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Human Reproduction (Oxford, England) Oct 2023In modern post-transition societies, we are reproducing later and living longer. While the impact of age on female reproductive function has been well studied, much less...
In modern post-transition societies, we are reproducing later and living longer. While the impact of age on female reproductive function has been well studied, much less is known about the intersection of age and male reproduction. Our current understanding is that advancing age brings forth a progressive decline in male fertility accompanied by a reduction in circulating testosterone levels and the appearance of age-dependent reproductive pathologies including benign prostatic hypertrophy and erectile dysfunction. Paternal ageing is also associated with a profound increase in sperm DNA damage, the appearance of multiple epigenetic changes in the germ line and an elevated mutational load in the offspring. The net result of such changes is an increase in the disease burden carried by the progeny of ageing males, including dominant genetic diseases such as Apert syndrome and achondroplasia, as well as neuropsychiatric conditions including autism and spontaneous schizophrenia. The genetic basis of these age-related effects appears to involve two fundamental mechanisms. The first is a positive selection mechanism whereby stem cells containing mutations in a mitogen-activated protein kinase pathway gain a selective advantage over their non-mutant counterparts and exhibit significant clonal expansion with the passage of time. The second is dependent on an age-dependent increase in oxidative stress which impairs the steroidogenic capacity of the Leydig cells, disrupts the ability of Sertoli cells to support the normal differentiation of germ cells, and disrupts the functional and genetic integrity of spermatozoa. Given the central importance of oxidative stress in defining the impact of chronological age on male reproduction, there may be a role for antioxidants in the clinical management of this process. While animal studies are supportive of this strategy, carefully designed clinical trials are now needed if we are to realize the therapeutic potential of this approach in a clinical context.
Topics: Animals; Male; Female; Semen; Reproduction; Aging; Spermatozoa; Mutation
PubMed: 37568254
DOI: 10.1093/humrep/dead157 -
Neurological Sciences : Official... Mar 2024The mutations on microtubule associated protein tau (MAPT) gene manifest clinically with behavioural frontotemporal dementia (FTD), parkinsonism, such as progressive...
The mutations on microtubule associated protein tau (MAPT) gene manifest clinically with behavioural frontotemporal dementia (FTD), parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration, and rarely with amyotrophic lateral sclerosis (ALS). FTD-parkinsonism and FTD-ALS are clinical overlaps included in the spectrum of MAPT mutation's phenotypes. The mutations on MAPT gene cause the dysfunction of tau protein determining its accumulation in neurofibrillary tangles. Recent data describe frequently the co-occurrence of the aggregation of tau protein and α-synuclein in patients with parkinsonism and Parkinson disease (PD), suggesting an interaction of the two proteins in determining neurodegenerative process. The sporadic description of PD-ALS clinical complex, known as Brait-Fahn-Schwarz disease, supports the hypothesis of common neuropathological pathways between different disorders. Here we report the case of a 54-year-old Italian woman with idiopathic PD later complicated by ALS carrying a novel MAPT variant (Pro494Leu). The variant is characterized by an amino acid substitution and is classified as damaging for MAPT functions. The case supports the hypothesis of tau dysfunction as the basis of multiple neurodegenerative disorders.
Topics: Female; Humans; Middle Aged; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; tau Proteins; Parkinson Disease; Mutation; Parkinsonian Disorders
PubMed: 37730935
DOI: 10.1007/s10072-023-07081-4 -
Clinical Cancer Research : An Official... Jul 2023ATM is the most commonly mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC); however, limited characterization has been pursued.
PURPOSE
ATM is the most commonly mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC); however, limited characterization has been pursued.
EXPERIMENTAL DESIGN
Clinicopathologic, genomic, and treatment data were collected for 5,172 patients with NSCLC tumors which underwent genomic profiling. ATM IHC was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets.
