DNA methylation in newborns conceived by assisted reproductive technology DOI Creative Commons
Siri E. Håberg, Christian M. Page, Yunsung Lee

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: April 7, 2022

Assisted reproductive technology (ART) may affect fetal development through epigenetic mechanisms as the timing of ART procedures coincides with extensive remodeling occurring between fertilization and embryo implantation. However, it is unknown to what extent alter epigenome. Underlying parental characteristics subfertility also play a role. Here we identify differences in cord blood DNA methylation, measured using Illumina EPIC platform, 962 conceived 983 naturally singleton newborns. We show that newborns display widespread overall less methylation across genome. There were 607 genome-wide differentially methylated CpGs. find 176 known genes, including genes related growth, neurodevelopment, other health outcomes have been associated ART. Both fresh frozen transfer differences. Associations persist after controlling for parents' are not explained by subfertility.

Language: Английский

Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes DOI Creative Commons
Nasim Mavaddat, Leila Dorling, Sara Carvalho

et al.

JAMA Oncology, Journal Year: 2022, Volume and Issue: 8(3), P. e216744 - e216744

Published: Jan. 27, 2022

Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes unclear. This information is relevant guidelines for gene panel testing and risk prediction.To characterize tumors BC susceptibility large-scale population- or hospital-based studies.The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients 46 387 control participants, comprising women aged 18 79 years who were sampled independently family history from 38 studies. Studies conducted between 1991 2016. Sequencing took place 2016 2021.Protein-truncating likely pathogenic missense ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, TP53.The intrinsic-like as defined by estrogen receptor, progesterone ERBB2 (formerly known HER2) status, tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) carrying protein-truncating 9 genes.The mean (SD) ages at interview (control participants) diagnosis (cases) 55.1 (11.9) 55.8 (10.6) years, respectively; all participants European East Asian ethnicity. There was substantial heterogeneity distribution intrinsic gene. BARD1 mainly triple-negative (OR, 6.19 [95% CI, 3.17-12.12]; OR, 2.99-12.79]; 10.05 5.27-19.19], respectively). CHEK2 (with ORs ranging 2.21-3.17) except disease. For ATM variants, association strongest hormone receptor (HR)+ERBB2- high-grade subtype 4.99; 95% 3.68-6.76). BRCA1 subtypes, varied widely, being highest 55.32; 40.51-75.55). BRCA2 PALB2 also TP53 most strongly HR+ERBB2+ HR-ERBB2+ subtypes. Tumors occurring variant carriers higher grade. a decline observed increasing age. Together, 27.3% 40 younger.The results this suggest that differ substantially pathology generally and/or Knowing age distributions individual can potentially aid testing, prediction, classification guide targeted screening strategies.

Language: Английский

Citations

89
Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies DOI Creative Commons
Antonella Padella, Andrea Ghelli Luserna di Rorà, Giovanni Marconi

et al.

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Jan. 22, 2022

Abstract The members of the Poly(ADP‐ribose) polymerase (PARP) superfamily are involved in several biological processes and, particular, DNA damage response (DDR). most studied members, PARP1, PARP2 and PARP3, act as sensors damages, order to activate different intracellular repair pathways, including single-strand repair, homologous recombination, conventional alternative non-homologous end joining. This review recapitulates functional role PARPs DDR also relationship with cell cycle phases, which drives our knowledge mechanisms action PARP inhibitors (PARPi), encompassing inhibition breaks base excision trapping sensitization antileukemia immune responses. Several studies have demonstrated a preclinical activity current available PARPi, olaparib, rucaparib, niraparib, veliparib talazoparib, single agent and/or combination cytotoxic, hypomethylating or targeted drugs acute leukemia, thus encouraging development clinical trials. We here summarize recent findings discuss synthetic lethal interactions PARPi myeloid leukemia (AML) lymphoblastic (ALL). Despite low frequency genomic alterations other DDR-related genes selective vulnerabilities been reported disease subgroups, along “BRCAness phenotype.” AML carrying RUNX1-RUNX1T1 PML-RARA fusion mutations signaling ( FLT3 -ITD TET2 DNMT3A deficiency), cohesin complex STAG2 ), TP53 BCOR co-occurring lesions, IDH1/2 ALL cases expressing TCF3-HLF chimera TET1 was highly sensitive studies. These data, warning coming from observation therapy-related malignancies among patients receiving for solid tumors treatment, indicate that represents promising strategy personalized medicine setting. characterization clonal subclonal genetic background functionality is crucial select will likely benefit PARPi-based therapeutic regimens.

