The New Era of Cancer Cytogenetics and Cytogenomics.

The promises of the cancer genome sequencing project, combined with various -omics technologies, have raised questions about the importance of cancer cytogenetic analyses. It is suggested that DNA sequencing provides high resolution, speed, and automation, potentially replacing cytogenetic testing. We disagree with this reductionist prediction. On the contrary, various sequencing projects have unexpectedly challenged gene theory and highlighted the importance of the genome or karyotype in organizing gene network interactions. Consequently, profiling the karyotype can be more meaningful than solely profiling gene mutations, especially in cancer where karyotype alterations mediate cellular macroevolution dominance. In this chapter, recent studies that illustrate the ultimate importance of karyotype in cancer genomics and evolution are briefly reviewed. In particular, the long-ignored non-clonal chromosome aberrations or NCCAs are linked to genome or chromosome instability, genome chaos is linked to genome reorganization under cellular crisis, and the two-phased cancer evolution reconciles the relationship between genome alteration-mediated punctuated macroevolution and gene mutation-mediated stepwise microevolution. By further synthesizing, the concept of karyotype coding is discussed in the context of information management. Altogether, we call for a new era of cancer cytogenetics and cytogenomics, where an array of technical frontiers can be explored further, which is crucial for both basic research and clinical implications in the cancer field.

Tracking Karyotype Changes in Treatment-Induced Drug-Resistant Evolution.

Karyotype coding, which encompasses the complete chromosome sets and their topological genomic relationships within a given species, encodes system-level information that organizes and preserves genes' function, and determines the macroevolution of cancer. This new recognition emphasizes the crucial role of karyotype characterization in cancer research. To advance this cancer cytogenetic/cytogenomic concept and its platforms, this study outlines protocols for monitoring the karyotype landscape during treatment-induced rapid drug resistance in cancer. It emphasizes four key perspectives: combinational analyses of phenotype and karyotype, a focus on the entire evolutionary process through longitudinal analysis, a comparison of whole landscape dynamics by including various types of NCCAs (including genome chaos), and the use of the same process to prioritize different genomic scales. This protocol holds promise for studying numerous evolutionary aspects of cancers, and it further enhances the power of karyotype analysis in cancer research.

Characterizing Chemotherapy/Radiotherapy-Induced Genome Chaos in Hodgkin's Lymphoma Patients Using M-FISH.

Hodgkin lymphoma (HL) is one of the most common lymphomas, with an incidence of 3 per 100,000 persons. Current treatment uses a cocktail of genotoxic agents, including adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), along with or without radiotherapy. This treatment regimen has proved to be efficient in killing cancer cells, resulting in HL patients having a survival rate of >90% cancer-free survival at five years. However, this therapy does not have a specific cell target, and it can induce damage in the genome of non-cancerous cells. Previous studies have shown that HL survivors often exhibit karyotypes characterized by complex chromosomal abnormalities that are difficult to analyze by conventional banding. Multicolor fluorescence in situ hybridization (M-FISH) is a powerful tool to analyze complex karyotypes; we used M-FISH to investigate the presence of chromosomal damage in peripheral blood lymphocytes from five healthy individuals and five HL patients before, during, and one year after anti-cancer treatment. Our results show that this anti-cancer treatment-induced genomic chaos that persists in the hematopoietic stem cells from HL patients one year after finishing therapy. This chromosomal instability may play a role in the occurrence of second primary cancers that are observed in 10% of HL survivors. This chapter will describe a protocol for utilizing M-FISH to study treatment-induced genome chaos in Hodgkin's lymphoma (HL) patients, following a brief discussion.

The Digital World of Cytogenetic and Cytogenomic Web Resources.

The dynamic growth of technological capabilities at the cellular and molecular level has led to a rapid increase in the amount of data on the genes and genomes of organisms. In order to store, access, compare, validate, classify, and understand the massive data generated by different researchers, and to promote effective communication among research communities, various genome and cytogenetic online databases have been established. These data platforms/resources are essential not only for computational analyses and theoretical syntheses but also for helping researchers select future research topics and prioritize molecular targets. Furthermore, they are valuable for identifying shared recurrent genomic patterns related to human diseases and for avoiding unnecessary duplications among different researchers. The website interface, menu, graphics, animations, text layout, and data from databases are displayed by a front end on the screen of a monitor or smartphone. A database front-end refers to the user interface or application that enables accessing tabular, structured, or raw data stored in the database. The Internet makes it possible to reach a greater number of users around the world and gives them quick access to information stored in databases. The number of ways of presenting this data by front-ends increases as well. This requires unifying the ways of operating and presenting information by front-ends and ensuring contextual switching between front-ends of different databases. This chapter aims to present selected cytogenetic and cytogenomic Internet resources in terms of obtaining the needed information and to indicate how to increase the efficiency of access to stored information. Through a brief introduction of these databases and by providing examples of their usage in cytogenetic analyses, we aim to bridge the gap between cytogenetics and molecular genomics by encouraging their utilization.