RESULTS
A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATM-mutant (ATMMUT) NSCLC was significantly associated with female sex (P = 0.02), ever smoking status (P < 0.001), non-squamous histology (P = 0.004), and higher tumor mutational burden (DFCI, P < 0.0001; MSK, P < 0.0001) compared with ATM-wild-type (ATMWT) cases. Among 3,687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q < 0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs. 28.6%; P < 0.0001) compared with tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N = 1,522) and chemo-immunotherapy (N = 951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy.
CONCLUSIONS
Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC.
Topics: Female; Humans; Ataxia Telangiectasia Mutated Proteins; Carcinoma, Non-Small-Cell Lung; Genomics; Lung Neoplasms; Mutation; Mutation, Missense
PubMed: 37097610
DOI: 10.1158/1078-0432.CCR-22-3413 -
Annual Review of Pathology Jan 2024Genetic material is constantly subjected to genotoxic insults and is critically dependent on DNA repair. Genome maintenance mechanisms differ in somatic and germ cells... (Review)
Review
Genetic material is constantly subjected to genotoxic insults and is critically dependent on DNA repair. Genome maintenance mechanisms differ in somatic and germ cells as the soma only requires maintenance during an individual's lifespan, while the germline indefinitely perpetuates its genetic information. DNA lesions are recognized and repaired by mechanistically highly diverse repair machineries. The DNA damage response impinges on a vast array of homeostatic processes and can ultimately result in cell fate changes such as apoptosis or cellular senescence. DNA damage causally contributes to the aging process and aging-associated diseases, most prominently cancer. By causing mutations, DNA damage in germ cells can lead to genetic diseases and impact the evolutionary trajectory of a species. The mechanisms ensuring tight control of germline DNA repair could be highly instructive in defining strategies for improved somatic DNA repair. They may provide future interventions to maintain health and prevent disease during aging.
Topics: Humans; Aging; DNA Repair; Genomic Instability; Mutation; Apoptosis
PubMed: 37832947
DOI: 10.1146/annurev-pathmechdis-051122-093128 -
Journal of Translational Medicine Apr 2024Inflammatory breast cancer (IBC) is the most pro-metastatic form of BC. Better understanding of its enigmatic pathophysiology is crucial. We report here the largest...
BACKGROUND
Inflammatory breast cancer (IBC) is the most pro-metastatic form of BC. Better understanding of its enigmatic pathophysiology is crucial. We report here the largest whole-exome sequencing (WES) study of clinical IBC samples.
METHODS
We retrospectively applied WES to 54 untreated IBC primary tumor samples and matched normal DNA. The comparator samples were 102 stage-matched non-IBC samples from TCGA. We compared the somatic mutational profiles, spectra and signatures, copy number alterations (CNAs), HRD and heterogeneity scores, and frequencies of actionable genomic alterations (AGAs) between IBCs and non-IBCs. The comparisons were adjusted for the molecular subtypes.
RESULTS
The number of somatic mutations, TMB, and mutational spectra were not different between IBCs and non-IBCs, and no gene was differentially mutated or showed differential frequency of CNAs. Among the COSMIC signatures, only the age-related signature was more frequent in non-IBCs than in IBCs. We also identified in IBCs two new mutational signatures not associated with any environmental exposure, one of them having been previously related to HIF pathway activation. Overall, the HRD score was not different between both groups, but was higher in TN IBCs than TN non-IBCs. IBCs were less frequently classified as heterogeneous according to heterogeneity H-index than non-IBCs (21% vs 33%), and clonal mutations were more frequent and subclonal mutations less frequent in IBCs. More than 50% of patients with IBC harbored at least one high-level of evidence (LOE) AGA (OncoKB LOE 1-2, ESCAT LOE I-II), similarly to patients with non-IBC.
CONCLUSIONS
We provide the largest mutational landscape of IBC. Only a few subtle differences were identified with non-IBCs. The most clinically relevant one was the higher HRD score in TN IBCs than in TN non-IBCs, whereas the most intriguing one was the smaller intratumor heterogeneity of IBCs.
