Multi-omics data integration reveals correlated regulatory features of triple negative breast cancer

Chappell, Kevin; Manna, Kanishka; Washam, Charity L.; Graw, Stefan; Alkam, Duah; Thompson, Matthew D.; Zafar, Maroof K.; Hazeslip, Lindsey; Randolph, Christopher E.; Gies, Allen; Bird, John; Byrd, Alicia K.; Miah, Sayem; Byrum, Stephanie D.

doi:10.1039/d1mo00117e

Cited by 12 publications

(9 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overall, we identified the associations between methylation and mRNA expression on pathways with biological significance and synchronous tumor-derived models retained the traditional understanding of the linkage with methylated CpG sites of gene promoter region and reduction of gene expression 31 , 32 . These two sets of inter-correlations connecting three different molecular levels of omics data also reemphasized the effect of integrative actionable targets on certain drug responses in the previous studies 33 . Since the treatment of clonally variable synchronous neoplasia requires clone-specific inspection of variable molecular layers in clinical practice 3 , our multi-omics platform enabled a more precise distinction of clonal difference in synchronous tumors, which provides superior clinical application.…”

Section: Resultsmentioning

confidence: 58%

Multifocal organoids reveal clonal associations between synchronous intestinal tumors with pervasive heterogeneous drug responses

et al. 2022

View full text Add to dashboard Cite

Multifocal colorectal cancer (CRC) comprises both clonally independent primary tumors caused by inherited predisposition and clonally related tumors mainly due to intraluminal spreading along an intact basement membrane. The distinction between these multifocal CRCs is essential because therapeutic strategies vary according to the clonal association of multiple tumor masses. Here, we report one unique case of synchronous intestinal cancer (SIC) with tumors occurring along the entire bowel tract, including the small intestine. We established six patient-derived organoids (PDOs), and patient-derived cell lines (PDCs) from each site of the SIC, which were subjected to extensive genomic, transcriptomic, and epigenomic sequencing. We also estimated the drug responses of each multifocal SIC to 25 clinically relevant therapeutic compounds to validate how the clinically actionable alternations between SICs were associated with drug sensitivity. Our data demonstrated distinct clonal associations across different organs, which were consistently supported by multi-omics analysis, as well as the accordant responses to various therapeutic compounds. Our results indicated the imminent drawback of a single tumor-based diagnosis of multifocal CRC and suggested the necessity of an in-depth molecular analysis of all tumor regions to avoid unexpected resistance to the currently available targeted therapies.

show abstract

Section: Resultsmentioning

confidence: 58%

Multifocal organoids reveal clonal associations between synchronous intestinal tumors with pervasive heterogeneous drug responses

et al. 2022

View full text Add to dashboard Cite

show abstract

“…According to the cell definitions of Chappell et al ( 29 ) and Subik et al ( 30 ), we selected three types of BCa cell lines (ER+, HER2+, and TNBC). Therefore, datasets GSE96860, MCF7 (ER+), AU565 (HER2+), MB231 (TNBC), and MB468 (TNBC) were included as cancer cell lines, and MCF10A and 76NF2V were selected as the normal healthy cell lines.…”

Section: Resultsmentioning

confidence: 99%

Screening and Identification of Human Endogenous Retrovirus-K mRNAs for Breast Cancer Through Integrative Analysis of Multiple Datasets

Wei¹,

Wei

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

ObjectiveHuman endogenous retroviruses (HERVs) make up 8% of the human genome. HERVs are biologically active elements related to multiple diseases. HERV-K, a subfamily of HERVs, has been associated with certain types of cancer and suggested as an immunologic target in some tumors. The expression levels of HERV-K in breast cancer (BCa) have been studied as biomarkers and immunologic therapeutic targets. However, HERV-K has multiple copies in the human genome, and few studies determined the transcriptional profile of HERV-K copies across the human genome for BCa.MethodsNinety-one HERV-K indexes with entire proviral sequences were used as the reference database. Nine raw sequencing datasets with 243 BCa and 137 control samples were mapped to this database by Salmon software. The differential proviral expression across several groups was analyzed by DESeq2 software.ResultsFirst, the clustering of each dataset demonstrated that these 91 HERV-K proviruses could well cluster the BCa and control samples when the normal controls were normal cells or healthy donor tissues. Second, several common HERV-K proviruses that are closely related with BCa risk were significantly differentially expressed (padj < 0.05 and absolute log2FC > 1.5) in the tissues and cell lines. Additionally, almost all the HERV-K proviruses had higher expression in BCa tissue than in healthy donor tissue. Notably, we first found the expression of 17p13.1 provirus that located with TP53 should regulate TP53 expression in ER+ and HER2+ BCa.ConclusionThe expression profiling of these 91 HERV-K proviruses can be used as biomarkers to distinguish individuals with BCa and healthy controls. Some proviruses, especially 17p13.1, were strongly associated with BCa risk. The results suggest that HERV-K expression profiles may be appropriate biomarkers and targets for BCa.

