Methylomics of breast cancer: Seeking epimarkers in peripheral blood of young subjects

Khakpour, Golnaz; Noruzinia, Mehrdad; Izadi, Pantea; Karami, Fatemeh; Ahmadvand, Mohammad; Heshmat, Ramin; Amoli, Mahsa M.; Bazzaz, Javad Tavakkoly

doi:10.1177/1010428317695040

Cited by 16 publications

(10 citation statements)

References 67 publications

(89 reference statements)

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“…Finally, RAB40C protein regulates, via an ubiquitin-proteasome system, the degradation of RACK1 protein, which is important in tumour growth and T-cell migration [39] . The RAB40C gene was also among the main genes silenced with methylation in breast cancer [40] , matching the lower expression in TOL compared to Non-TOL KTRs that we observed. There are, therefore, sound reasons to believe that the seven consensus genes are biologically, as well as statistically important for OT.…”

Section: Discussionsupporting

confidence: 85%

Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy

et al. 2020

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Background Kidney transplant recipients (KTRs) with “operational tolerance” (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs. Methods We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression. Findings IS drugs explained up to 50% of the variability in gene-expression and 20–30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4–1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0⋅92 (95% confidence interval 0⋅88–0⋅94) in cross-validation and 0⋅97 (0⋅93–1⋅00) in six months follow-up samples. Interpretation We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial. Funding FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas’ Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007–2013 [HEALTH-F5–2010–260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19–06–00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].

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Section: Discussionsupporting

confidence: 85%

Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy

et al. 2020

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“…For example, TMSB10 is overexpressed in breast cancer cells, has elevated protein expression in serum of breast cancer patients, and is elevated with increasing breast cancer stage and distant metastasis [45]. Linking a systemic marker of breast cancer risk to our tissue-specific approach, promoter CpG island hypomethylation of ZNF584 was associated with a breast cancer diagnosis both here and in peripheral blood DNA from breast cancer patients [46]. Further, using TCGA breast tumor data, we showed the functional relationship of ZNF584 DNA methylation with gene expression.…”

Section: Discussionmentioning

confidence: 99%

Prediagnostic breast milk DNA methylation alterations in women who develop breast cancer

Salas

Lundgren

Browne

et al. 2019

Preprint

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Background: Prior candidate gene studies have shown tumor suppressor DNA methylation in breast milk related with history of breast biopsy, an established risk factor for breast cancer. To further establish the utility of breast milk as a tissue-specific biospecimen for investigations of breast carcinogenesis we measured genome-wide DNA methylation in breast milk from women with and without a diagnosis of breast cancer in two independent cohorts. Methods: DNA methylation was assessed using Illumina HumanMethylation450k in 87 breast milk samples. After quality control, 368,171 autosomal CpG loci were analyzed. Cell type proportion estimates from RefFreeCellMix were calculated and adjusted for in this Epigenome Wide Association Study using linear mixed effects models adjusted for history of breast biopsy, age, time of delivery, cell type proportion estimates, array chip, and subject as random effect. Results: Epigenome-wide analyses identified 58 differentially methylated CpG sites associated with a breast cancer diagnosis in the prospectively collected milk samples from the breast that would develop cancer compared with women without a diagnosis of breast cancer (q-value < 0.05). Nearly all CpG sites associated with a breast cancer diagnosis were hypomethylated in cases compared with controls, and were enriched for CpG islands. In addition, inferred repeat element methylation was lower in breast milk DNA from cases compared to controls, and cases exhibited increased estimated epigenetic mitotic tick rate as well as DNA methylation age compared with controls. Conclusion: Breast milk has utility as a biospecimen for prospective assessment of disease risk, for understanding the underlying molecular basis of breast cancer risk factors, and improving primary and secondary prevention of breast cancer.

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“…Besides, UC-derived MSCs were also obtained from Royan Institute for Stem Cell Biology and Asian Pacific Journal of Cancer Prevention, Vol 23 3085 DOI:10.31557/APJCP.2022.23.9.3083 MSC-Educated Macrophages Quantitative RT-PCR Total RNA was extracted from MQ after direct/indirect treatment and also MQ at day +5 as a control group using TRIZOL (Sigma Aldrich, Missouri, USA). The quality of isolated RNA was verified by Nanodrop 1000 (Fisher scientific, Pittsburgh, PA, USA), and one to 5μg of the resultant RNA reversely transcribed to cDNA using a reverse transcription kit according to the manufacturer's instruction (BIO FACT, Korea) (Khakpour et al, 2017;Eskandari et al, 2019;Motaei et al, 2019;Abedi et al, 2020). The quantitative polymerase chain reaction was then performed for cDNA using SYBR green master mix (BIO FACT, Korea) on Corbett Rotor gene 6000 instruments (QIAGEN, Germany) using standard protocols.…”

Section: Bm and Uc-derived Mscs Culturementioning

confidence: 99%

A Comparative Study of the Bone Marrow- and Umbilical Cord-Derived Mesenchymal Stem Cells (MSCs) Efficiency on Generating MSC-Educated Macrophages (MEMs)

Shirin

Agharezaeei

Alizadeh

et al. 2022

Asian Pac J Cancer Prev

Self Cite

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Background: Mesenchymal stem cells (MSCs) have gained much more attention in cell therapy and regenerative medicine due to their immunosuppressive effects. MSCs have interaction with other immune cells, such as macrophages (MQs). Bone marrow (BM)-derived MSCs can educate MQs toward MSC-educated MQs (MEMs) which possess an anti-inflammatory immunophenotype. Given this and based on the important limitations of BM collection, we hypothesized whether co-culture of MQs with umbilical cord (UC)-derived MSCs can result in the MEM phenotype. Methods: First, isolated monocytes cultured for five days to obtain M0 MQs. Then, they were co-cultured with either BM-or UC-MSCs under direct and indirect conditions. After three days of co-culture, MEM-specific surface markers, as well as the gene expression of inflammatory and anti-inflammatory cytokines, were evaluated. Results: Surface expression of CD163/CD206, as specific markers for M2 MQs, increased in MEMs after co-culture with BM-and UC-derived MSCs, while CD80/CD86 expression (specific markers for M1 MQs) didn't change significantly. The mRNA expressions of PDL-1 as well as anti-inflammatory cytokines, including IL-6, IL-10, and TGFβ also increased in MEMs after co-culture of UC-MSCs compared to control MQs (p <.05), while the expression of IL-12 was significantly decreased (p<.001). Conclusions: To the best of our knowledge, this study shows for the first time that the co-culture of MQs with UC-derived MSCs efficiently contributes to the generation of MEMs even greater than BM-MSCs; shedding light on the promising potential of UC as an alternative source to educate MQs in vitro.

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Methylomics of breast cancer: Seeking epimarkers in peripheral blood of young subjects

Cited by 16 publications

References 67 publications

Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy

Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy

Prediagnostic breast milk DNA methylation alterations in women who develop breast cancer

A Comparative Study of the Bone Marrow- and Umbilical Cord-Derived Mesenchymal Stem Cells (MSCs) Efficiency on Generating MSC-Educated Macrophages (MEMs)

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