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Article ; Online: Integrating somatic CNV and gene expression in breast cancers from women with PTEN hamartoma tumor syndrome.

Brewer, Takae / Yehia, Lamis / Bazeley, Peter / Eng, Charis

2023 Volume 8, Issue 1, Page(s) 14

Abstract: Women with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS) have up to 85% lifetime risk of female breast cancer (BC). We previously showed that PHTS-derived BCs are distinct from sporadic BCs both at the clinical and genomic levels. In this ... ...

Abstract	Women with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS) have up to 85% lifetime risk of female breast cancer (BC). We previously showed that PHTS-derived BCs are distinct from sporadic BCs both at the clinical and genomic levels. In this study, we examined somatic copy number variations (CNV) and transcriptome data to further characterize the somatic landscape of PHTS-derived BCs. We analyzed exome sequencing data from 44 BCs from women with PHTS for CNV. The control group comprised of 558 women with sporadic BCs from The Cancer Genome Atlas (TCGA) dataset. Here, we found that PHTS-derived BCs have several distinct CNV peaks compared to TCGA. Furthermore, RNA sequencing data revealed that PHTS-derived BCs have a distinct immunologic cell type signature, which points toward cancer immune evasion. Transcriptomic data also revealed PHTS-derived BCs with pathogenic germline PTEN variants appear to have vitamin E degradation as a key pathway associated with tumorigenesis. In conclusion, our study revealed distinct CNV x transcript features in PHTS-derived BCs, which further facilitate understanding of BC biology arising in the setting of germline PTEN mutations.
Language	English
Publishing date	2023-07-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2813848-X
ISSN	2056-7944 ; 2056-7944
ISSN (online)	2056-7944
ISSN	2056-7944
DOI	10.1038/s41525-023-00361-0
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Article ; Online: Single-cell transcriptomic profiling of microvascular endothelial cell heterogeneity in congenital diaphragmatic hernia.

Robertson, Jason O / Bazeley, Peter / Erzurum, Serpil C / Asosingh, Kewal

Scientific reports

2023 Volume 13, Issue 1, Page(s) 9851

Abstract: Congenital diaphragmatic hernia (CDH) is a neonatal anomaly that includes pulmonary hypoplasia and hypertension. We hypothesized that microvascular endothelial cell (EC) heterogeneity is different in CDH lungs and related to lung underdevelopment and ... ...

Abstract	Congenital diaphragmatic hernia (CDH) is a neonatal anomaly that includes pulmonary hypoplasia and hypertension. We hypothesized that microvascular endothelial cell (EC) heterogeneity is different in CDH lungs and related to lung underdevelopment and remodeling. To test this, we evaluated rat fetuses at E21.5 in a nitrofen model of CDH to compare lung transcriptomes among healthy controls (2HC), nitrofen-exposed controls (NC) and nitrofen-exposed subjects with CDH. Single-cell RNA sequencing with unbiased clustering revealed 3 distinct microvascular EC clusters: a general population (mvEC), a proliferative population and a population high in hemoglobin. Only the CDH mvEC cluster had a distinct inflammatory transcriptomic signature as compared to the 2HC and NC endothelial cells, e.g. greater activation and adhesion of inflammatory cells and production of reactive oxygen species. Furthermore, CDH mvECs had downregulated Ca4, Apln and Ednrb gene expression. Those genes are markers for ECs important to lung development, gas exchange and alveolar repair (mvCa4+). mvCa4+ ECs were reduced in CDH (2HC [22.6%], NC [13.1%] and CDH [5.3%], p < 0.0001). Overall, these findings identify transcriptionally distinct microvascular endothelial cell clusters in CDH, including the distinctly inflammatory mvEC cluster and the depleted group of mvCa4+ ECs, which together may contribute to pathogenesis.
MeSH term(s)	Humans ; Rats ; Animals ; Hernias, Diaphragmatic, Congenital/genetics ; Hernias, Diaphragmatic, Congenital/pathology ; Endothelial Cells ; Transcriptome ; Rats, Sprague-Dawley ; Lung/pathology ; Disease Models, Animal
Chemical Substances	nitrofen (N71UYG034A)
Language	English
Publishing date	2023-06-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-37050-y
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Article ; Online: Exome sequencing reveals a distinct somatic genomic landscape in breast cancer from women with germline PTEN variants.

Brewer, Takae / Yehia, Lamis / Bazeley, Peter / Eng, Charis

American journal of human genetics

2022 Volume 109, Issue 8, Page(s) 1520–1533

Abstract: Germline PTEN variants (PTEN hamartoma tumor syndrome [PHTS]) confer up to 85% lifetime risk of female breast cancer (BC). BCs arising in PHTS are clinically distinct from sporadic BCs, including younger age of onset, multifocality, and an increased risk ...

