Cancer-type specific aneuploidies hard-wire chromosome-wide gene expression patterns of their tissue of origin

SUMMARYMost carcinomas have characteristic chromosomal aneuploidies specific to the tissue of tumor origin. The reason for this specificity is unknown. As aneuploidies directly affect gene expression, we hypothesized that cancer-type specific aneuploidies, which emerge at early stages of tumor evolution, confer adaptive advantages to the physiological requirements of the tissue of origin. To test this hypothesis, we compared chromosomal aneuploidies reported in the TCGA database to chromosome arm-wide gene expression levels of normal tissues from the GTEx database. We find that cancer-type specific chromosomal aneuploidies mirror differential gene expression levels specific to the respective normal tissues which cannot be explained by copy number alterations of resident cancer driver genes. We propose that cancer-type specific aneuploidies “hard-wire” chromosome arm-wide gene expression levels present in normal tissues, favoring clonal expansion and tumorigenesis.One sentence summaryThe clonal evolution of cancer is initiated by tissue-specific transcriptional requirements

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Hard wiring of normal tissue-specific chromosome-wide gene expression levels is an additional factor driving cancer type-specific aneuploidies

Genome Medicine ◽

10.1186/s13073-021-00905-y ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Sushant Patkar ◽

Kerstin Heselmeyer-Haddad ◽

Noam Auslander ◽

Daniela Hirsch ◽

Jordi Camps ◽

...

Keyword(s):

Gene Expression ◽

Normal Tissue ◽

Cancer Type ◽

Tissue Specific ◽

Expression Levels ◽

Specific Distribution ◽

Tumor Origin ◽

Chromosome Arm ◽

Gains And Losses ◽

Gene Expression Levels

Abstract Background Many carcinomas have recurrent chromosomal aneuploidies specific to the tissue of tumor origin. The reason for this specificity is not completely understood. Methods In this study, we looked at the frequency of chromosomal arm gains and losses in different cancer types from the The Cancer Genome Atlas (TCGA) and compared them to the mean gene expression of each chromosome arm in corresponding normal tissues of origin from the Genotype-Tissue Expression (GTEx) database, in addition to the distribution of tissue-specific oncogenes and tumor suppressors on different chromosome arms. Results This analysis revealed a complex picture of factors driving tumor karyotype evolution in which some recurrent chromosomal copy number reflect the chromosome arm-wide gene expression levels of the their normal tissue of tumor origin. Conclusions We conclude that the cancer type-specific distribution of chromosomal arm gains and losses is potentially “hardwiring” gene expression levels characteristic of the normal tissue of tumor origin, in addition to broadly modulating the expression of tissue-specific tumor driver genes.

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High heterogeneity undermines generalization of differential expression results in RNA-Seq analysis

Human Genomics ◽

10.1186/s40246-021-00308-5 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Weitong Cui ◽

Huaru Xue ◽

Lei Wei ◽

Jinghua Jin ◽

Xuewen Tian ◽

...

Keyword(s):

Gene Expression ◽

Differential Expression ◽

Small Sample ◽

Differentially Expressed ◽

Cancer Type ◽

Rna Seq ◽

Sample Sizes ◽

Large Sample ◽

Expression Levels ◽

Gene Expression Levels

Abstract Background RNA sequencing (RNA-Seq) has been widely applied in oncology for monitoring transcriptome changes. However, the emerging problem that high variation of gene expression levels caused by tumor heterogeneity may affect the reproducibility of differential expression (DE) results has rarely been studied. Here, we investigated the reproducibility of DE results for any given number of biological replicates between 3 and 24 and explored why a great many differentially expressed genes (DEGs) were not reproducible. Results Our findings demonstrate that poor reproducibility of DE results exists not only for small sample sizes, but also for relatively large sample sizes. Quite a few of the DEGs detected are specific to the samples in use, rather than genuinely differentially expressed under different conditions. Poor reproducibility of DE results is mainly caused by high variation of gene expression levels for the same gene in different samples. Even though biological variation may account for much of the high variation of gene expression levels, the effect of outlier count data also needs to be treated seriously, as outlier data severely interfere with DE analysis. Conclusions High heterogeneity exists not only in tumor tissue samples of each cancer type studied, but also in normal samples. High heterogeneity leads to poor reproducibility of DEGs, undermining generalization of differential expression results. Therefore, it is necessary to use large sample sizes (at least 10 if possible) in RNA-Seq experimental designs to reduce the impact of biological variability and DE results should be interpreted cautiously unless soundly validated.

