GATA3 somatic mutations are associated with clinicopathological features and expression profile in TCGA breast cancer patients

Afzaljavan, Fahimeh; Sadr, Ayeh Sadat; Savas, Sevtap; Pasdar, Alireza

doi:10.1038/s41598-020-80680-9

Cited by 18 publications

(13 citation statements)

References 71 publications

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“…TP53 mutations were only found in HG-DCIS and associated with high CNA burden (Mann-Whitney, p=0.018), while GATA3 mutations were only found in cribriform or ADH histologies and associated with LG-DCIS (Fisher Exact, p=0.005). Interestingly, GATA3 mutations were identified in larger lesions (Mann Whitney, p=0.038), consistent with a similar observation in invasive cancer and the larger tumor size of GATA3 mutated xenograft models 31,32 . Another 9 selected genes known to be mutated in IBC were recurrently affected by 18 mutations predicted to be deleterious, 4 of which are known somatic mutations 7 .…”

Section: Subtype Differences In Mutational Landscapesupporting

confidence: 85%

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

Nachmanson

Mori

et al. 2021

Preprint

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The increased detection and treatment of early stage breast cancer as well as ductal carcinoma in situ (DCIS) has not led to significant survival benefits. Therefore, the current standard treatment of DCIS is questionable. An informed evidence-based treatment strategy, and likely de-escalation from the current standards requires new prognostic models built from more comprehensive characterization with objective criteria. Parallel profiling of the molecular landscape and micro-environment in pure DCIS remains challenging due to histological heterogeneity and the inevitable reliance on small archived specimens. Leveraging recent methodological advances, we characterized the mutational, transcriptional, histological and microenvironmental landscape across multiple micro-dissected regions from 39 cases to generate a multi-modal breast precancer atlas. The histological architecture was associated with grade, adiposity, and intrinsic expression subtypes. Similar to previous findings, high-grade lesions had higher mutational burden, including TP53 mutations, while low-grade lesions had more frequent 16q losses and GATA3 mutations. Multi-region analysis revealed most somatic alterations, including whole genome duplication events, were clonal, but genetic divergence increased with distance between regions. In 7/12 evaluable cases, somatic mutations in putative driver genes affected a subset of regions only. This genetic heterogeneity often accompanied phenotypic heterogeneity and regions with low risk features (Normal-like, Luminal A) occurred earlier than those with high-risk features (Her2-like, Basal or necrosis) according to the phylogenetic analysis. The immune-environment was evaluated using multiplex immuno-histochemistry to measure relative stromal and epithelial densities of B lymphocyte (B-cell), T lymphocyte (T-cell) and regulatory T cells (T-reg) and identify 3 immune-states: Active, Suppressed and Excluded (lower epithelial density). All states included both DCIS and adjacent benign regions, and none associated with intrinsic subtypes. The Excluded state was enriched in high-grade DCIS and, compared to benign areas, more likely acquired in DCIS, showing transcriptional evidence of stronger immune-suppression and possible evasion. The breast pre-cancer atlas therefore reveals correlated levels of phenotypic and genotypic heterogeneity, including at sub-histological resolution. These uniquely integrated observations will help scope future studies, prioritize candidate markers for progression risk modelling and identify functional similarities in precursor lesions from other types of adenocarcinomas.

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Section: Subtype Differences In Mutational Landscapesupporting

confidence: 85%

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

Nachmanson

Mori

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…TP53 mutations were only found in HG-DCIS and associated with high CNA burden (Mann-Whitney, p = 0.018), while GATA3 mutations were only found in cribriform or ADH histologies and associated with LG-DCIS (Fisher Exact, p = 0.005). Interestingly, GATA3 mutations were identified in larger lesions (Mann-Whitney, p = 0.038), consistent with a similar observation in invasive cancer and the larger tumor size of GATA3 mutated xenograft models 33,34 . Another nine selected genes known to be mutated in IBC were recurrently affected by 18 mutations predicted to be deleterious, four of which are known somatic mutations 7 .…”

Section: Subtype Differences In the Mutational Landscapesupporting

confidence: 85%

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

et al. 2022

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

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“…GATA3 mutations can lead to active forms of the GATA3 protein that contribute to tumor growth in BC cell xenografts and promote precocious lobuloalveolar development in transgenic mice [ 167 ]. In addition, ER-positive breast tumors with GATA3 mutations were reported to have a worse prognosis compared to wt tumors [ 168 ]. In the MCF7 cell line, GATA3 is affected by a heterozygous D336fs mutation in the second zinc finger that leads to a truncated protein with reduced affinity for DNA.…”

Section: Luminal Esr1 Transcriptional Regulatorsmentioning

confidence: 99%

Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis

Porras

Ismail

Mader

2021

Cells

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

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GATA3 somatic mutations are associated with clinicopathological features and expression profile in TCGA breast cancer patients

Cited by 18 publications

References 71 publications

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

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

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

Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis

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