Abstract	Germline PTEN variants (PTEN hamartoma tumor syndrome [PHTS]) confer up to 85% lifetime risk of female breast cancer (BC). BCs arising in PHTS are clinically distinct from sporadic BCs, including younger age of onset, multifocality, and an increased risk of second primary BCs. Yet, there is no previous investigation into the underlying genomic landscape of this entity. We sought to address the hypothesis that BCs arising in PHTS have a distinct genomic landscape compared to sporadic counterparts. We performed and analyzed exome sequencing data from 44 women with germline PTEN variants who developed BCs. The control cohort comprised of 497 women with sporadic BCs from The Cancer Genome Atlas (TCGA) dataset. We demonstrate that PHTS-derived BCs have a distinct somatic mutational landscape compared to the sporadic counterparts, namely second somatic hits in PTEN, distinct mutational signatures, and increased genomic instability. The PHTS group had a significantly higher frequency of somatic PTEN variants compared to TCGA (22.7% versus 5.6%; odds ratio [OR] 4.93; 95% confidence interval [CI] 2.21 to 10.98; p < 0.001) and a lower mutational frequency in PIK3CA (22.7% versus 33.4%; OR 0.59; 95% CI 0.28 to 1.22; p = 0.15). Somatic variants in PTEN and PIK3CA were mutually exclusive in PHTS (p = 0.01) but not in TCGA. Our findings have important implications for the personalized management of PTEN-related BCs, especially in the context of more accessible genetic testing.
MeSH term(s)	Breast Neoplasms/genetics ; Class I Phosphatidylinositol 3-Kinases/genetics ; Exome/genetics ; Female ; Genomics ; Germ Cells/pathology ; Germ-Line Mutation/genetics ; Hamartoma Syndrome, Multiple/genetics ; Humans ; PTEN Phosphohydrolase/genetics
Chemical Substances	Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67)
Language	English
Publishing date	2022-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2022.07.005
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Zs.A 107: Show issues

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Article ; Online: Inheritance of a common androgen synthesis variant allele is associated with female COVID susceptibility in UK Biobank.

McManus, Jeffrey M / Sabharwal, Navin / Bazeley, Peter / Sharifi, Nima

European journal of endocrinology

2022 Volume 187, Issue 1, Page(s) 1–14

Abstract: Context: A sex discordance in COVID exists, with males disproportionately affected. Although sex steroids may play a role in this discordance, no definitive genetic data exist to support androgen-mediated immune suppression neither for viral ... ...

Abstract	Context: A sex discordance in COVID exists, with males disproportionately affected. Although sex steroids may play a role in this discordance, no definitive genetic data exist to support androgen-mediated immune suppression neither for viral susceptibility nor for adrenally produced androgens. Objective: The common adrenal-permissive missense-encoding variant HSD3B1(1245C) that enables androgen synthesis from adrenal precursors and that has been linked to suppression of inflammation in severe asthma was investigated in COVID susceptibility and outcomes reported in the UK Biobank. Methods: The UK Biobank is a long-term study with detailed medical information and health outcomes for over 500 000 genotyped individuals. We obtained COVID test results, inpatient hospital records, and death records and tested for associations between COVID susceptibility or outcomes and HSD3B1(1245A/C) genotype. Primary analyses were performed on the UK Biobank Caucasian cohort. The outcomes were identification as a COVID case among all subjects, COVID positivity among COVID-tested subjects, and mortality among subjects identified as COVID cases. Results: Adrenal-permissive HSD3B1(1245C) genotype was associated with identification as a COVID case (odds ratio (OR): 1.11 per C allele, 95% CI: 1.04-1.18, P = 0.0013) and COVID-test positivity (OR: 1.09, 95% CI: 1.02-1.17, P = 0.011) in older (≥70 years of age) women. In women identified as COVID cases, there was a positive linear relationship between age and 1245C allele frequency (P < 0.0001). No associations were found between genotype and mortality or between genotype and circulating sex hormone levels. Conclusion: Our study suggests that a common androgen synthesis variant regulates immune susceptibility to COVID infection in women, with increasingly strong effects as women age.
MeSH term(s)	Aged ; Alleles ; Androgens/biosynthesis ; Biological Specimen Banks ; COVID-19/epidemiology ; COVID-19/genetics ; Female ; Humans ; Male ; Multienzyme Complexes/genetics ; Progesterone Reductase ; Steroid Isomerases ; United Kingdom/epidemiology
Chemical Substances	3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase ; Androgens ; Multienzyme Complexes ; Progesterone Reductase (EC 1.1.1.145) ; Steroid Isomerases (EC 5.3.3.-)
Language	English
Publishing date	2022-05-12
Publishing country	England
Document type	Journal Article
ZDB-ID	1183856-5
ISSN	1479-683X ; 0804-4643
ISSN (online)	1479-683X
ISSN	0804-4643
DOI	10.1530/EJE-21-0996
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Uh III Zs.147: Show issues

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Article ; Online: Evidence of Clonal Hematopoiesis and Risk of Heart Failure.