Comprehensive preimplantation genetic testing for balanced insertional translocation carriers.

BACKGROUND: Balanced insertional translocations (BITs) can increase the risk of infertility, recurrent miscarriages or neonatal birth defects due to chromosomal imbalances in gametes. However, studies on preimplantation genetic testing (PGT) for patients carrying BITs are inadequate. METHODS: A preimplantation genetic genotyping and haplotype analysis approach was developed and implemented in this study. Genome-wide SNP genotyping was performed, followed by core family-based haplotype analysis. The balanced insertion segments in euploid embryos were inferred from the haplotypes inherited from the carrier parent. RESULTS: A total of 10 BIT carrier couples were enrolled in our study. 15 in vitro fertilisation cycles were conducted, resulting in 73 blastocysts biopsied and subjected to PGT analysis. Among these, 20 blastocysts displayed rearrangement-related imbalances, 13 exhibited de novo aneuploidies, 15 presented a complex anomaly involving both imbalances and additional aneuploidies, while 25 were euploid. Within the euploid embryos, 12 were balanced carrier embryos and 13 were non-carrier embryos. To date, eight non-carrier and one carrier embryos have been transferred, resulting in seven clinical pregnancies. All pregnancies were recommended to perform prenatal diagnosis, our date revealed complete concordance between fetal genetic testing results and PGT results. Presently, five infants have been born from these pregnancies, and two pregnancies are still ongoing. CONCLUSION: The proposed method facilitates comprehensive chromosome screening and the concurrent identification of balanced insertions or normal karyotypes in embryos. This study offers an effective and universally applicable strategy for BIT carriers to achieve a healthy pregnancy and prevent the transmission of BITs to their offspring.

Gain-Type Aneuploidies Influence the Burden of Selective Long Non-Coding Transcripts in Colorectal Cancer.

Chromosomal instability is a hallmark of colorectal carcinogenesis and produces an accumulation of different forms of aneuploidies or broad copy number aberrations. Colorectal cancer is characterized by gain-type broad copy number aberrations, specifically in Chr20, Chr8q, Chr13 and Chr7, but their roles and mechanisms in cancer progression are not fully understood. It has been suggested that broad copy number gains might contribute to tumor development through the so-called caricature transcriptomic effect. We intend to investigate the impact of broad copy number gains on long non-coding RNAs' expression in colorectal cancer, given their well-known role in oncogenesis. The influence of such chromosomal aberrations on lncRNAs' transcriptome profile was investigated by SNP and transcriptome arrays in our series of colorectal cancer samples and cell lines. The correlation between aneuploidies and transcriptomic profiles led us to obtain a class of Over-UpT lncRNAs, which are transcripts upregulated in CRC and further overexpressed in colon tumors bearing specific chromosomal aberrations. The identified lncRNAs can contribute to a wide interaction network to establish the cancer driving effect of gain-type aneuploidies.

Genotoxic and Anti-Genotoxic Potential of Hydrosols from Water-Steam Distillation of Oil-Bearing Roses Rosa centifolia L. and Rosa gallica L. from Bulgaria.

