Genomic regression analysis of coordinated expression

Cai, Ling; Li, Qiwei; Du, Yi; Yun, Jonghyun; Xie, Yang; DeBerardinis, Ralph J.; Xiao, Guanghua

doi:10.1038/s41467-017-02181-0

Cited by 18 publications

(17 citation statements)

References 36 publications

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“…Although in the presence of somatic copy number change we do not expect a linear correlation between copy number, mRNA or mRNA and protein expressions for all affected genes [ 23 ], the AIFM3 and DLK1 proteins’ expression increased in most MTC tissues, while their expression was absent in normal thyroid. As such, even if a change in DNA copy number is just one mechanism associated with changes in gene expression, the expression analysis allows us to demonstrate that the DLK1 copy number gain was positively correlated with protein expression, even in a nonlinear way.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma

Araújo

Camacho

Mendes

et al. 2021

Cancers

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Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C-cells that can occur either in sporadic (70–80%) or hereditary (20–30%) form. In this study we aimed to identify recurrent copy number alterations (CNA) that might be related to the pathogenesis or progression of MTC. We used Affymetrix SNP array 6.0 on MTC and paired-blood samples to identify CNA using PennCNV and Genotyping Console software. The algorithms identified recurrent copy number gains in chromosomes 15q, 10q, 14q and 22q in MTC, whereas 4q cumulated losses. Coding genes were identified within CNA regions. The quantitative PCR analysis performed in an independent series of MTCs (n = 51) confirmed focal recurrent copy number gains encompassing the DLK1 (14q32.2) and AIFM3 (22q11.21) genes. Immunohistochemistry confirmed AIFM3 and DLK1 expression in MTC cases, while no expression was found in normal thyroid tissues and few MTC samples were found with normal copy numbers. The functional relevance of CNA was also assessed by in silico analysis. CNA status correlated with protein expression (DLK1, p = 0.01), tumor size (DLK1, p = 0.04) and AJCC staging (AIFM3p = 0.01 and DLK1p = 0.05). These data provide a novel insight into MTC biology, and suggest a common CNA landscape, regardless of if it is sporadic or hereditary MTC.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma

Araújo

Camacho

Mendes

et al. 2021

Cancers

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“…However, co-expression analysis results from WGCNA may be hard to interpret since copy number variant (CNV) itself is a common feature in cancer 31 . In order to adjust for the variation in gene expression contributed by CNV, we also implemented an additional co-expression analysis with GRACE 32 — a recently proposed method which removes the influence of CNV before analysis. To implement the two analyses, we selected cervical cancer patients from TCGA who had both gene expression and copy number alteration, and finally kept 34 genes of 284 patients for GRACE and 48 genes of 296 patients for WGCNA.…”

Section: Methodsmentioning

confidence: 99%

New novel non-MHC genes were identified for cervical cancer with an integrative analysis approach of transcriptome-wide association study

Chen¹,

Wang²,

Huang³

et al. 2021

J. Cancer

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“…Three SMAD corepressors have been identified including the homeodomain protein TG-interacting factors (TGIFs), Ski, and SnoN protein [19][20][21]. We therefore examined genes that are negatively correlated with these corepressors in the TCGA data set on ccRCC [22]. Intriguingly, this analysis identified that TGIF2 is inversely correlated with the expression of genes involved in the TCA cycle enzymes.…”

Section: Hdac7 Acts As a Corepressor For Tgf-β Mediated Suppression Omentioning

confidence: 99%

TGF-β signaling suppresses TCA cycle metabolism in renal cancer

Nam

Kundu

Karki

et al. 2021

Preprint

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The Warburg effect is one of most-well studied metabolic phenomenon in cancer cells. For the most part, these studies have focused on enhanced rates of glycolysis observed in various models. The presumption has been that mitochondrial metabolism is suppressed. However, recent studies indicate that the extent of mitochondrial metabolism is far more heterogeneous in tumors than originally presumed. One tumor type with suppression of mitochondrial metabolism is renal cell carcinoma (RCC). Prior studies indicate that suppressed TCA cycle enzyme mRNA expression is associated with aggressive RCC. Yet, the mechanisms that regulate the TCA cycle in RCC remain uncharacterized. Here, we demonstrate that loss of TCA cycle enzyme expression is retained in RCC metastatic tissues. Moreover, proteomic analysis demonstrates that reduced TCA cycle enzyme expression is far more pronounced in RCC relative to other tumor types. Loss of TCA cycle enzyme expression is correlated with reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) which is also lost in RCC tissues. PGC-1α re-expression in RCC cells restores the expression of TCA cycle enzymes in vitro and in vivo and leads to enhanced glucose carbon incorporation into TCA cycle intermediates. Mechanistically, TGF-β signaling, in concert with histone deacetylase 7 (HDAC7), suppresses TCA cycle enzyme expression. In turn, pharmacologic inhibition of TGF-β restores expression of TCA cycle enzyme expression and suppresses tumor growth in an orthotopic model of RCC. Taken together, our findings reveal a novel role for the TGF-β/HDAC7 axis in global suppression of TCA cycle enzymes in RCC and provide novel insight into the molecular basis of altered mitochondrial metabolism in this malignancy.

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Genomic regression analysis of coordinated expression

Cited by 18 publications

References 36 publications

Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma

Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma

New novel non-MHC genes were identified for cervical cancer with an integrative analysis approach of transcriptome-wide association study

TGF-β signaling suppresses TCA cycle metabolism in renal cancer

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