Dataset Information

Integrative omics reveals magnesium deficiency as a driver factor of colorectal cancer

ABSTRACT: Magnesium (Mg) deficiency is associated with increased risk and malignancy of colorectal cancer (CRC), but the underlying mechanisms remain elusive. In our study, we used genomic, proteomic, and phosphoproteomic data to reveal the effects of low Mg content on genomic instability and tumor metastasis in CRC. Genomic analysis showed that 160 genes co-occurred and had higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed high mutation frequencies in High-Mg tumors. Additionally, proteomics and phosphoproteomics indicated that the lack of Mg in tumors could activate epithelial-mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the level of phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. Mutation in S142 to D (DBN1S142D) that mimic the effect of phosphorylation upregulated MMP2 and increased cell migration, while MgCl2 treatment reduced DBN1S142p and reversed this phenotype. Mechanistically, our results suggested that Mg2+ weakened the interaction between DBN1 and ACTN4 by reducing DBN1S142p, enhancing the binding of ACTN4 to F-actin and promoting F-actin polymerization, which ultimately reduced MMP2 expression. These findings shed new light on the significance of Mg deficiency in the advancement of CRC and suggest that Mg supplementation could be a promising strategy for prevention and treatment.

ORGANISM(S): Homo Sapiens

SUBMITTER: Lunzhi Dai

PROVIDER: PXD042746 | iProX | Mon Jun 05 00:00:00 BST 2023

REPOSITORIES: iProX

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Integrative Omics Uncovers Low Tumorous Magnesium Content as A Driver Factor of Colorectal Cancer.

Zhang Rou R Hu Meng M Liu Yu Y Li Wanmeng W Xu Zhiqiang Z He Siyu S Lu Ying Y Gong Yanqiu Y Wang Xiuxuan X Hai Shan S Li Shuangqing S Qi Shiqian S Li Yuan Y Shu Yang Y Du Dan D Zhang Huiyuan H Xu Heng H Zhou Zongguang Z Lei Peng P Chen Hai-Ning HN Dai Lunzhi L

Genomics, proteomics & bioinformatics 20241001 4

Magnesium (Mg) deficiency is associated with increased risk and malignancy in colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here, we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequen ...[more]

PMID: 39052867

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Project description:High-throughput genomic studies have identified thousands of genetic alterations in colorectal cancer (CRC). Distinguishing driver from passenger mutations is critical for developing rational therapeutic strategies. Because only a few transcriptional subtypes exist in previously studied tumor types, we hypothesize that highly heterogeneous genomic alterations may converge to a limited number of distinct mechanisms that drive unique gene expression patterns in different transcriptional subtypes. In this study, we defined transcriptional subtypes for CRC and identified driver networks/pathways for each subtype, respectively. Applying consensus clustering to a patient cohort with 1173 samples identified three transcriptional subtypes, which were validated in an independent cohort with 485 samples. The three subtypes were characterized by different transcriptional programs related to normal adult colon, early colon embryonic development, and epithelial mesenchymal transition, respectively. They also showed statistically different clinical outcomes. For each subtype, we mapped somatic mutation and copy number variation data onto an integrated signaling network and identified subtype-specific driver networks using a random walk-based strategy. We found that genomic alterations in the Wnt signaling pathway were common among all three subtypes; however, unique combinations of pathway alterations including Wnt, VEGF, Notch and TGF-beta drove distinct molecular and clinical phenotypes in different CRC subtypes. Our results provide a coherent and integrated picture of human CRC that links genomic alterations to molecular and clinical consequences, and which provides insights for the development of personalized therapeutic strategies for different CRC subtypes. To characterize the embryonic development of colon, we conducted a time course microarray study using the inbred C57BL/6 (Jackson Laboratories, Bar Harbor, ME) mice. Seven samples corresponding to the mouse colonic development from E13.5 to E18.5 and adult (eight week post-natal) were collected. RNA samples were submitted to the Vanderbilt Functional Genomics Shared Resource (FSGR, http://array.mc.vanderbilt.edu), where RNA was hybridized to the Affymetrix Mouse Genome 430 2.0 GeneChip Expression Arrays (Santa Clara, CA) according to manufacturer’s instructions. The RMA algorithm was used for data normalization. Mouse gene symbols were mapped to human gene symbols by the Human and Mouse Orthology list available from the Mouse Genome Informatics (http://www.informatics.jax.org/).

Project description:Introduction: CHEK2 is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about two fold. We pursued to investigate gene copy number aberrations and gene expression profiles that are typical for breast tumors of CHEK2 1100delC mutation carriers. Materials and methods: A total of 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array comparative genomic hybridization (aCGH) and gene expression experiments (GEX). After dimensionality reduction with CGHregions R package, CHEK2 1100delC associated regions in the aCGH data were detected by Wilcoxon rank sum test. Linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by Bayesian method. Results: We discovered four lost and three gained CHEK2 1100delC related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2 and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3 and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors nominating them as candidates for CHEK2 1100delC associated tumor progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM and LRP1 on 12q13. Altogether 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44 lowered expression levels. Our results suggest WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. Conclusions: We have shown that copy number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions we have identified potential drivers of CHEK2 1100delC associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of CHEK2 1100delC mutation. 78 samples from breast tumors: 13 tumors from CHEK2 1100delC mutation carriers, 65 other tumors

Dataset Information

Integrative omics reveals magnesium deficiency as a driver factor of colorectal cancer

Publications

Integrative Omics Uncovers Low Tumorous Magnesium Content as A Driver Factor of Colorectal Cancer.

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