Copy number loss or silencing of apoptosis-effector genes in cancer

Mauro, James A.; Butler, Shanitra N.; Ramsamooj, Michael; Blanck, George

doi:10.1016/j.gene.2014.10.021

Cited by 18 publications

(16 citation statements)

References 13 publications

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“…The copies of apoptosis effector genes are often lost during cancer development, in comparison with the frequent amplification of proliferation-related genes. 19 A recent study on 183 primary GC samples suggested that some established or potential anticancer drug target genes exhibited high levels of CNVs, including HER2, TUBB3 and TOP2A. 20 Given the indicative value of CNVs in deregulated signaling pathways, CNV may provide useful information for the molecular subtyping of GC and optimization of therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

Liang

2015

Oncogene

128

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Gastric cancer (GC) is among the most common malignancy in the world with poor prognosis and limited treatment options. It has been established that gastric carcinogenesis is caused by a complex interaction between host and environmental factors. Copy number variation (CNV) refers to a form of genomic structural variation that results in abnormal gene copy numbers, including gene amplification, gain, loss and deletion. DNA CNV is an important influential factor for the expression of both protein-coding and non-coding genes, affecting the activity of various signaling pathways. CNV arises as a result of preferential selection that favors cancer development, and thus, targeting the amplified 'driver genes' in GC may provide novel opportunities for personalized therapy. The detection of CNVs in chromosomal or mitochondrial DNA from tissue or blood samples may assist the diagnosis, prognosis and targeted therapy of GC. In this review, we discuss the recent CNV discoveries that shed light on the molecular pathogenesis of GC, with a specific emphasis on CNVs that display diagnostic, prognostic or therapeutic significances in GC.

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Section: Introductionmentioning

confidence: 99%

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

Liang

2015

Oncogene

128

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“…For the subsequent analyses in this report, we grouped the oncoprotein and tumor suppressor coding regions, keeping in mind the clear degeneracy of aberrant signaling pathway activation that sustains cancer growth, particular apparent recently with the activation of alternative signaling pathways in designer drug resistant cancer cells. 28,29 The barcodes with oncoprotein coding region mutations had a greater level of RNA expression for a previously and rigorously defined set of apoptosis-effector genes 21,22,30 compared to the randomly selected barcodes lacking mutations in the indicated oncogene set (Tables 1, 2; Random Set 1 p < 0.018, Set 2 p < 0.018, Set 3 p < 7.76E-05).…”

Section: Resultsmentioning

confidence: 97%

“…From the gene quantification file, RPKM values of the apoptosis-effector gene set (Table 1) were collected for each barcode. This (Table 1) set of apoptosis genes is referred to as "Set A" in several previous publications, 21,22,30 and represents a high stringency standard for the definition of apoptosis-effector gene, as described. 21,22,30 However, due to issues related to data availability for the STAD RNASeq files, the following 3 genes were eliminated from the apoptosis-effector gene set described in refs.…”

Section: Methodsmentioning

confidence: 99%

“…21 Pro-proliferative effector genes also have more regions of open chromatin, i.e., more functionally effective regulatory regions than do apoptosis-effector genes. 21,22 The above data and paradigm are well represented in cancer medicine by only one case, whereby it has been established that MYCN amplification represents a relatively good prognosis for neuroblastoma specifically in cases where the caspase 8 apoptosis-effector gene is present. [23][24][25][26][27] This case prompted us to readdress this issue but by focusing on activating mutations rather than amplification, particularly after having noted that there are patient cases where there are multiple oncoprotein mutations and other cases where cancer develops in the absence of any known oncoprotein mutation, a relatively unexpected situation considering the comprehensive wealth of knowledge known about the available oncoproteins and their considerable role in the theory of oncogenesis.…”

Section: Introductionmentioning

confidence: 99%

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TCGA: Increased oncoprotein coding region mutations correlate with a greater expression of apoptosis-effector genes and a positive outcome for stomach adenocarcinoma

