twin-embryo frequency was highly correlated with HIR. Among 237 twin-embryo kernels, we identified 30 haploid twin-embryo kernels (12.66%), a frequency which was much greater than the average HI rate for three other inducer lines (frequency range 2–10%). In addition, aneuploids, occurred at high frequency (8 in 41 twin plants). This level of aneuploidy provides new insight into the abnormal double fertilization during HI. Moreover, we observed differences in growth rate between twin plants in the field, as 4.22% of the twin plants grew at a significantly different rate. Both simple sequence repeats markers (SSR) and 3072 SNP-chip genotyping results revealed that > 90% of the twin plants shared the same origin, and the growth difference could be attributed to aneuploidy, competition for nutrients, and possible hormone regulation.ConclusionThese results demonstrate that an enhanced HI ability can increase twin-embryo kernel frequency, and high frequency of both haploid twin-embryo kernels and aneuploidy observed in this research give us new insights to understand the mechanism of both HI and abnormal embryogenesis.

Genetic interactions between specific chromosome copy number alterations dictate complex aneuploidy patterns.

Cells that contain an abnormal number of chromosomes are called aneuploid. High rates of aneuploidy in cancer are correlated with an increased frequency of chromosome missegregation, termed chromosomal instability (CIN). Both high levels of aneuploidy and CIN are associated with cancers that are resistant to treatment. Although aneuploidy and CIN are typically detrimental to cell growth, they can aid in adaptation to selective pressures. Here, we induced extremely high rates of chromosome missegregation in yeast to determine how cells adapt to CIN over time. We found that adaptation to CIN occurs initially through many different individual chromosomal aneuploidies. Interestingly, the adapted yeast strains acquire complex karyotypes with specific subsets of the beneficial aneuploid chromosomes. These complex aneuploidy patterns are governed by synthetic genetic interactions between individual chromosomal abnormalities, which we refer to as chromosome copy number interactions (CCNIs). Given enough time, distinct karyotypic patterns in separate yeast populations converge on a refined complex aneuploid state. Surprisingly, some chromosomal aneuploidies that provided an advantage early on in adaptation are eventually lost due to negative CCNIs with even more beneficial aneuploid chromosome combinations. Together, our results show how cells adapt by obtaining specific complex aneuploid karyotypes in the presence of CIN.

Meiotic nondisjunction and sperm aneuploidy in humans.

Infertility is relatively common affecting approximately 1-in-6 couples. Although the genetic basis of infertility is increasingly being uncovered, the contribution of male infertility often remains unexplained. The leading cause of pregnancy loss and cognitive impairment in humans is chromosome aneuploidy. Sperm aneuploidy is routinely evaluated by fluorescence in situ hybridization. The majority of studies have reported similar findings, namely: (1) all men produce aneuploid sperm; (2) certain chromosomes are more prone to undergo chromosome nondisjunction; (3) infertile men typically have significantly higher levels of sperm aneuploidy compared to controls and (4) the level of aneuploidy is often correlated with the severity of the infertility. Despite this, sperm aneuploidy screening is rarely evaluated in the infertility clinic. Within recent years, there appears to be renewed interest in the clinical relevance of sperm aneuploidy. We shall examine the gender differences in meiosis between the sexes and explore why less emphasis is placed on the paternal contribution to aneuploidy. Increased sperm aneuploidy is often perceived to be modest and not clinically relevant, compared to the female contribution. However, even small increases in sperm aneuploidy may impact fertility and IVF cycle outcomes. Evidence demonstrating the clinical relevance of sperm aneuploidy will be discussed, as well as some of the challenges precluding widespread clinical implementation. Technological developments that may lead to widespread clinical implementation will be discussed. Recommendations will be suggested for specific patient groups that may benefit from sperm aneuploidy screening and whether preimplantation genetic testing for aneuploidy should be discussed with these patients.

Aneuploidy in intestinal stem cells promotes gut dysplasia in Drosophila.

Aneuploidy is associated with different human diseases including cancer. However, different cell types appear to respond differently to aneuploidy, either by promoting tumorigenesis or causing cell death. We set out to study the behavior of adult Drosophila melanogaster intestinal stem cells (ISCs) after induction of chromosome missegregation either by abrogation of the spindle assembly checkpoint or through kinetochore disruption or centrosome amplification. These conditions induce moderate levels of aneuploidy in ISCs, and we find no evidence of apoptosis. Instead, we observe a significant accumulation of ISCs associated with increased stem cell proliferation and an excess of enteroendocrine cells. Moreover, aneuploidy causes up-regulation of the JNK pathway throughout the posterior midgut, and specific inhibition of JNK signaling in ISCs is sufficient to prevent dysplasia. Our findings highlight the importance of understanding the behavior of different stem cell populations to aneuploidy and how these can act as reservoirs for genomic alterations that can lead to tissue pathologies.