Rosa centifolia L. and Rosa gallica L. (Rosaceae) are grown as raw materials for valuable essential oils and hydrosols. There are scarce data about the biological activities and the genoprotective potential of the hydrosols of these roses. The aim of the study was to provide information on their cytotoxic/genotoxic activity and anti-cytotoxic/anti-genotoxic capacity against mutagenic N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The evaluation was performed using classical tests for chromosomal aberrations and micronuclei in the higher plant Hordeum vulgare and human lymphocyte test systems. The experimental schemes included combined hydrosol and mutagen treatment. Both hydrosols (6, 14, 20%) had no cytotoxic effect on barley and showed low genotoxicity in both test systems as the injuries were enhanced to a lesser extent compared to the controls. Lymphocytes were more susceptible than H. vulgare. Under the conditions of combined treatment, it was found that the two hydrosols possessed good anti-cytotoxic and anti-genotoxic potential against MNNG. Both rose products exerted genoprotective potential to a similar extent, decreasing the frequencies of aberrations in chromosomes and micronuclei to a significant degree in both types of cells when non-toxic concentrations of hydrosols were applied before MNNG. This was performed both with and without any inter-treatment time. The observed cytoprotective/genoprotective potential suggests that these hydrosols are promising for further application in phytotherapy and medicine.

Congenital hand difference associated with 12q13.13 microdeletion.

We report the case of a 15-year-old boy with a de novo chromosomal deletion in the 12q13.13 region, presenting with congenital hand difference. This case emphasizes the clinical significance of recognizing such genetic anomalies and their implications.

Pan-neuronal expression of human mutant SOD1 in Drosophila impairs survival and motor performance, induces early neuroinflammation and chromosome aberrations.

Several mutations in the SOD1 gene encoding for the antioxidant enzyme Superoxide Dismutase 1, are associated with amyotrophic lateral sclerosis, a rare and devastating disease characterized by motor neuron degeneration and patients' death within 2-5 years from diagnosis. Motor neuron loss and related symptomatology manifest mostly in adult life and, to date, there is still a gap of knowledge on the precise cellular and molecular events preceding neurodegeneration. To deepen our awareness of the early phases of the disease, we leveraged two Drosophila melanogaster models pan-neuronally expressing either the mutation A4V or G85R of the human gene SOD1 (hSOD1A4V or hSOD1G85R). We demonstrate that pan-neuronal expression of the hSOD1A4V or hSOD1G85R pathogenic construct impairs survival and motor performance in transgenic flies. Moreover, protein and transcript analysis on fly heads indicates that mutant hSOD1 induction stimulates the glial marker Repo, up-regulates the IMD/Toll immune pathways through antimicrobial peptides and interferes with oxidative metabolism. Finally, cytological analysis of larval brains demonstrates hSOD1-induced chromosome aberrations. Of note, these parameters are found modulated in a timeframe when neurodegeneration is not detected. The novelty of our work is twofold: we have expressed for the first time hSOD1 mutations in all neurons of Drosophila and confirmed some ALS-related pathological phenotypes in these flies, confirming the power of SOD1 mutations in generating ALS-like phenotypes. Moreover, we have related SOD1 pathogenesis to chromosome aberrations and antimicrobial peptides up-regulation. These findings were unexplored in the SOD1-ALS field.

Systematic reanalysis of copy number losses of uncertain clinical significance.

BACKGROUND: Reanalysis of exome/genome data improves diagnostic yield. However, the value of reanalysis of clinical array comparative genomic hybridisation (aCGH) data has never been investigated. Case-by-case reanalysis can be challenging in busy diagnostic laboratories. METHODS AND RESULTS: We harmonised historical postnatal clinical aCGH results from ~16 000 patients tested via our diagnostic laboratory over ~7 years with current clinical guidance. This led to identification of 37 009 copy number losses (CNLs) including 33 857 benign, 2173 of uncertain significance and 979 pathogenic. We found benign CNLs to be significantly less likely to encompass haploinsufficient genes compared with the pathogenic or CNLs of uncertain significance in our database. Based on this observation, we developed a reanalysis pipeline using up-to-date disease association data and haploinsufficiency scores and shortlisted 207 CNLs of uncertain significance encompassing at least one autosomal dominant disease-gene associated with haploinsufficiency or loss-of-function mechanism. Clinical scientist reviews led to reclassification of 15 CNLs of uncertain significance as pathogenic or likely pathogenic. This was ~0.7% of the starting cohort of 2173 CNLs of uncertain significance and 7.2% of 207 shortlisted CNLs. The reclassified CNLs included first cases of CNV-mediated disease for some genes where all previously described cases involved only point variants. Interestingly, some CNLs could not be reclassified because the phenotypes of patients with CNLs seemed distinct from the known clinical features resulting from point variants, thus raising questions about accepted underlying disease mechanisms. CONCLUSIONS: Reanalysis of clinical aCGH data increases diagnostic yield.

Acute myeloid leukemia with rare recurring translocations-an overview of the entities included in the international consensus classification.