Topics: Humans; Female; Inflammatory Breast Neoplasms; Breast Neoplasms; Retrospective Studies; Mutation; Genomics
PubMed: 38637846
DOI: 10.1186/s12967-024-05198-4 -
Frontiers in Immunology 2023Advancements in sequencing technologies and bioinformatics algorithms have expanded our ability to identify tumor-specific somatic mutation-derived antigens... (Review)
Review
Advancements in sequencing technologies and bioinformatics algorithms have expanded our ability to identify tumor-specific somatic mutation-derived antigens (neoantigens). While recent studies have shown neoantigens to be compelling targets for cancer immunotherapy due to their foreign nature and high immunogenicity, the need for increasingly accurate and cost-effective approaches to rapidly identify neoantigens remains a challenging task, but essential for successful cancer immunotherapy. Currently, gene expression analysis and algorithms for variant calling can be used to generate lists of mutational profiles across patients, but more care is needed to curate these lists and prioritize the candidate neoantigens most capable of inducing an immune response. A growing amount of evidence suggests that only a handful of somatic mutations predicted by mutational profiling approaches act as immunogenic neoantigens. Hence, unbiased screening of all candidate neoantigens predicted by Whole Genome Sequencing/Whole Exome Sequencing may be necessary to more comprehensively access the full spectrum of immunogenic neoepitopes. Once putative cancer neoantigens are identified, one of the largest bottlenecks in translating these neoantigens into actionable targets for cell-based therapies is identifying the cognate T cell receptors (TCRs) capable of recognizing these neoantigens. While many TCR-directed screening and validation assays have utilized bulk samples in the past, there has been a recent surge in the number of single-cell assays that provide a more granular understanding of the factors governing TCR-pMHC interactions. The goal of this review is to provide an overview of existing strategies to identify candidate neoantigens using genomics-based approaches and methods for assessing neoantigen immunogenicity. Additionally, applications, prospects, and limitations of some of the current single-cell technologies will be discussed. Finally, we will briefly summarize some of the recent models that have been used to predict TCR antigen specificity and analyze the TCR receptor repertoire.
Topics: Humans; Neoplasms; Antigens, Neoplasm; Receptors, Antigen, T-Cell; Mutation; Immunotherapy
PubMed: 38149253
DOI: 10.3389/fimmu.2023.1301100 -
Nature Communications Oct 2023The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPA) in acute myeloid leukemia (AML) with a combination of...
The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPA) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPA), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. The most frequently co-mutated genes in CEBPA AML are GATA2 and TET2, however the molecular mechanisms underlying this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPA AML. Elevated CEBPA levels, driven by CEBPA, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Concurrent loss of TET2 in CEBPA AML induces a competitive advantage by increasing Gata2 promoter methylation, thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.
Topics: Humans; Leukemia, Myeloid, Acute; CCAAT-Enhancer-Binding Proteins; Mutation; Regulatory Sequences, Nucleic Acid; Promoter Regions, Genetic; GATA2 Transcription Factor; DNA-Binding Proteins; Dioxygenases
PubMed: 37794021
DOI: 10.1038/s41467-023-41927-x -
Leukemia & Lymphoma Sep 2023The year 2023 marks the semi-centennial of the introduction of classic '7 + 3' chemotherapy for acute myeloid leukemia (AML) in 1973. It also marks the decennial of... (Review)
Review
The year 2023 marks the semi-centennial of the introduction of classic '7 + 3' chemotherapy for acute myeloid leukemia (AML) in 1973. It also marks the decennial of the first comprehensive sequencing efforts from The Cancer Genome Atlas (TCGA), which revealed that dozens of unique genes are recurrently mutated in AML genomes. Although more than 30 distinct genes have been implicated in AML pathogenesis, the current therapeutic armamentarium that is commercially available only targets and mutations, with olutasidenib as the most recent addition. This focused review spotlights management approaches that exploit the exquisite molecular dependencies of specific subsets of AML, with an emphasis on emerging therapies in the pipeline, including agents targeting -mutant cells. We summarize precision and strategic targeting of AML based on leveraging functional dependencies and explore how mechanisms involving critical gene products can inform rational therapeutic design in 2024.