Bazeley, Peter / Morales, Rommel / Tang, W H Wilson

Current heart failure reports

2020 Volume 17, Issue 5, Page(s) 271–276

Abstract: Purpose of review: Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by persistent clonal expansion of adult hematopoietic stem cells, which has been increasingly found to be associated with cardiovascular disease and adverse ... ...

Abstract	Purpose of review: Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by persistent clonal expansion of adult hematopoietic stem cells, which has been increasingly found to be associated with cardiovascular disease and adverse outcomes in heart failure. Here we outline emerging studies on the prevalence of CHIP, and its association with cardiovascular and heart disease. Recent findings: Previous genomic studies have found CHIP mutations to be associated with increased risks of arterial disease, stroke, and mortality. Murine studies exploring TET2, DNMT3A, and JAK2 mutations have shown changes in cellularity that decrease cardiac function after insult, as well as increase inflammasome activation. Mutations in driver genes are associated with worse clinical outcomes in heart failure patients, as a potential result of the proinflammatory selection in clonal hematopoiesis. Advances in the field have yielded therapeutic targets tested in recent clinical studies and may provide a valuable diagnostic of risk in heart failure.
MeSH term(s)	Clonal Hematopoiesis/genetics ; DNA/genetics ; DNA Mutational Analysis ; Heart Failure/genetics ; Hematopoietic Stem Cells/cytology ; Humans ; Mutation
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2020-08-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2151202-4
ISSN	1546-9549 ; 1546-9530
ISSN (online)	1546-9549
ISSN	1546-9530
DOI	10.1007/s11897-020-00476-w
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Zs.A 5936: Show issues

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Jg. 1995 - 2021: Lesesall (2.OG)
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Article ; Online: Online, low-volume meditation does not alter immune-related biomarkers.

Graham, Brett / Jin, Yuxuan / Bazeley, Peter / Husni, Elaine / Calabrese, Leonard H

Brain, behavior, & immunity - health

2022 Volume 26, Page(s) 100531

Abstract: Objectives: Prior studies of mindfulness meditation have demonstrated anti-inflammatory and immunoregulatory effects but whether meditation courses delivered online can exert similar effects is poorly understood. Barriers to large scale implementation ... ...

Abstract	Objectives: Prior studies of mindfulness meditation have demonstrated anti-inflammatory and immunoregulatory effects but whether meditation courses delivered online can exert similar effects is poorly understood. Barriers to large scale implementation of traditional mindfulness meditation programs has created an increased interest in the effect of less time- and resource-intensive online meditation courses. The purpose of this study was to determine whether a 6-week online mindfulness program with low time demands on nurses would lead to changes in gene expression, cytokine profiles, telomerase activity, and cortisol profiles. Methods: This was a randomized, parallel pilot study comparing an online mindfulness-based stress management program to an active control group from December 2018 to May 2019. Healthy nurses with above average levels of perceived stress were randomized to receive a 6-week online mindfulness-based stress management program including ≥5 min daily meditation practice or listen to relaxing music for ≥5 min daily as the control arm. Blood samples were collected at baseline and after 6 weeks, and various self-reported measures of stress, physical and emotional health were collected at baseline, after 6 weeks, and after 12 weeks. Whole transcriptome mRNA sequencing of whole blood at baseline and after 6 weeks was performed along with measurement of plasma IL-6, IL-8, IL-10, TNF-α, and IFN-γ. Peripheral blood mononuclear cells were isolated, and telomerase activity was measured. Diurnal salivary cortisol profiles were assessed at baseline and after 6 weeks. The primary outcome was change over time in a pre-determined set of 53 genes representative of the immune-related changes seen with stress, which was analyzed using a mixed linear model. Secondary outcomes included all other self-reported measures and biomarkers mentioned above. Results: A total of 61 nurses were randomized, with 52 having sufficient data to include in the final analysis. After 6 weeks, nurses in the control group reported significant reductions in stress as measured by the Perceived Stress Scale while those in the mindfulness group did not. However, after 12 weeks, the mindfulness group also showed a significant reduction in stress. When compared to the control group, no significant changes in RNA gene expression or any other biomarkers were observed in the nurses who participated in the mindfulness program. Conclusions: Our study found that this brief online mindfulness-based intervention was effective in reducing stress in nurses, albeit with a delayed effect compared to listening to relaxing music. Regarding immunoregulatory effects, there were no significant differences between treatment and control groups in transcriptomic or other tested biomarkers of immune function. This study provides evidence for a floor effect of mindfulness on transcriptional and circulating biomarkers of immune function.
Language	English
Publishing date	2022-10-03
Publishing country	United States
Document type	Journal Article
ISSN	2666-3546
ISSN (online)	2666-3546
DOI	10.1016/j.bbih.2022.100531
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Article ; Online: Association Between Adrenal-Restrictive HSD3B1 Inheritance and Hormone-Independent Subtypes of Endometrial and Breast Cancer.

