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Chromosome-wide gene dosage rebalance may benefit tumor progression

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Abstract

The high-risk of tumor initiation in patients with Turner syndrome (TS) characterized by X chromosome monosomy in women has been well established and aneuploidy, defined as an abnormal number of chromosomes, is a common feature in human cancer. However, the underlying mechanisms of X chromosome aneuploidy promoting tumorigenesis remain obscure. We propose that chromosome-wide gene dosage imbalance (CDI) may serve as an important mechanism. Here, we assess the relative expression ratios of X chromosome and autosomes (expression ratios of X:AA) between tumor samples and adjacent normal samples across 16 tumor types using expression datasets from The Cancer Genome Atlas (TCGA) project. Our results show that the expression ratios of X:AA in tumor samples are frequently rebalanced to a lower level compared to those in adjacent normal samples, which is termed chromosome-wide gene dosage rebalance (CDR) thereafter. Gene ontology (GO) analysis of differentially expression genes from X chromosome reveals that downregulation of multicellularity-related genes and upregulation of unicellularity-related genes in tumors form a distinctive feature and enrichment analysis shows that downregulated genes are enriched in tumor suppressor genes, which indicate that CDR benefits tumor progression. Further experimental results prove that disturbance of X chromosome expression by knocking down of XIST in breast cancer cells, which functions in initiation phase of X chromosome inactivation (XCI), inhibits tumor progression. Our results demonstrate that the prevalent CDRs across tumor types serve as an important mechanism in promoting tumor progression, which partially explains the high risk of tumor in patients with TS and also provides a new cancer therapy from the CDR perspective.

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References

  • Aken BL, Achuthan P, Akanni W, Amode MR, Bernsdorff F, Bhai J, Billis K, Carvalho-Silva D, Cummins C, Clapham P, Gil L, Giron CG, Gordon L, Hourlier T, Hunt SE, Janacek SH, Juettemann T, Keenan S, Laird MR, Lavidas I, Maurel T, McLaren W, Moore B, Murphy DN, Nag R, Newman V, Nuhn M, Ong CK, Parker A, Patricio M, Riat HS, Sheppard D, Sparrow H, Taylor K, Thormann A, Vullo A, Walts B, Wilder SP, Zadissa A, Kostadima M, Martin FJ, Muffato M, Perry E, Ruffier M, Staines DM, Trevanion SJ, Cunningham F, Yates A, Zerbino DR, Flicek P (2017) Ensembl 2017. Nucleic Acids Res 45:D635–D642

    Article  PubMed  CAS  Google Scholar 

  • Barr ML, Moore KL (1957) Chromosomes, sex chromatin, and cancer. Proc Can Cancer Conf 2:3–16

    PubMed  CAS  Google Scholar 

  • Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate—a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol 57:289–300

    Google Scholar 

  • Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R, Willard HF (1991) A gene from the region of the human X-inactivation center is expressed exclusively from the inactive X-chromosome. Nature 349:38–44

    Article  PubMed  CAS  Google Scholar 

  • Chaligne R, Popova T, Mendoza-Parra MA, Saleem MAM, Gentien D, Ban K, Piolot T, Leroy O, Mariani O, Gronemeyer H, Vincent-Salomon A, Stern MH, Heard E (2015) The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer. Genome Res 25:488–503

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen H, Lin F, Xing K, He X (2015) The reverse evolution from multicellularity to unicellularity during carcinogenesis. Nat Commun 6:6367

    Article  PubMed  CAS  Google Scholar 

  • Chen DL, Ju HQ, Lu YX, Chen LZ, Zeng ZL, Zhang DS, Luo HY, Wang F, Qiu MZ, Wang DS, Xu DZ, Zhou ZW, Pelicano H, Huang P, Xie D, Wang FH, Li YH, Xu RH (2016) Long non-coding RNA XIST regulates gastric cancer progression by acting as a molecular sponge of miR-101 to modulate EZH2 expression. J Exp Clin Cancer Res 35:142

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen DL, Chen LZ, Lu YX, Zhang DS, Zeng ZL, Pan ZZ, Huang P, Wang FH, Li YH, Ju HQ, Xu RH (2017) Long noncoding RNA XIST expedites metastasis and modulates epithelial–mesenchymal transition in colorectal cancer. Cell Death Dis 8:e3011

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Clemente-Ruiz M, Murillo-Maldonado JM, Benhra N, Barrio L, Perez L, Quiroga G, Nebreda AR, Milan M (2016) Gene dosage imbalance contributes to chromosomal instability-induced tumorigenesis. Dev Cell 36:290–302

