Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 22, 2023

Abstract Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools ( www.regtools.org ), a computationally efficient, free, open-source software package designed to integrate somatic variants from genomic data with splice junctions bulk or single cell transcriptomic identify cause aberrant splicing. We apply over 9000 tumor samples both DNA RNA sequence data. discovers 235,778 events where splice-associated variant significantly increases the splicing of particular junction, across 158,200 unique 131,212 junctions. To characterize these their associated isoforms, annotate them Variant Effect Predictor, SpliceAI, Genotype-Tissue Expression junction counts compare our results other tools While many corroborated by aforementioned tools, flexibility also allows us known cancer drivers, such as TP53 , CDKN2A B2M genes.

Language: Английский

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Obesity-associated changes in molecular biology of primary breast cancer

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 21, 2023

Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on biology remains understudied humans. This study investigates how the untreated primary differs according to patients' body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent overweight or obese patients compared lean report evidence supporting ageing accelerating effect obesity at genetic level. show BMI-associated differences bulk transcriptomic profile subtle, while single cell profiling allows detection more pronounced changes different compartments. These analyses further reveal elevated unresolved inflammation tumor microenvironment obesity, distinct characteristics contingent estrogen receptor status. Collectively, our imply inflammaging-like phenotype. conclude patient adiposity may play a significant role heterogeneity should be considered for treatment tailoring.

Language: Английский

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RegTools: Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2018, Volume and Issue: unknown

Published: Oct. 5, 2018

Abstract Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools ( www.regtools.org ), a computationally efficient, free, open-source software package designed to integrate somatic variants from genomic data with splice junctions bulk or single cell transcriptomic identify cause aberrant splicing. was applied over 9,000 tumor samples both DNA RNA sequence data. We discovered 235,778 events where splice-associated variant significantly increased the splicing of particular junction, across 158,200 unique 131,212 junctions. To characterize these their associated isoforms, annotated them Variant Effect Predictor (VEP), SpliceAI, Genotype-Tissue Expression (GTEx) junction counts compared our results other tools While many were corroborated by aforementioned tools, flexibility also allowed us novel previously unreported patterns disruption known cancer drivers, such as TP53, CDKN2A , B2M well genes not considered cancer-relevant.

Language: Английский

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Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis

Cells, Journal Year: 2021, Volume and Issue: 10(11), P. 2966 - 2966

Published: Oct. 31, 2021

Estrogen receptor alpha (ERα, NR3A1) contributes through its expression in different tissues to a spectrum of physiological processes, including reproductive system development and physiology, bone mass maintenance, as well cardiovascular central nervous functions. It is also one the main drivers tumorigenesis breast uterine cancer can be targeted by several types hormonal therapies. ERα expressed subset luminal cells corresponding less than 10% normal mammary epithelial over 70% tumors (ER+ tumors), but basis for selective or remains incompletely understood. The mapping alternative promoters regulatory elements has delineated complex genomic structure ESR1 gene shed light on mechanistic tissue-specific regulation expression. However, much uncovered better understand how regulated cancer. This review recapitulates current body knowledge mechanisms controlling tumors. In particular, we discuss impact genetic alterations, chromatin modifications, enhanced other transcription regulators tumor cells.

Language: Английский

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Circular RNA hsa_circ_0044234 as distinct molecular signature of triple negative breast cancer: a potential regulator of GATA3

Cancer Cell International, Journal Year: 2021, Volume and Issue: 21(1)

Published: June 14, 2021

Abstract Background Circular RNAs (circRNAs) have been implicated in the initiation and development of breast cancer as functional non-coding (ncRNA). The roles circRNAs competing endogenous (ceRNAs) to sponge microRNAs (miRNAs) also indicated. However, functions not totally elucidated. This study aimed explore clinical implications possible circ_0044234 carcinogenesis most problematic BC subtype, triple negative (TNBC), which are desperate need biomarkers targeted therapies. Methods importance one dysregulated TNBC was discovered through microarray expression profile analysis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) performed confirm downregulation tumors cell lines versus non-triple ones. bioinformatics prediction revealed that could act an upstream miR-135b/GATA3 axis, two transcripts TNBC. Results Our experimental investigation expressions various subtypes well reveals expresses at a substantially lower level than non-TNBC. ROC curve analysis indicates it be applied discriminative biomarker identify from other subtypes. Moreover, independent prognostic BC. Interestingly, substantial inverse correlation detected between miR-135b-5p GATA3 tumors. Conclusions usefulness promising distinct upcoming therapeutic target for indicated this research. comprehensive approach potential circ_0044234/miR135b-5p/GATA3 ceRNA axis