Two different systems exist for subclassification of acute myeloid leukemia (AML); the World Health Organization (WHO) Classification and the International Consensus Classification (ICC) of myeloid malignancies. The two systems differ in their classification of AML defined by recurrent chromosomal abnormalities. One difference is that the ICC classification defines an AML subset that includes 12 different genetic abnormalities that occur in less than 4% of AML patients. These subtypes exhibit distinct clinical traits and are associated with treatment outcomes, but detailed description of these entities is not easily available and is not described in detail even in the ICC. We searched in the PubMed database to identify scientific publications describing AML patients with the recurrent chromosomal abnormalities/translocations included in this ICC defined patient subset. This patient subset includes AML with t(1;3)(p36.3;q21.3), t(3;5)(q25.3;q35.1), t(8;16)(p11.2;p13.3), t(1;22)(p13.3;q13.1), t(5;11)(q35.2;p15.4), t(11;12)(p15.4;p13.3) (involving NUP98), translocation involving NUP98 and other partner, t(7;12)(q36.3;p13.2), t(10;11)(p12.3;q14.2), t(16;21)(p11.2;q22.2), inv(16)(p13.3q24.3) and t(16;21)(q24.3;q22.1). In this updated review we describe the available information with regard to frequency, biological functions of the involved genes and the fusion proteins, morphology/immunophenotype, required diagnostic procedures, clinical characteristics (including age distribution) and prognostic impact for each of these 12 genetic abnormalities.

Persons chronically exposed to low doses of ionizing radiation: A cytogenetic dosimetry study.

The dosimetry and control of exposure for individuals chronically exposed to ionizing radiation are important and complex issues. Assessment may be optimized by evaluating individual adaptation and radiosensitivity, but it is not possible for a single model to account for all relevant parameters. Our goal was to develop approaches for the calculation of doses for persons chronically exposed to ionizing radiation, taking their radiosensitivities into consideration. On the basis of ex vivo radiation of blood samples, dose-effect models were constructed for dose ranges 0.01-2.0 and 0.01-0.4 Gy, using different cytogenetic criteria. The frequencies of "dicentric chromosomes and rings" at low doses are too low to have predictive value. The different responses of subjects to radiation made it possible to categorize them according to their radiosensitivities and to generate separate dose-effect curves for radiosensitive, average, and radioresistant individuals, reducing the amount of error in retrospective dosimetry.

M-FISH evaluation of chromosome aberrations to examine for historical exposure to ionising radiation due to participation at British nuclear test sites.

Veterans of the British nuclear testing programme represent a population of ex-military personnel who had the potential to be exposed to ionising radiation through their participation at nuclear testing sites in the 1950s and 1960s. In the intervening years, members of this population have raised concerns about the status of their health and that of their descendants, as a consequence. Radiation dose estimates based on film badge measurements of external dose recorded at the time of the tests suggest any exposure to be limited for the majority of personnel, however, only ∼20% of personnel were monitored and no measurement for internalised exposure are on record. Here, to in-part address families concerns, we assay for chromosomal evidence of historical radiation exposure in a group of aged nuclear test (NT) veterans, using multiplexin situhybridisation (M-FISH), for comparison with a matched group of veterans who were not present at NT sites. In total, we analysed 9379 and 7698 metaphase cells using M-FISH (24-colour karyotyping) from 48 NT and 38 control veteran samples, representing veteran servicemen from the army, Royal Airforce and Royal Navy. We observed stable and unstable simple- and complex-type chromosome aberrations in both NT and control veterans' samples, however find no significant difference in yield of any chromosome aberration type between the two cohorts. We do observe higher average frequencies of complex chromosome aberrations in a very small subset of veterans previously identified as having a higher potential for radiation exposure, which may be indicative of internalised contamination to long-lived radionuclides from radiation fallout. By utilising recently published whole genome sequence analysis data of a sub-set of the same family groups, we examined for but found no relationship between paternal chromosome aberration burden, germline mutation frequency and self-reported concerns of adverse health in family members, suggesting that the previously reported health issues by participants in this study are unlikely to be associated with historical radiation exposure. We did observe a small number of families, representing both control and NT cohorts, showing a relationship between paternal chromosome aberrations and germline mutation sub-types which should be explored in future studies. In conclusion, we find no cytogenetic evidence of historical radiation exposure in the cohort of nuclear veterans sampled here, offering reassurance that attendance at NTs sites by the veterans sampled here, was not associated with significant levels of exposure to radiation.