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Correlation of messenger RNA expression patterns of ERCC1, TS, EGFR, and VEGFR2 with KRAS and BRAF mutational status in advanced colorectal cancer: Implications for targeted therapies.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.383 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 383-383

Author(s):

Martin K. H. Maus ◽

Craig Stephens ◽

Stephanie H. Astrow ◽

Peter Philipp Grimminger ◽

Dongyun Yang ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Mrna Expression ◽

Advanced Colorectal Cancer ◽

Expression Patterns ◽

Mrna Levels ◽

Expression Levels ◽

Mutational Status ◽

Mrna Expression Levels ◽

Gene Expression Levels

383 Background: Gene expression levels of ERCC1, TS, EGFR and VEGFR2 may have predictive value for the personalized use of standard chemotherapeutics as well as agents targeting the EGFR and VEGF pathways and the efficacy of EGFR directed monoclonal antibodies like panitumumab and cetuximab has been confirmed to be dependent on wt KRAS and wt BRAF in patients with advanced colorectal cancer. We investigated the correlations between KRAS/BRAF mutational status and the mRNA expression levels of these genes. Methods: Formalin-fixed paraffin-embedded tumor specimens from 600 patients with advanced colorectal adenocarcinoma were microdissected and DNA and RNA was extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. Results: Mt KRAS tumors had significantly lower TS and EGFR gene expression levels compared with wt KRAS (p<0,001), whereas mt BRAF tumors showed significantly increased TS and EGFR mRNA levels compared to wt BRAF (p<0,001). Mt BRAF tumors showed significantly higher mRNA levels than mt KRAS tumors (p<0,001). ERCC1 and VEGFR2 mRNA levels were significantly down-regulated in mt KRAS specimen (p<0,001), but showed no significant correlation with BRAF mutational status. Conclusions: KRAS and BRAF mutations are associated with opposite mRNA expression levels for TS and EGFR. Recently, resistance to BRAF inhibition in mt BRAF colorectal tumors has been shown in preclinical models to be associated with up-regulation of EGFR. Our data suggests that BRAF mutants are associated with high EGFR levels at the time of diagnosis, and not necessarily part of an acquired mechanism of resistance. Significantly lower mRNA expression levels of VEGFR2 in mt KRAS tumors may explain lower response to angiogenesis inhibition seen in the TML study.

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Influence of Insulin-Like Growth Factor 1 Gene Expression in Women with Breast Cancer: A Systematic Review

10.21203/rs.3.rs-69892/v1 ◽

2020 ◽

Author(s):

Danylo Rafhael Costa-Silva ◽

Francisco Adelton Alves-Ribeiro ◽

Maria da Conceição Barros-Oliveira ◽

Larysse Cardoso Campos-Verdes ◽

Renato de Oliveira Pereira ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Systematic Review ◽