McManus, Jeffrey M / Vargas, Roberto / Bazeley, Peter S / Schumacher, Fredrick R / Sharifi, Nima

JNCI cancer spectrum

2022 Volume 6, Issue 5

Abstract: Background: The germline variant rs1047303 (HSD3B1[1245A/C]), restricting or enabling production of potent androgens and estrogens from adrenal precursors, affects outcomes of castration-resistant prostate cancer and is associated with estrogen receptor ...

Abstract	Background: The germline variant rs1047303 (HSD3B1[1245A/C]), restricting or enabling production of potent androgens and estrogens from adrenal precursors, affects outcomes of castration-resistant prostate cancer and is associated with estrogen receptor positivity in postmenopausal breast cancer. Like breast cancer, endometrial cancer is another malignancy with hormone-dependent and hormone-independent subtypes. We hypothesized that adrenal-restrictive HSD3B1 genotype would associate with hormone-independent cancer subtypes. Methods: We employed a previously described classification of tumors in The Cancer Genome Atlas into genomic clusters. We determined HSD3B1 genotype frequencies by endometrial cancer genomic cluster and calculated the odds per adrenal-restrictive A allele for the largely hormone-independent copy-number (CN) high subtype vs other subtypes. An equivalent analysis was performed for the genomically similar, hormone-independent basal breast cancer subtype. Last, we performed survival analyses for UK Biobank participants with endometrial cancer by HSD3B1 genotype. All statistical tests were 2-sided. Results: The adrenal-restrictive HSD3B1(1245A) allele was associated with the CN-high endometrial cancer subtype (odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.14 to 2.32; P = .007). Similarly, HSD3B1(1245A) was associated with the basal breast cancer subtype (OR = 1.54, 95% CI = 1.13 to 2.08; P = .006). In the UK Biobank, endometrial cancer patients homozygous for HSD3B1(1245A) had worse overall (hazard ratio [HR] = 1.39, 95% CI = 1.16 to 1.68; P < .001) and cancer-specific (HR = 1.39, 95% CI = 1.14 to 1.70; P = .001) survival, consistent with the A allele being enriched in the more aggressive CN-high subtype. Conclusions: These findings suggest roles for adrenal-restrictive vs adrenal-permissive steroidogenesis, by way of rs1047303 genotype, in the development of and/or outcomes from at least 3 commonly hormone-associated types of cancer: prostate, breast, and endometrial.
MeSH term(s)	Androgen Antagonists ; Androgens ; Breast Neoplasms/genetics ; Endometrial Neoplasms/genetics ; Female ; Humans ; Multienzyme Complexes/genetics ; Progesterone Reductase/genetics ; Steroid Isomerases/genetics
Chemical Substances	3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase ; Androgen Antagonists ; Androgens ; Multienzyme Complexes ; Progesterone Reductase (EC 1.1.1.145) ; Steroid Isomerases (EC 5.3.3.-)
Language	English
Publishing date	2022-08-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2515-5091
ISSN (online)	2515-5091
DOI	10.1093/jncics/pkac061
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Article ; Online: Molecular subtypes of epilepsy associated with post-surgical seizure recurrence.

Hershberger, Courtney E / Louis, Shreya / Busch, Robyn M / Vegh, Deborah / Najm, Imad / Bazeley, Peter / Eng, Charis / Jehi, Lara / Rotroff, Daniel M

Brain communications

2023 Volume 5, Issue 5, Page(s) fcad251

Abstract: Approximately 50% of individuals who undergo resective epilepsy surgery experience seizure recurrence. The heterogenous post-operative outcomes are not fully explained by clinical, imaging and electrophysiological variables. We hypothesized that ... ...