Language: Английский

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Vitamin D May Protect against Breast Cancer through the Regulation of Long Noncoding RNAs by VDR Signaling

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(6), P. 3189 - 3189

Published: March 16, 2022

Dietary vitamin D3 has attracted wide interest as a natural compound for breast cancer prevention and therapy, supported by in vitro animal studies. The exact mechanism of such action is unknown may include several independent or partly dependent pathways. active metabolite D3, 1α,25-dihydroxyvitamin (1,25(OH)2D, calcitriol), binds to the D receptor (VDR) induces its translocation nucleus, where it transactivates myriad genes. Vitamin involved maintenance normal epigenetic profile whose disturbance contribute cancer. In general, protective effect against underlined inhibition proliferation migration, stimulation differentiation apoptosis, epithelial/mesenchymal transition cells. also inhibit transformation mammary progenitors into stem cells that initiate sustain growth tumors. As long noncoding RNAs (lncRNAs) play an important role pathogenesis, specific mechanisms underlying this are poorly understood, we provided arguments D3/VDR induce effects through modulation lncRNAs pathogenesis. main candidates mediate lncBCAS1-4_1, AFAP1 antisense RNA 1 (AFAP1-AS1), metastasis-associated lung adenocarcinoma transcript (MALAT1), intergenic non-protein-coding 511 (LINC00511), LINC00346, small nucleolar host gene 6 (SNHG6), SNHG16, but there rationale explore other lncRNAs.

Language: Английский

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Reduced GATA3 expression during breast cancer progression: A potential anchor for pulmonary metastatic deposition

Pathology - Research and Practice, Journal Year: 2025, Volume and Issue: 266, P. 155821 - 155821

Published: Jan. 13, 2025

Language: Английский

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The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ

npj Breast Cancer, Journal Year: 2022, Volume and Issue: 8(1)

Published: Jan. 13, 2022

Abstract Microenvironmental and molecular factors mediating the progression of Breast Ductal Carcinoma In Situ (DCIS) are not well understood, impeding development prevention strategies safe testing treatment de-escalation. We addressed methodological barriers characterized mutational, transcriptional, histological, microenvironmental landscape across 85 multiple microdissected regions from 39 cases. Most somatic alterations, including whole-genome duplications, were clonal, but genetic divergence increased with physical distance. Phenotypic subtype heterogeneity was frequently associated underlying low-risk features preceded those high-risk according to inferred phylogeny. B- T-lymphocytes spatial analysis identified three immune states, an epithelial excluded state located preferentially at DCIS regions, by histological escape, independently subtypes. Such breast pre-cancer atlas uniquely integrated observations will help scope future expansion studies build finer models outcomes risk.

Language: Английский

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Spatial molecular profiling of mixed invasive ductal and lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(31)

Published: July 23, 2024

Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive negative morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct also have biology risk recurrence. Our spatially resolved transcriptomic, genomic, single-cell profiling revealed clinically significant differences between tumor regions including intrinsic heterogeneity – e.g., MDLC triple-negative (TNBC) or basal estrogen receptor (ER+) luminal regions, enrichment cell cycle arrest/senescence oncogenic (ER MYC ) signatures, genetic epigenetic CDH1 inactivation in but not subpopulations unique signatures further highlighting intraregional heterogeneity. Altogether, we demonstrated that intratumoral morphological/histological underpinned by which may result prognostic uncertainty therapeutic dilemma.

Language: Английский

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Transcriptome Analysis Identifies GATA3-AS1 as a Long Noncoding RNA Associated with Resistance to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients

Journal of Molecular Diagnostics, Journal Year: 2021, Volume and Issue: 23(10), P. 1306 - 1323

Published: Aug. 4, 2021

Breast cancer is one of the leading causes mortality in women worldwide, and neoadjuvant chemotherapy has emerged as an option for management locally advanced breast cancer. Extensive efforts have been made to identify new molecular markers predict response chemotherapy. Transcripts that do not encode proteins, termed long noncoding RNAs (lncRNAs), shown display abnormal expression profiles different types cancer, but their role biomarkers extensively studied. Herein, lncRNA was profiled using RNA sequencing biopsies from patients who subsequently showed either or no treatment. GATA3-AS1 overexpressed nonresponder group most stable feature when performing selection multiple random forest models. experimentally validated by quantitative RT-PCR extended 68 patients. Expression analysis confirmed primarily were nonresponsive chemotherapy, with a sensitivity 92.9% specificity 75.0%. The statistical model based on luminal B-like adjusted menopausal status phenotype (odds ratio, 37.49; 95% CI, 6.74-208.42; P = 0.001); established independent predictor response. Thus, proposed potential predictive biomarker nonresponse

Language: Английский

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