    Article  PubMed  CAS  Google Scholar 

  • Clemson CM, McNeil JA, Willard HF, Lawrence JB (1996) XIST RNA paints the inactive X chromosome at interphase: Evidence for a novel RNA involved in nuclear chromosome structure. J Cell Biol 132:259–275

    Article  PubMed  CAS  Google Scholar 

  • Dexter F (2013) Wilcoxon–Mann–Whitney test used for data that are not normally distributed. Anesth Analg 117:537–538

    Article  PubMed  Google Scholar 

  • Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21

    Article  PubMed  CAS  Google Scholar 

  • Durrbaum M, Storchova Z (2016) Effects of aneuploidy on gene expression: implications for cancer. FEBS J 283:791–802

    Article  PubMed  CAS  Google Scholar 

  • Fish EN (2008) The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol 8:737–744

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ganmore I, Smooha G, Izraeli S (2009) Constitutional aneuploidy and cancer predisposition dagger. Hum Mol Genet 18:R84–R93

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hasle H, Olsen JH, Nielsen J, Hansen J, Friedrich U, Tommerup N (1996) Occurrence of cancer in women with Turner syndrome. Br J Cancer 73:1156–1159

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Heng H (2007) Cancer genome sequencing: the challenges ahead (vol 29, pg 783–794, 2007). Bioessays 29:1070

    Article  Google Scholar 

  • Heng HHQ (2009) The genome-centric concept: resynthesis of evolutionary theory. Bioessays 31:512–525

    Article  PubMed  Google Scholar 

  • Heng HHQ, Liu G, Bremer S, Ye KJ, Stevens J, Ye CJ (2006) Clonal and non-clonal chromosome aberrations and genome variation and aberration. Genome 49:195–204

    Article  PubMed  CAS  Google Scholar 

  • Heng HH, Stevens JB, Lawrenson L, Liu G, Ye KJ, Bremer SW, Ye CJ (2008) Patterns of genome dynamics and cancer evolution. Cell Oncol 30:513–514

    PubMed  PubMed Central  Google Scholar 

  • Heng HH, Liu G, Stevens JB, Bremer SW, Ye KJ, Abdallah BY, Horne SD, Ye CJ (2011) Decoding the genome beyond sequencing: the new phase of genomic research. Genomics 98:242–252

    Article  PubMed  CAS  Google Scholar 

  • Heng HH, Bremer SW, Stevens JB, Horne SD, Liu G, Abdallah BY, Ye KJ, Ye CJ (2013) Chromosomal instability (CIN): what it is and why it is crucial to cancer evolution. Cancer Metastasis Rev 32:325–340

    Article  PubMed  Google Scholar 

  • Ji JG, Zoller B, Sundquist J, Sundquist K (2016) Risk of solid tumors and hematological malignancy in persons with Turner and Klinefelter syndromes: a national cohort study. Int J Cancer 139:754–758

    Article  PubMed  CAS  Google Scholar 

  • Kachitvichyanukul V, Schmeiser B (1985) Computer-generation of hypergeometric random variates. J Stat Comput Simul 22:127–145

    Article  Google Scholar 

  • Lancar R, Funck-Brentano C (1999) Survival analysis example based on an event history model from a clinical trial in cardiology. Rev Epidemiol Sante Publique 47:613–618

    PubMed  CAS  Google Scholar 

  • Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E (2004) Klinefelter’s syndrome. Lancet 364:273–283

    Article  PubMed  CAS  Google Scholar 

  • Lee JT (2011) Gracefully ageing at 50, X-chromosome inactivation becomes a paradigm for RNA and chromatin control. Nat Rev Mol Cell Biol 12:815–826

    Article  PubMed  CAS  Google Scholar 

  • Lee MC, Conway GS (2014) Turner’s syndrome: challenges of late diagnosis. Lancet Diabetes Endocrinol 2:333–338

    Article  PubMed  Google Scholar 

  • Liao Y, Smyth GK, Shi W (2014) featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30:923–930

    Article  PubMed  CAS  Google Scholar 

  • Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170

    PubMed  CAS  Google Scholar 

  • Marahrens Y, Loring J, Jaenisch R (1998) Role of the Xist gene in X chromosome choosing. Cell 92:657–664

    Article  PubMed  CAS  Google Scholar 

  • Nawata H, Kashino G, Tano K, Daino K, Shimada Y, Kugoh H, Oshimura M, Watanabe M (2011) Dysregulation of gene expression in the artificial human trisomy cells of chromosome 8 associated with transformed cell phenotypes. Plos One 6:e25319