Growth Factor ◽

Expression Patterns ◽

Insulin Like Growth Factor ◽

Expression Levels ◽

Cancer Support ◽

Increased Risk ◽

Gene Expression Levels

Abstract Background: Breast cancer, the leading cause of cancer death among women worldwide, one of the major risk factors for breast cancer is genetic changes. Changes in the expression levels of the insulin-like growth factor 1 (IGF-1) gene have been associated with increased risk and aggressiveness of breast cancer. The IGF-1 gene encodes the IGF-1 peptide that is present in most human tissues, as in the normal and neoplastic mammary gland. Here, we conducted a systematic review to investigate the influence of IGF-1 gene expression levels in women with breast cancer.Methods: PubMed, Scopus, and Web of Science databases were searched for relevant studies published between February 2 and May 15, 2019, using inclusion and exclusion criteria in accordance with PRISMA guidelines. We analyzed the studies to find association between IGF-1gene expression and breast cancer.Results: A growing number of studies in women with breast cancer support, with controversial results, the influence of IGF-1 gene expression levels on clinical-pathological factors, disease-free survival, overall survival, and resistance to tamoxifen.Conclusions: Therefore, the elucidation of IGF-1 gene expression patterns through further studies may enable the characterization of women at high risk for breast cancer, as well as the development of effective prognostic and therapeutic strategies.

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Gene expression patterns are correlated with genomic and genic structure in soybean

Genome ◽

10.1139/g10-090 ◽

2011 ◽

Vol 54 (1) ◽

pp. 10-18 ◽

Cited By ~ 15

Author(s):

Jenna L. Woody ◽

Andrew J. Severin ◽

Yung-Tsi Bolon ◽

Bindu Joseph ◽

Brian W. Diers ◽

...

Keyword(s):

Gene Expression ◽

Sequence Data ◽

Expression Patterns ◽

Nucleotide Composition ◽

Physical Parameters ◽

Expression Levels ◽

Noncoding Regions ◽

Expression Breadth ◽

Gene Expression Levels

Studies have indicated that exon and intron size and intergenic distance are correlated with gene expression levels and expression breadth. Previous reports on these correlations in plants and animals have been conflicting. In this study, next-generation sequence data, which has been shown to be more sensitive than previous expression profiling technologies, were generated and analyzed from 14 tissues. Our results revealed a novel dichotomy. At the low expression level, an increase in expression breadth correlated with an increase in transcript size because of an increase in the number of exons and introns. No significant changes in intron or exon sizes were noted. Conversely, genes expressed at the intermediate to high expression levels displayed a decrease in transcript size as their expression breadth increased. This was due to smaller exons, with no significant change in the number of exons. Taking advantage of the known gene space of soybean, we evaluated the positioning of genes and found significant clustering of similarly expressed genes. Identifying the correlations between the physical parameters of individual genes could lead to uncovering the role of regulation owing to nucleotide composition, which might have potential impacts in discerning the role of the noncoding regions.

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Reference gene selection for qRT-PCR analyses of luffa (Luffa cylindrica) plants under abiotic stress conditions

Scientific Reports ◽

10.1038/s41598-021-81524-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Min-dong Chen ◽

Bin Wang ◽

Yong-ping Li ◽

Mei-juan Zeng ◽

Jian-ting Liu ◽

...

Keyword(s):

Gene Expression ◽

Reference Gene ◽

Reference Genes ◽

Gene Selection ◽

Expression Patterns ◽

Suitable Reference Gene ◽

Expression Levels ◽

Qrt Pcr ◽

Suitable Reference ◽

Gene Expression Levels

AbstractSelecting suitable internal reference genes is an important prerequisite for the application of quantitative real-time PCR (qRT-PCR). However, no systematic studies have been conducted on reference genes in luffa. In this study, seven reference genes were selected, and their expression levels in luffa plants exposed to various simulated abiotic stresses [i.e., cold, drought, heat, salt, H2O2, and abscisic acid (ABA) treatments] were analyzed by qRT-PCR. The stability of the reference gene expression levels was validated using the geNorm, NormFinder, BestKeeper, and RefFinder algorithms. The results indicated that EF-1α was the most stably expressed and suitable reference gene overall and for the heat, cold, and ABA treatments. Additionally, UBQ expression was stable following the salt treatment, whereas TUB was identified as a suitable reference gene for H2O2 and drought treatments. The reliability of the selected reference genes was verified by analyzing the expression of copper/zinc superoxide dismutase (Cu/Zn-SOD) gene in luffa. When the most unstable reference genes were used for data normalizations, the resulting expression patterns had obvious biases when compared with the expression patterns for the most ideal reference genes used alone or combined. These results will be conducive to more accurate quantification of gene expression levels in luffa.