show abstract

“…Alterations in protein phosphorylation in breast cancer cells and tissues has revealed the heterogeneity of breast cancer 38,39 . However, differences in protein phosphorylation between IDC and ILC are still not very clear.…”

Section: Protein Expression and Phosphorylation Between Idc And Ilc B...mentioning

confidence: 99%

“…Kinases are categorized into ten groups based on statistical sequence analysis 42 . The greatest number of identi ed phosphorylated protein kinases (39) belonged to the CMGC group, followed by the AGC group (26) and CAMK group (25) (Fig. 6b).…”

Section: Protein and Phosphorylation Features Between Idc And Ilc Bre...mentioning

confidence: 99%

Comprehensive proteome and phosphoproteome analysis reveals the protein characterization of invasive ductal and lobular carcinoma with specific molecular subgroup

Yang

Zuo

et al. 2022

Preprint

View full text Add to dashboard Cite

Background Breast cancer is one of the most frequently occurring malignant cancers worldwide. Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the two most common histological subtypes of breast cancer. The prognosis and survival of the two subtypes were significantly different even with specific molecular subgroup. In this study, we aimed to deeply explore molecular characteristics and the relationship between IDC and ILC subtypes in same molecular subgroup of breast cancer using comprehensive proteomics and phosphoproteomics analysis. Methods Cancer tissues and noncancerous adjacent tissues (NATs) with the luminal subtype (ER- and PR-positive, HER2-negative) were obtained from paired IDC and ILC patients respectively. Label-free quantitative proteomics and phosphoproteomics methods were used to detect differentially expressed proteins and the phosphorylation status between 10 paired breast cancer and NATs. Then, bioinformatics analysis was performed to explore the difference between IDC and ILC subtypes, including the difference in protein expression levels and the degree of phosphorylation. Meanwhile, Kinase-Substrate Enrichment Analysis (KSEA) revealed the activation difference of kinases and their substrates between IDC and ILC. Results A total of 5,044 high-confidence proteins and 3,808 phosphoproteins were identified from breast cancer tissues. The protein phosphorylation level in ILC tissues was higher than that in IDC tissues. From the quantitative analysis of 1259 proteins and 560 phosphoproteins with high patient coverage, Histone H1.10, Complement C4-B and Crk-like protein were found to be significantly differentially expressed in the two subtype tissues from the proteomics analysis. Moreover, the differences in protein expression of Septin-2, Septin-9, Heterogeneous nuclear ribonucleoprotein A1 and Kinectin and their phosphorylation clearly distinguished IDC from ILC. In addition, differentially expressed proteins and differentially expressed phosphoproteins in IDC were primarily related to energy metabolism and MAPK pathway, while ILC subtypes were more closely involved in the AMPK and p53/p21 pathways. Furthermore, the kinomes from IDC were primarily significantly activated in the CMGC (Cyclin-dependent kinases, Mitogen-activated protein kinases, Glycogen synthase kinases and CDK-like kinases) groups. Conclusions Our research provides insights into the molecular characterization of IDC and ILC and contributes to discovering novel targets for further drug development and targeted treatment.

show abstract

Multi-omics data integration reveals correlated regulatory features of triple negative breast cancer

Abstract: Multi-omics data integration of triple negative breast cancer (TNBC) provides insight into biological pathways.

Cited by 12 publications

References 74 publications

Multifocal organoids reveal clonal associations between synchronous intestinal tumors with pervasive heterogeneous drug responses

Multifocal organoids reveal clonal associations between synchronous intestinal tumors with pervasive heterogeneous drug responses

Screening and Identification of Human Endogenous Retrovirus-K mRNAs for Breast Cancer Through Integrative Analysis of Multiple Datasets

Comprehensive proteome and phosphoproteome analysis reveals the protein characterization of invasive ductal and lobular carcinoma with specific molecular subgroup

Contact Info

Product

Resources

About