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pavelka N, Rancati G, Zhu J, Bradford WD, Saraf A, Florens L, Sanderson BW, Hattem GL, Li R (2010) Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 468:321–325

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (1996) Requirement for Xist in X chromosome inactivation. Nature 379:131–137

    Article  PubMed  CAS  Google Scholar 

  • Perry PM (1971) Evaluation of breast tumour cellular sex chromatin (Barr body) as an index of survival and response to pituitary ablation. Br J Surg 58:294–295

    Article  PubMed  CAS  Google Scholar 

  • Pinheiro I, Dejager L, Libert C (2011) X-chromosome-located microRNAs in immunity: might they explain male/female differences? The X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females. Bioessays 33:791–802

    Article  PubMed  CAS  Google Scholar 

  • Plath K, Mlynarczyk-Evans S, Nusinow DA, Panning B (2002) Xist RNA and the mechanism of X chromosome inactivation. Annu Rev Genet 36:233–278

    Article  PubMed  CAS  Google Scholar 

  • Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A, Liao X, Iglehart JD, Livingston DM, Ganesan S (2006) X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9:121–132

    Article  PubMed  CAS  Google Scholar 

  • Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26:139–140

    Article  PubMed  CAS  Google Scholar 

  • Scott RH, Stiller CA, Walker L, Rahman N (2006) Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J Med Genet 43:705–715

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stevens JB, Horne SD, Abdallah BY, Ye CJ, Heng HH (2013) Chromosomal instability and transcriptome dynamics in cancer. Cancer Metastasis Rev 32:391–402

    Article  PubMed  CAS  Google Scholar 

  • Timp W, Feinberg AP (2013) Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat Rev Cancer 13:497–510

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xiong YY, Chen XS, Chen ZD, Wang XZ, Shi SH, Wang XQ, Zhang JZ, He XL (2010) RNA sequencing shows no dosage compensation of the active X-chromosome. Nat Genet 42:U1043–U1029

    Article  CAS  Google Scholar 

  • Ye CJ, Liu G, Bremer SW, Heng HHQ (2007) The dynamics of cancer chromosomes and genomes. Cytogenet Genome Res 118:237–246

    Article  PubMed  CAS  Google Scholar 

  • Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT, Lee JT (2013) Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152:727–742

    Article  PubMed  CAS  Google Scholar 

  • Yu GC, Li F, Qin YD, Bo XC, Wu YB, Wang SQ (2010) GOSemSim: an R package for measuring semantic similarity among GO terms and gene products. Bioinformatics 26:976–978

    Article  PubMed  CAS  Google Scholar 

  • Yu GC, Wang LG, Han YY, He QY (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. Omics J Integr Biol 16:284–287

    Article  CAS  Google Scholar 

  • Zhang GW, Xia BS, Liu T, Zhang JF, Niu M, Xu SP, Bai XN, You ZL, Xu QJ, Zhang Y, Cleveland J, Zhang DK, Pang D (2016) A high-quality biobank supports breast cancer research in Harbin, China. Biopreserv Biobank 14:375–382

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Drs. Ceshi Chen, Jiali Li, Qingpeng Kong, Benyang Liao, Binghui Li and Weimin Ci for constructive suggestions, and thank Dr. Christine Watts for text editing.

Funding

This work was funded by the Strategic Priority Research Program of the Chinese Academy of Sciences [Grant no. XDB13030400], Yunnan Applied Basic Research Projects [Grant no. 2016FB038], National Science Foundation of China [Grant no. 31371502] and Open Project from State Key Laboratory of Genetic Resources and Evolution [Grant nos. GREKF15-11, GREKF14-05].

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Author notes

  1. Honglei Zhang and Xing Yang are contributed equally to the work.

Authors and Affiliations

  1. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China

    Honglei Zhang, Xing Yang, Xu Feng, Haibo Xu, Qin Yang, Li Zou & Baowei Jiao

  2. University of the Chinese Academy of Sciences, Beijing, 100049, China

    Xing Yang & Haibo Xu

  3. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650050, Yunnan, China

    Xu Feng

  4. Department of Breast Surgery, Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, Yunnan, China

    Mei Yan & Dequan Liu

  5. Biomedical Research Center, First Hospital of Kunming, Kunming, 650011, Yunnan, China

    Xiaosan Su

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  1. Honglei Zhang
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Correspondence to Baowei Jiao.

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Zhang, H., Yang, X., Feng, X. et al. Chromosome-wide gene dosage rebalance may benefit tumor progression. Mol Genet Genomics 293, 895–906 (2018). https://doi.org/10.1007/s00438-018-1429-2

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