Yavorski

Blanck

2016

Cell Cycle

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Oncogene mutations are primarily thought to facilitate uncontrolled cell growth. However, overexpression of oncoproteins likely leads to apoptosis in a feed forward mechanism, whereby a certain level of oncoprotein leads to the activation of pro-proliferation effector genes and higher levels lead to activation of pro-apoptotic effector genes. TCGA STAD barcodes having no oncoprotein coding region mutations represented reduced expression of the apoptosis-effector genes compared with barcodes with multiple oncoprotein coding region mutations. Furthermore, STAD barcodes in a "no-subsequent tumor" group, representing 224 samples, and in a "positive outcome" group, had more oncoprotein coding regions mutated, on average, than barcodes of the new tumor and negative outcome groups, respectively. BRAF, CTNNB1, KRAS and MTOR coding region mutations (as a group) had the strongest association with the no-subsequent tumor group. Tumor suppressor coding region mutations were also correlated with no-subsequent tumor. These results are consistent with an oncoprotein-mediated, feed-forward mechanism of apoptosis in patients. Importantly, the nosubsequent tumor group also had more overall mutations. This result leads to considerations of unhealthy cells or cells with more neo-antigens for immune rejection. However, a probabilistic aspect of mutagenesis is also consistent with more oncoprotein and tumor suppressor protein mutations, in cases of more overall mutations, and thus a higher likelihood of activation of feed forward apoptosis pathways.

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“…10 Thus, while one CpG may not have a dramatic impact on expression levels as detected by routine laboratory approaches, the potential for a "shifting of the balance" remains important, particularly in considering such paradigms as feed-forward mechanisms of apoptosis, whereby a shift in transcription factor levels, as opposed to simple presence or absence of a transcription factor, likely determines the difference between cell proliferation and apoptosis. [11][12][13][14] It has become apparent that cancers traditionally representing different tissue types have extensive molecular overlaps, i.e., have many molecular bases in common for the cancer phenotype. 10,15 Thus, by taking a multi-cancer approach, it is possible to enhance statistical power when attempting to learn of potential over-representations of biomarkers in cancer.…”

Section: Discussionmentioning

confidence: 99%

Impact of SNPs on CpG Islands in the MYC and HRAS oncogenes and in a wide variety of tumor suppressor genes: A multi-cancer approach

et al. 2016

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Single nucleotide polymorphisms (SNPs) that occur within CpG Islands may lead to increased hypermethylation if a SNP allele has the potential to form a CpG dinucleotide, as well as potentially lead to hypomethylation if a SNP allele eliminates a CpG dinucleotide. We analyzed CpG-related SNP allele frequencies in whole genome sequences (WGS) across 5 TCGA cancer datasets, thereby exploiting a more recent appreciation for signaling pathway degeneracy in cancer. The cancer data sets were analyzed for SNPs in CpG islands associated with the oncogenes, HRAS and MYC, and in the CpG islands associated with the tumor suppressor genes, APC, DCC, and RB1. We determined that one SNP allele (rs3824120) in a CpG island associated with MYC which eliminated a CpG was more common in the cancer datasets than in the 100Genomes databases (p < 0.01). For HRAS, 2 SNP alleles (rs112690925, rs7939028) that created CpG's occurred significantly less frequently in the cancer data sets than in the general SNP databases (e.g., rs7939028, p < 0.0002, in comparison with AllSNPs (142)). Also, one SNP allele (rs4940177) that created a CpG in a CpG island associated with the DCC tumor suppressor gene, was more common in the cancer datasets (p < 0.0007). To understand a broader picture of the potential of SNP alleles to create CpG's in CpG islands of tumor suppressor genes, we developed a scripted algorithm to assess the SNP alleles associated with the CpG islands of 43 tumor suppressor genes. The following tumor suppressor genes have the possibility of significant, percent increases in their CpG counts, depending on which SNP allele(s) is present: VHL, BRCA1, BRCA2, CHEK2, PTEN and RB1.

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Copy number loss or silencing of apoptosis-effector genes in cancer

Cited by 18 publications

References 13 publications

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

TCGA: Increased oncoprotein coding region mutations correlate with a greater expression of apoptosis-effector genes and a positive outcome for stomach adenocarcinoma

Impact of SNPs on CpG Islands in the MYC and HRAS oncogenes and in a wide variety of tumor suppressor genes: A multi-cancer approach

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