Experience of copy number variation sequencing applied in spontaneous abortion.

PURPOSE: We evaluated the value of copy number variation sequencing (CNV-seq) and quantitative fluorescence (QF)-PCR for analyzing chromosomal abnormalities (CA) in spontaneous abortion specimens. METHODS: A total of 650 products of conception (POCs) were collected from spontaneous abortion between April 2018 and May 2020. CNV-seq and QF-PCR were performed to determine the characteristics and frequencies of copy number variants (CNVs) with clinical significance. The clinical features of the patients were recorded. RESULTS: Clinically significant chromosomal abnormalities were identified in 355 (54.6%) POCs, of which 217 (33.4%) were autosomal trisomies, 42(6.5%) were chromosomal monosomies and 40 (6.2%) were pathogenic CNVs (pCNVs). Chromosomal trisomy occurs mainly on chromosomes 15, 16, 18, 21and 22. Monosomy X was not associated with the maternal or gestational age. The frequency of chromosomal abnormalities in miscarriages from women with a normal live birth history was 55.3%; it was 54.4% from women without a normal live birth history (P > 0.05). There were no significant differences among women without, with 1, and with ≥ 2 previous miscarriages regarding the rate of chromosomal abnormalities (P > 0.05); CNVs were less frequently detected in women with advanced maternal age than in women aged ≤ 29 and 30-34 years (P < 0.05). CONCLUSION: Chromosomal abnormalities are the most common cause of pregnancy loss, and maternal and gestational ages are strongly associated with fetal autosomal trisomy aberrations. Embryo chromosomal examination is recommended regardless of the gestational age, modes of conception or previous abortion status.

Monitoring Genomic Structural Rearrangements Resulting from Gene Editing.

The cytogenomics-based methodology of directional genomic hybridization (dGH) enables the detection and quantification of a more comprehensive spectrum of genomic structural variants than any other approach currently available, and importantly, does so on a single-cell basis. Thus, dGH is well-suited for testing and/or validating new advancements in CRISPR-Cas9 gene editing systems. In addition to aberrations detected by traditional cytogenetic approaches, the strand specificity of dGH facilitates detection of otherwise cryptic intra-chromosomal rearrangements, specifically small inversions. As such, dGH represents a powerful, high-resolution approach for the quantitative monitoring of potentially detrimental genomic structural rearrangements resulting from exposure to agents that induce DNA double-strand breaks (DSBs), including restriction endonucleases and ionizing radiations. For intentional genome editing strategies, it is critical that any undesired effects of DSBs induced either by the editing system itself or by mis-repair with other endogenous DSBs are recognized and minimized. In this paper, we discuss the application of dGH for assessing gene editing-associated structural variants and the potential heterogeneity of such rearrangements among cells within an edited population, highlighting its relevance to personalized medicine strategies.

Maternal age and the risk of fetal aneuploidy: A nationwide cohort study of more than 500 000 singleton pregnancies in Denmark from 2008 to 2017.

INTRODUCTION: In this register-based study of pregnancies in Denmark, we assessed the associations between maternal age and the risk of fetal aneuploidies (trisomy 21, trisomy 18, trisomy 13, triploidy, monosomy X and other sex chromosome aberrations). Additionally, we aimed to disentangle the maternal age-related effect on fetal aneuploidies by cases with translocation trisomies and mosaicisms. MATERIAL AND METHODS: We followed a nationwide cohort of 542 375 singleton-pregnant women attending first trimester screening in Denmark between 2008 and 2017 until delivery, miscarriage or termination of pregnancy. We used six maternal age categories and retrieved information on genetically confirmed aneuploidies of the fetus and infant from the national cytogenetic register. RESULTS: We confirmed the known associations between advanced maternal age and higher risk of trisomy 21, 18, 13 and other sex chromosome aberrations, especially in women aged ≥35 years, whereas we found no age-related associations with triploidy or monosomy X. Cases with translocation trisomies and mosaicisms did not influence the overall reported association between maternal age and aneuploidies. CONCLUSION: This study provides insight into the accurate risk of fetal aneuploidies that pregnant women of advanced ages encounter.

Clinical application of single nucleotide polymorphism microarray analysis in pregnancy loss in Northwest China.