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Abstract 12423: Normoxic Therapy Attenuated Oxidative Stress Related mRNA Gene Expressions in a Post-Cardiac Arrest Rat Model

Circulation ◽

10.1161/circ.144.suppl_2.12423 ◽

2021 ◽

Vol 144 (Suppl_2) ◽

Author(s):

Tomoaki Aoki ◽

Koichiro Shinozaki ◽

Yu Okuma ◽

Kei Hayashida ◽

Ryosuke Takegawa ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Cardiac Arrest ◽

Signaling Pathways ◽

Expression Patterns ◽

Expression Levels ◽

Mrna Gene ◽

The Brain ◽

Mrna Gene Expression ◽

Gene Expression Levels

Objective: We recently reported that post-resuscitation normoxic therapy attenuates oxidative stress in multiple organs and improves post-cardiac arrest (CA) organ injury, oxygen metabolism, and survival. Yet, detailed mechanisms of gene expression patterns and signaling pathways mitigated by normoxic therapy have not been elucidated. Therefore, we assessed post-resuscitation normoxic therapy-modified gene expression of oxidative stress-related signaling molecules. Methods: Rats were resuscitated from 10 minutes of asphyxial CA and divided into 2 groups: those that inhaled 100% supplemental O 2 (CA-FIO2 1.0) and those that inhaled 30% supplemental O 2 (CA-FIO2 0.3). Control groups were also prepared for comparison (control-FIO2 1.0, control-FIO2 0.3). At 2 hours after resuscitation, brain and heart tissues were collected, and mRNA purifications followed by real-time PCR measurements were performed to compare gene expression of hyperoxia-induced inflammatory and apoptosis-related signaling pathways amongst these groups. Results: In the brain, relative IL-1 beta mRNA gene expression levels, which represent inflammatory signaling pathways, increased post-CA (8.1±2.3 in CA-FIO2 1.0 and 1.0±0.4 in control-FIO2 0.3, p<0.05), but were significantly attenuated by normoxic therapy (2.3±0.2 in CA-FIO2 0.3, p<0.05). Likewise, normoxic therapy significantly reduced oxidative stress-induced inflammatory (NFKB1, TGFB1, MAPK14, TRAF6) and apoptosis-related (BAX, EGF) mRNA gene expression levels in the brain, whereas no statistical differences were detected in the heart. Conclusions: Post-CA normoxic therapy significantly attenuated the gene expression of oxidative stress-induced inflammation and apoptosis in the brain, while there were no remarkable changes in the heart. Therefore, it is inferred that the heart is more tolerant to hyperoxic injury compared to the brain.

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Influence of Insulin-Like Growth Factor 1 Gene Expression in Women with Breast Cancer: A Systematic Review

10.21203/rs.3.rs-104528/v1 ◽

2020 ◽

Author(s):

Danylo Rafhael Costa-Silva ◽

Maria da Conceição Barros-Oliveira ◽

Larysse Cardoso Campos-Verdes ◽

Renato de Oliveira Pereira ◽

Cleciton Braga Tavares ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Systematic Review ◽

Growth Factor ◽

Expression Patterns ◽

Insulin Like Growth Factor ◽

Expression Levels ◽

Cancer Support ◽

Increased Risk ◽

Gene Expression Levels

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ACE2 and TMPRSS2 expression by clinical, HLA, immune, and microbial correlates across 34 human cancers and matched normal tissues: implications for SARS-CoV-2 COVID-19

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001020 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001020 ◽

Cited By ~ 2

Author(s):

Riyue Bao ◽

Kyle Hernandez ◽

Lei Huang ◽

Jason John Luke

Keyword(s):