Abstract IA02: The role of aneuploidy during tumorigenesis

Abstract Since Boveri’s postulates in 1914, aneuploidy has been recognized as a hallmark of human cancer; however, no comprehensive theory exists to explain its patterns and its role in tumor evolution. We have developed Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method for the prediction of tumor suppressor genes (TSG) and oncogenes (OG) through the analysis of the pattern of somatic mutations in cancer. By integrating our prediction of TSGs and OGs with information of copy number alterations, we found that the distribution on chromosomes and the potency of TSGs and OGs can predict the frequency of arm-level and chromosome-level deletions and amplification (Davoli et al., 2013). We propose that it is the decrease or increase in the gene dosage of TSG and OG genes in deletion and amplification to determine the recurrent patterns of aneuploidy selected during tumor evolution. More recently, we have performed gene expression analysis on tumor samples, comparing tumors with different levels of aneuploidy (Davoli et al., 2017). We have found that tumors with high levels of aneuploidy show increased markers of proliferation as well as a strong decrease in infiltrating immune cells, especially CD8+ T cells. Notably, we show that aneuploidy predicts patients’ survival in two clinical trails of immunotherapy in cancer patients. Compared to neoantigen load, aneuploidy represents an independent and stronger predictor of survival. A combined score including aneuploidy and neoantigen load allows superior prediction of survival after immunotherapy. We are now investigating the mechanism by which aneuploidy affects cancer immune evasion. I will present novel data suggesting that aneuploidy may play a role in inhibiting and dysregulating antigen processing and presentation in tumor cells. Overall, our data indicate that aneuploidy is a driver event in human tumorigenesis. Citation Format: Teresa Davo4li. The role of aneuploidy during tumorigenesis [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA02.

Chromosome segregation and chromatin integrity in spermatozoa from a t(2;8)(p24;p21)mat carrier: A case-report

Chromosome rearrangements can produce genomic imbalance in gametes which causes a drastic decrease in fertility. Several studies have described the relationship between high levels of DNA damage and chromosomal alterations in the spermatozoa of infertile or subfertile males. However, the nature of this relation is poorly understood. In this study, the meiotic segregation pattern and chromatin integrity were analyzed in the ejaculated spermatozoa of a 46, XY, t(2;8)(p24;p21)mat carrier with normozoospermia and a lack of conception. A 39-year-old infertile man with a 46, XY, t(2;8)(p24;p21)mat inherited from his mother, was studied. The wife of the proband (30 yrs old) had a normal karyotype and no reproductive problems. The meiotic segregation pattern and aneuploidy of chromosome-8 and chromosome-2 were analyzed by FISH. Sperm DNA damage was evaluated by the Sperm Dispersion Chromatin, alkaline comet assay and DNA breaking detection. Five healthy male donors were included as controls. The frequency of genetically unbalanced spermatozoa was 61.6%. Analysis of the aneuploidy of chromosome-8 and chromosome-Y revealed approximately three and 24 fold increased level respectively in comparison with that of the control group. We suggest that the accumulation of genetically unbalanced spermatozoa, and increased sperm aneuploidy level is related to male infertility. Interestingly, the case described here has a high level of sperm chromosomal imbalance appears to be linked to sperm DNA fragmentation status. This information could be useful in assisted reproductive techniques.

On the loss of human sex chromosomes in lymphocytes with age: a quantitative treatment.

Increasing levels of aneuploidy of the sex chromosomes in human lymphocytes with age have been noted for several decades. The percentage of chromosome Y loss can reach up to 1.5% or even more, whereas the levels of X0 cells in females can increase up to 5% with age. Here, I propose simple mathematical models of the dynamics of 'normal' sex chromosome loss with age. These exponential models provide more mechanistic insights than linear regressions. They account for the lower incidence of sex chromosome loss in young individuals and its increase with age. Moreover, the exponential models show that aneuploidy of the sex chromosomes provides a selective advantage. As there are no longitudinal data available (for the same individual at different time points), the parameters reported here are average values derived from a population. Hopefully, this study will stimulate further work based on next-generation technologies to obtain better estimates of sex chromosome aneuploidy and of the parameters of the models discussed here.

Chromosomal instability-induced senescence potentiates cell non-autonomous tumourigenic effects

Chromosomal instability (CIN), a high rate of chromosome loss or gain, is often associated with poor prognosis and drug resistance in cancers. Aneuploid, including near-polyploid, cells contain an abnormal number of chromosomes and exhibit CIN. The post-mitotic cell fates following generation of different degrees of chromosome mis-segregation and aneuploidy are unclear. Here we used aneuploidy inducers, nocodazole and reversine, to create different levels of aneuploidy. A higher extent of aneuploid and near-polyploid cells in a given population led to senescence. This was in contrast to cells with relatively lower levels of abnormal ploidy that continued to proliferate. Our findings revealed that senescence was accompanied by DNA damage and robust p53 activation. These senescent cells acquired the senescence-associated secretory phenotype (SASP). Depletion of p53 reduced the number of senescent cells with concomitant increase in cells undergoing DNA replication. Characterisation of these SASP factors demonstrated that they conferred paracrine pro-tumourigenic effects such as invasion, migration and angiogenesis both in vitro and in vivo. Finally, a correlation between increased aneuploidy and senescence was observed at the invasive front in breast carcinomas. Our findings demonstrate functional non-equivalence of discernable aneuploidies on tumourigenesis and suggest a cell non-autonomous mechanism by which aneuploidy-induced senescent cells and SASP can affect the tumour microenvironment to promote tumour progression.