Background: Spontaneous abortion is the most common complication of early pregnancy. In this study, we aim to investigate the clinical application value of genetic diagnosis using single nucleotide polymorphism (SNP) microarray analysis on the products of conception and to characterize the types of genetic abnormalities and their prevalence in pregnancy loss in Northwest China. Methods: Over 48 months, we selected 652 products of conception, which included chorionic villi, fetal tissues, germ cell samples, amniotic fluid samples, cord blood samples, and a cardiac blood sample. We analyzed the distribution of chromosomal abnormalities leading to fetal arrest or abortion using SNP array. The patients were then categorized divided into groups based on maternal age, gestational age, number of miscarriages, and maternal ethnic background. The incidences of various chromosomal abnormalities in each group were compared. Results: Of the 652 cases, 314 (48.16%) exhibited chromosomal abnormalities. These included 286 cases with numerical chromosomal abnormalities, 24 cases with copy number variation, and four cases with loss of heterozygosity. Among them, there were 203 trisomy cases, 55 monosomy cases, and 28 polyploidy cases. In the subgroup analysis, significant differences were found in the frequency of numerical chromosomal abnormalities and copy number variation between the advanced and younger maternal age group as well as between the early and late abortion groups. Furthermore, we identified significant differences in the frequency of numerical chromosomal abnormalities between the first spontaneous abortion and recurrent miscarriage groups. However, there were no significant differences in the frequency of numerical chromosomal abnormalities between the Han and Uighur groups. Conclusion: Our research highlights chromosomal abnormalities as the primary cause of spontaneous abortion, with a higher incidence in early pregnancy and among women of advanced age. The use of SNP array analysis emerges as an effective and reliable technique for chromosome analysis in aborted fetuses. This method offers a comprehensive and dependable genetic investigation into the etiology of miscarriage, establishing itself as a valuable routine selection for genetic analysis in cases of natural abortions.

Detection of chromosome aberrations in 17 054 individuals with fertility problems and their subsequent assisted reproductive technology treatments in Central China.

STUDY QUESTION: How do the types and frequency of chromosome aberrations in couples in central China affect fertility and ART treatment? SUMMARY ANSWER: Men with chromosome aberrations or polymorphisms have an increased risk of semen quality impairment and infertility, and couples affected by reciprocal translocations had a lower pregnancy rate compared with other chromosome aberrations. WHAT IS KNOWN ALREADY: Karyotyping is crucial for patients affected by infertility as chromosome aberrations play an important role in the etiology of male infertility. However, the influence of chromosome aberrations and polymorphisms on sperm motility and morphology remains controversial. Data on ART treatment outcomes in infertile couples affected by chromosome aberrations are insufficient. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective study involving 17 054 patients affected by infertility who underwent karyotyping in our center between January 2020 and May 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Karyotyping was performed on 17 054 patients with reproductive failure. All patients were from the central regions of China. The following data were collected from a medical records system using patient identification numbers: couples' ages, history of pregnancy and childbirth, type of infertility, years of infertility, cause of infertility, chromosome karyotypes, semen analysis results, assisted reproductive techniques performed, and treatment outcomes of ART. MAIN RESULTS AND THE ROLE OF CHANCE: The incidence of chromosome aberrations was 2.04%; 2.49% in men and 1.57% in women. By analyzing the relationships between chromosome aberrations/polymorphisms and abnormal semen parameters, we found that there were significantly higher rates of asthenozoospermia, oligospermia, and teratozoospermia among men with Robertsonian translocations and sex chromosomal structural aberrations compared with those with normal karyotypes. Higher rates of asthenozoospermia and teratozoospermia were also observed among men with autosomal reciprocal translocations. The incidence of chromosome aberrations in azoospermic men (13.75%), and in men with cryptozoospermia or severe oligospermia (6.97%) was significantly higher than that in men with mild oligospermia or normospermia (0.88-2.12%). In addition, we found that the progressive movement of sperm is impaired in men with Chromosome 21 polymorphisms compared with men with normal karyotypes (39.46% ± 20.51% vs 48.61% ± 18.76%, P = 0.026). The percentage of morphologically normal forms was lower in the chromosomal polymorphism group than in the normal karyotype group (5.01% ± 2.41% vs 5.59% ± 2.14%, P = 0.001), especially in men with polymorphisms on Chromosome 9 (enlarged Chromosome 9 heterochromatin [9qh+]: 4.48% ± 2.22% vs 5.59% ± 2.14%, P = 0.006; pericentric inversion of Chromosome 9 [inv(9)]: 5.09% ± 3.11% vs 5.59% ± 2.14%, P = 0.008). ART treatment was successful in 36.00% of couples affected by chromosome aberrations. However, couples affected by reciprocal translocations achieved a lower pregnancy rate (24.07%), which may be due to the lower euploidy rates (27.31%) when compared with that in other chromosome aberrations. LIMITATIONS, REASONS FOR CAUTION: First, although the initial cohort was large, chromosome aberrations were identified in a small number of patients. Second, the observational nature of the study design is limiting. Third, the couples affected by infertility in this study were all outpatients that did not undergo identical comprehensive examinations except for karyotyping, leading to the incomplete collection of medical records. Also, the population included in this study mainly focused on couples affected by infertility, which may not be included in the European Association of Urology (EAU) recommendation on male infertility. WIDER IMPLICATIONS OF THE FINDINGS: Men with chromosome aberrations or polymorphisms have an increased risk of semen quality impairment and infertility. Constitutional chromosome analysis is recommended for men affected by infertility and severe oligospermia or azoospermia to facilitate early and appropriate guidance for the most suitable treatment. Carriers of chromosome aberrations can achieve acceptable pregnancy outcomes through IVF. However, couples affected by reciprocal translocations have lower pregnancy rates, and more treatment cycles are needed before a successful pregnancy. A possible explanation may be the fewer euploid embryos obtained. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Grant 2021YFC2700603 from the National Key Research & Development Program of China. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Prevalence and Prognosis of Secondary Genetic Aberrations Among Patients With Core Binding Factor Acute Myeloid Leukemia: A Mitelman Database Analysis.