Gene Expression ◽

Single Cell ◽

Case Series ◽

Immune Gene ◽

Clinical Factors ◽

Expression Levels ◽

Normal Tissues ◽

Immune Gene Expression ◽

Organ Systems ◽

Gene Expression Levels

BackgroundPandemic COVID-19 by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) infection is facilitated by the ACE2 receptor and protease TMPRSS2. Modestly sized case series have described clinical factors associated with COVID-19, while ACE2 and TMPRSS2 expression analyses have been described in some cell types. Patients with cancer may have worse outcomes to COVID-19.MethodsWe performed an integrated study of ACE2 and TMPRSS2 gene expression across and within organ systems, by normal versus tumor, across several existing databases (The Cancer Genome Atlas, Census of Immune Single Cell Expression Atlas, The Human Cell Landscape, and more). We correlated gene expression with clinical factors (including but not limited to age, gender, race, body mass index, and smoking history), HLA genotype, immune gene expression patterns, cell subsets, and single-cell sequencing as well as commensal microbiome.ResultsMatched normal tissues generally display higher ACE2 and TMPRSS2 expression compared with cancer, with normal and tumor from digestive organs expressing the highest levels. No clinical factors were consistently identified to be significantly associated with gene expression levels though outlier organ systems were observed for some factors. Similarly, no HLA genotypes were consistently associated with gene expression levels. Strong correlations were observed between ACE2 expression levels and multiple immune gene signatures including interferon-stimulated genes and the T cell-inflamed phenotype as well as inverse associations with angiogenesis and transforming growth factor-β signatures. ACE2 positively correlated with macrophage subsets across tumor types. TMPRSS2 was less associated with immune gene expression but was strongly associated with epithelial cell abundance. Single-cell sequencing analysis across nine independent studies demonstrated little to no ACE2 or TMPRSS2 expression in lymphocytes or macrophages. ACE2 and TMPRSS2 gene expression associated with commensal microbiota in matched normal tissues particularly from colorectal cancers, with distinct bacterial populations showing strong associations.ConclusionsWe performed a large-scale integration of ACE2 and TMPRSS2 gene expression across clinical, genetic, and microbiome domains. We identify novel associations with the microbiota and confirm host immunity associations with gene expression. We suggest caution in interpretation regarding genetic associations with ACE2 expression suggested from smaller case series.

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Integrative pan cancer analysis reveals epigenomic variation in cancer type and cell specific chromatin domains

Nature Communications ◽

10.1038/s41467-021-21707-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lijin K. Gopi ◽

Benjamin L. Kidder

Keyword(s):

Gene Expression ◽

Human Cancer ◽

Expression Patterns ◽

Tumor Evolution ◽

Cancer Type ◽

Promoter Regions ◽

Binding Motifs ◽

Human Cancer Cell Lines ◽

Human Cancer Cells ◽

Genome Wide

AbstractEpigenetic mechanisms contribute to the initiation and development of cancer, and epigenetic variation promotes dynamic gene expression patterns that facilitate tumor evolution and adaptation. While the NCI-60 panel represents a diverse set of human cancer cell lines that has been used to screen chemical compounds, a comprehensive epigenomic atlas of these cells has been lacking. Here, we report an integrative analysis of 60 human cancer epigenomes, representing a catalog of activating and repressive histone modifications. We identify genome-wide maps of canonical sharp and broad H3K4me3 domains at promoter regions of tumor suppressors, H3K27ac-marked conventional enhancers and super enhancers, and widespread inter-cancer and intra-cancer specific variability in H3K9me3 and H4K20me3-marked heterochromatin domains. Furthermore, we identify features of chromatin states, including chromatin state switching along chromosomes, correlation of histone modification density with genetic mutations, DNA methylation, enrichment of DNA binding motifs in regulatory regions, and gene activity and inactivity. These findings underscore the importance of integrating epigenomic maps with gene expression and genetic variation data to understand the molecular basis of human cancer. Our findings provide a resource for mining epigenomic maps of human cancer cells and for identifying epigenetic therapeutic targets.

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