Functional synergies yet distinct modulators affected by genetic alterations in common human cancers

Marina Bessarabova, Olga Pustovalova, Weiwei Shi, Tatiana Serebriyskaya, Alex Ishkin, Kornelia Polyak, Victor E Velculescu, Tatiana Nikolskaya, Yuri Nikolsky

Research output: Contribution to journalArticle

Abstract

An important general concern in cancer research is how diverse genetic alterations and regulatory pathways can produce common signaling outcomes. In this study, we report the construction of cancer models that combine unique regulation and common signaling. We compared and functionally analyzed sets of genetic alterations, including somatic sequence mutations and copy number changes, in breast, colon, and pancreatic cancer and glioblastoma that had been determined previously by global exon sequencing and SNP (single nucleotide polymorphism) array analyses in multiple patients. The genes affected by the different types of alterations were mostly unique in each cancer type, affected different pathways, and were connected with different transcription factors, ligands, and receptors. In our model, we show that distinct amplifications, deletions, and sequence alterations in each cancer resulted in common signaling pathways and transcription regulation. In functional clustering, the impact of the type of alteration was more pronounced than the impact of the kind of cancer. Several pathways such as TGF-β/SMAD signaling and PI3K (phosphoinositide 3-kinase) signaling were defined as synergistic (affected by different alterations in all four cancer types). Despite large differences at the genetic level, all data sets interacted with a common group of 65 "universal cancer genes" (UCG) comprising a concise network focused on proliferation/apoptosis balance and angiogenesis. Using unique nodal regulators ("overconnected" genes), UCGs, and synergistic pathways, the cancer models that we built could combine common signaling with unique regulation. Our findings provide a novel integrated perspective on the complex signaling and regulatory networks that underlie common human cancers.

Original languageEnglish (US)
Pages (from-to)3471-3481
Number of pages11
JournalCancer Research
Volume71
Issue number10
DOIs
StatePublished - May 15 2011

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Neoplasms
1-Phosphatidylinositol 4-Kinase
Sequence Deletion
Neoplasm Genes
Regulator Genes
Glioblastoma
Pancreatic Neoplasms
Colonic Neoplasms
Single Nucleotide Polymorphism
Cluster Analysis
Exons
Transcription Factors
Apoptosis
Breast Neoplasms
Ligands
Mutation
Research
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Bessarabova, M., Pustovalova, O., Shi, W., Serebriyskaya, T., Ishkin, A., Polyak, K., ... Nikolsky, Y. (2011). Functional synergies yet distinct modulators affected by genetic alterations in common human cancers. Cancer Research, 71(10), 3471-3481. https://doi.org/10.1158/0008-5472.CAN-10-3038

Functional synergies yet distinct modulators affected by genetic alterations in common human cancers. / Bessarabova, Marina; Pustovalova, Olga; Shi, Weiwei; Serebriyskaya, Tatiana; Ishkin, Alex; Polyak, Kornelia; Velculescu, Victor E; Nikolskaya, Tatiana; Nikolsky, Yuri.

In: Cancer Research, Vol. 71, No. 10, 15.05.2011, p. 3471-3481.

Research output: Contribution to journalArticle

Bessarabova, M, Pustovalova, O, Shi, W, Serebriyskaya, T, Ishkin, A, Polyak, K, Velculescu, VE, Nikolskaya, T & Nikolsky, Y 2011, 'Functional synergies yet distinct modulators affected by genetic alterations in common human cancers', Cancer Research, vol. 71, no. 10, pp. 3471-3481. https://doi.org/10.1158/0008-5472.CAN-10-3038
Bessarabova M, Pustovalova O, Shi W, Serebriyskaya T, Ishkin A, Polyak K et al. Functional synergies yet distinct modulators affected by genetic alterations in common human cancers. Cancer Research. 2011 May 15;71(10):3471-3481. https://doi.org/10.1158/0008-5472.CAN-10-3038
Bessarabova, Marina ; Pustovalova, Olga ; Shi, Weiwei ; Serebriyskaya, Tatiana ; Ishkin, Alex ; Polyak, Kornelia ; Velculescu, Victor E ; Nikolskaya, Tatiana ; Nikolsky, Yuri. / Functional synergies yet distinct modulators affected by genetic alterations in common human cancers. In: Cancer Research. 2011 ; Vol. 71, No. 10. pp. 3471-3481.
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