Background: Core binding factor acute myeloid leukemia (CBF-AML) comprises t(8;21) and inv(16) and usually has a favorable prognosis. However, a wide spectrum of secondary genetic aberrations has been shown to be associated with worse outcomes with respect to overall survival (OS) and relapse. We aimed to identify secondary molecular and chromosomal aberrations within each group of CBF-AML, i.e., t(8;21) and inv(16), and to evaluate their prognosis with OS. Methods: Using the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer, we analyzed 193 cases of CBF-AML reported between 2011 and 2021. We conducted a survival analysis to determine the 5-year OS, and we conducted univariate and multivariate Cox regression to identify independent genetic factors related to OS. Results: Among the 193 cases with CBF-AML, structural and numerical chromosome rearrangements were 25.9% and 40.9%, respectively, and secondary genetic mutations were 54.9%. The 5-year OS for the presence of del(7) and trisomy 22 was significantly worse. NRAS mutations had a worse 5-year OS in the t(8;21) group in the univariate analysis but showed no significant difference in the multivariate analysis. Conclusions: CBF-AML has heterogeneous cytogenetic characteristics but no difference in the 5-year OS between the inv(16) and t(8;21) groups. Finally, the presence of del(7), trisomy 22 and NRAS mutations showed a potential prognostic impact in CBF-AML patients. Secondary genetic findings may need to be identified to determine its association to a worse prognosis, and in the future develop better targeted therapies in patients with CBF-AML.

Genetics of Sex Differences in Immunity.

Women have a stronger immune response and a higher frequency of most autoimmune diseases than men. While much of the difference between men and women is due to the effect of gonadal hormones, genetic differences play a major role in the difference between the immune response and disease frequencies in women and men. Here, we focus on the immune differences between the sexes that are not downstream of the gonadal hormones. These differences include the gene content of the sex chromosomes, the inactivation of chromosome X in women, the consequences of non-random X inactivation and escape from inactivation, and the states that are uniquely met by the immune system of women-pregnancy, birth, and breast feeding. While these female-specific states are temporary and involve gonadal hormonal changes, they may leave a long-lasting footprint on the health of women, for example, by fetal cells that remain in the mother's body for decades. We also briefly discuss the immune phenotype of congenital sex chromosomal aberrations and experimental models that enable hormonal and the non-hormonal effects of the sex chromosomes to be disentangled. The increasing human life expectancy lengthens the period during which gonadal hormones levels are reduced in both sexes. A better understanding of the non-hormonal effects of sex chromosomes thus becomes more important for improving the life quality during that period.