Abstract	Approximately 50% of individuals who undergo resective epilepsy surgery experience seizure recurrence. The heterogenous post-operative outcomes are not fully explained by clinical, imaging and electrophysiological variables. We hypothesized that molecular features may be useful in understanding surgical response, and that individuals with epilepsy can be classified into molecular subtypes that are associated with seizure freedom or recurrence after surgical resection. Pre-operative blood samples, brain tissue and post-operative seizure outcomes were collected from a cohort of 40 individuals with temporal lobe epilepsy, 23 of whom experienced post-operative seizure recurrence. Messenger RNA and microRNA extracted from the blood and tissue samples were sequenced. The messenger RNA and microRNA expression levels from the blood and brain were each subjected to a novel clustering approach combined with multiple logistic regression to separate individuals into genetic clusters that identify novel subtypes associated with post-operative seizure outcomes. We then compared the microRNAs and messenger RNAs from patient blood and brain tissue that were significantly associated with each subtype to identify signatures that are similarly over- or under-represented for an outcome and more likely to represent endophenotypes with common molecular aetiology. These target microRNAs and messenger RNAs were further characterized by pathway analysis to assess their functional role in epilepsy. Using blood-derived microRNA and messenger RNA expression levels, we identified two subtypes of epilepsy that were significantly associated with seizure recurrence (clusters A1 and B4) (adjusted
Language	English
Publishing date	2023-09-30
Publishing country	England
Document type	Journal Article
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcad251
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Article ; Online: A Between-Sex Comparison of the Genomic Architecture of Asthma.

Zein, Joe G / Bazeley, Peter / Meyers, Deborah / Bleecker, Eugene / Gaston, Benjamin / Hu, Bo / Attaway, Amy / Ortega, Victor

American journal of respiratory cell and molecular biology

2023 Volume 68, Issue 4, Page(s) 456–458

MeSH term(s)	Humans ; Asthma/genetics ; Genetic Predisposition to Disease ; Genomics
Language	English
Publishing date	2023-03-31
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2022-0430LE
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Zs.A 2851: Show issues

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Article ; Online: Spatial Transcriptomics Suggests That Alterations Occur in the Preneoplastic Breast Microenvironment of BRCA1/2 Mutation Carriers.

Caputo, Anthony / Vipparthi, Kavya / Bazeley, Peter / Downs-Kelly, Erinn / McIntire, Patrick / Duckworth, Lauren A / Ni, Ying / Hu, Bo / Keri, Ruth A / Karaayvaz, Mihriban

Molecular cancer research : MCR

2023 Volume 22, Issue 2, Page(s) 169–180

Abstract: Breast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide. Germline mutations in the BRCA1 and BRCA2 genes are significant risk factors for specific ... ...

Abstract	Breast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide. Germline mutations in the BRCA1 and BRCA2 genes are significant risk factors for specific subtypes of breast cancer. BRCA1 mutations are associated with basal-like breast cancers, whereas BRCA2 mutations are associated with luminal-like disease. Defects in mammary epithelial cell differentiation have been previously recognized in germline BRCA1/2 mutation carriers even before cancer incidence. However, the underlying mechanism is largely unknown. Here, we employ spatial transcriptomics to investigate defects in mammary epithelial cell differentiation accompanied by distinct microenvironmental alterations in preneoplastic breast tissues from BRCA1/2 mutation carriers and normal breast tissues from noncarrier controls. We uncovered spatially defined receptor-ligand interactions in these tissues for the investigation of autocrine and paracrine signaling. We discovered that β1-integrin-mediated autocrine signaling in BRCA2-deficient mammary epithelial cells may differ from BRCA1-deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues of BRCA1/2 mutation carriers is greater than in control tissues. More integrin-ligand pairs were differentially correlated in BRCA1/2-mutant breast tissues than noncarrier breast tissues with more integrin receptor-expressing stromal cells. Implications: These results suggest alterations in the communication between mammary epithelial cells and the microenvironment in BRCA1 and BRCA2 mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients.
MeSH term(s)	Humans ; Female ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Ligands ; Mutation ; Genes, BRCA1 ; Breast Neoplasms/genetics ; Breast Neoplasms/prevention & control ; Germ-Line Mutation ; Gene Expression Profiling ; Integrins ; Genetic Predisposition to Disease ; Tumor Microenvironment/genetics
Chemical Substances	BRCA1 protein, human ; BRCA1 Protein ; BRCA2 protein, human ; BRCA2 Protein ; Ligands ; Integrins
Language	English
Publishing date	2023-10-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-23-0489
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