Language: Английский

Citations

73
BRCA1 and Breast Cancer: Molecular Mechanisms and Therapeutic Strategies DOI Creative Commons
Xiaoyu Fu, Wei Phin Tan, Qibin Song

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: March 1, 2022

Breast cancer susceptibility gene 1 (

Language: Английский

Citations

73
The complementarity of DDR, nucleic acids and anti-tumour immunity DOI

Anand Kornepati,

Cody M. Rogers, Patrick Sung

et al.

Nature, Journal Year: 2023, Volume and Issue: 619(7970), P. 475 - 486

Published: July 19, 2023

Language: Английский

Citations

53
Targeting BRCA1-deficient PARP inhibitor-resistant cells with nickases reveals nick resection as a cancer vulnerability DOI

Jenna Whalen,

Jillian Earley,

Christi Wisniewski

et al.

Nature Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

Language: Английский

Citations

2
Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation DOI Creative Commons
Win Topatana, Sarun Juengpanich, Shijie Li

et al.

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: Sept. 3, 2020

Abstract Synthetic lethality is a lethal phenomenon in which the occurrence of single genetic event tolerable for cell survival, whereas co-occurrence multiple events results death. The main obstacle synthetic lies tumor biology heterogeneity and complexity, inadequate understanding interactions, drug resistance, challenges regarding screening clinical translation. Recently, DNA damage response inhibitors are being tested various trials with promising results. This review will describe current challenges, development, opportunities cancer therapy. characterization potential interactions novel technologies to develop more effective targeted patients be explored. Furthermore, this discuss development resistance mechanisms ultimate goal guide clinicians at selecting that receive maximum benefits

Language: Английский

Citations

135
Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models DOI Creative Commons
Vanessa C. Wheeler, Vincent Dion

Journal of Huntington s Disease, Journal Year: 2021, Volume and Issue: 10(1), P. 123 - 148

Published: Feb. 9, 2021

At fifteen different genomic locations, the expansion of a CAG/CTG repeat causes neurodegenerative or neuromuscular disease, most common being Huntington’s disease and myotonic dystrophy type 1. These disorders are characterized by germline somatic instability causative mutations. Repeat lengthening, expansion, in leads to an earlier age onset more severe symptoms next generation. In cells, is thought precipitate rate disease. The mechanisms underlying not well understood. Here we review mammalian model systems that have been used study instability, modifiers identified these systems. Mouse models demonstrated prominent roles for proteins mismatch repair pathway as critical drivers which also suggested recent genome-wide association studies humans. We draw attention network connections between across several might indicate crosstalk context could provide hypotheses further validation discovery. Overall, data dynamics be modulated altering levels DNA metabolic proteins, their regulation, interaction with chromatin, direct perturbation tract. Applying novel methodologies technologies this exciting area research will needed gain deeper mechanistic insight can harnessed therapies aimed at preventing promoting contraction.

Language: Английский

Citations

74
BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1 DOI
Samuel R. Witus, Anika L. Burrell, Daniel P. Farrell

et al.

Nature Structural & Molecular Biology, Journal Year: 2021, Volume and Issue: 28(3), P. 268 - 277

Published: Feb. 15, 2021

Language: Английский

Citations

74
Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets DOI Creative Commons
Rui Qin,

Feng‐Ming You,

Qian Zhao

et al.

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Sept. 14, 2022

Abstract Regulated cell death (RCD) is a critical and active process that controlled by specific signal transduction pathways can be regulated genetic signals or drug interventions. Meanwhile, RCD closely related to the occurrence therapy of multiple human cancers. Generally, subroutines are key tumorigenesis, which contributed our better understanding cancer pathogenesis therapeutics. Indole alkaloids derived from natural sources well defined for their outstanding biological pharmacological properties, like vincristine, vinblastine, staurosporine, indirubin, 3,3′-diindolylmethane, currently used in clinic under clinical assessment. Moreover, such compounds play significant role discovering novel anticancer agents. Thus, here we systemically summarized recent advances indole as agents targeting different subroutines, including classical apoptosis autophagic signaling crucial other ferroptosis, mitotic catastrophe, necroptosis, anoikis, cancer. further discussed cross talk between mediated combined strategies (e.g., 3,10-dibromofascaplysin with olaparib) exhibit therapeutic potential against various cancers regulating subroutines. In short, information provided this review on regulation targets expected beneficial design molecules greater thereby facilitating development new therapy. Graphic abstract

Language: Английский

Citations

67
Structural insight into BRCA1-BARD1 complex recruitment to damaged chromatin DOI Creative Commons

Linchang Dai,

Yaxin Dai, Jinhua Han

et al.

Molecular Cell, Journal Year: 2021, Volume and Issue: 81(13), P. 2765 - 2777.e6

Published: June 7, 2021

Language: Английский

Citations

66