Topics: Humans; Nucleophosmin; Leukemia, Myeloid, Acute; Mutation
PubMed: 37328939
DOI: 10.1080/10428194.2023.2224473 -
International Journal of Molecular... Sep 2023, a nuclear envelope protein critical for cellular structure and signaling, is downregulated in numerous malignancies. alterations are found in 10% of gynecologic...
, a nuclear envelope protein critical for cellular structure and signaling, is downregulated in numerous malignancies. alterations are found in 10% of gynecologic malignancies and 5% of epithelial ovarian cancers. Previous studies demonstrated an association between mutation, increased tumor mutation burden (TMB), and immunotherapy response. This study evaluates the mutation frequency, association with TMB, and downstream effects of mutation in ovarian cancer. Genetic information, including whole-exome sequencing, RNA analysis, and somatic tumor testing, was obtained for consenting ovarian cancer patients at an academic medical center. Mutation frequencies were compared between the institutional cohort and The Cancer Genome Atlas (TCGA). Bioinformatics analyses were performed. In our cohort of 50 patients, 16 had a mutation, and 15 had recurrent disease. Median TMB for mutated patients was 25 compared to 7 for wild-type patients ( < 0.0001). Compared to the TCGA cohort, our cohort had higher mutation rates (32% vs. 6%, < 0.001). Gene expression related to immune cell trafficking, inflammatory response, and immune response (z > 2.0) was significantly increased in mutated patients. mutation is associated with increased TMB and immune cell infiltration in ovarian cancer and may serve as an additional biomarker for immunotherapy response.
Topics: Humans; Female; Ovarian Neoplasms; Mutation; Carcinoma, Ovarian Epithelial; Genital Neoplasms, Female; Mutation Rate; Cytoskeletal Proteins; Nerve Tissue Proteins
PubMed: 37762518
DOI: 10.3390/ijms241814212 -
Genome Medicine Aug 2023Cancer mutations accumulate through replication errors and DNA damage coupled with incomplete repair. Individual mutational processes often show nucleotide sequence and...
BACKGROUND
Cancer mutations accumulate through replication errors and DNA damage coupled with incomplete repair. Individual mutational processes often show nucleotide sequence and functional region preferences. As a result, some sequence contexts mutate at much higher rates than others, with additional variation found between functional regions. Mutational hotspots, with recurrent mutations across cancer samples, represent genomic positions with elevated mutation rates, often caused by highly localized mutational processes.
METHODS
We count the 11-mer genomic sequences across the genome, and using the PCAWG set of 2583 pan-cancer whole genomes, we associate 11-mers with mutational signatures, hotspots of single nucleotide variants, and specific genomic regions. We evaluate the mutation rates of individual and combined sets of 11-mers and derive mutational sequence motifs.
RESULTS
We show that hotspots generally identify highly mutable sequence contexts. Using these, we show that some mutational signatures are enriched in hotspot sequence contexts, corresponding to well-defined sequence preferences for the underlying localized mutational processes. This includes signature 17b (of unknown etiology) and signatures 62 (POLE deficiency), 7a (UV), and 72 (linked to lymphomas). In some cases, the mutation rate and sequence preference increase further when focusing on certain genomic regions, such as signature 62 in transcribed regions, where the mutation rate is increased up to 9-folds over cancer type and mutational signature average.
CONCLUSIONS
We summarize our findings in a catalog of localized mutational processes, their sequence preferences, and their estimated mutation rates.
Topics: Humans; Mutation Rate; Mutation; Neoplasms; DNA Damage; Genomics
PubMed: 37592287
DOI: 10.1186/s13073-023-01217-z