Proteogenomic analysis reveals unanticipated adaptations of colorectal tumor cells to deficiencies in DNA mismatch repair

Patrick J. Halvey, Xiaojing Wang, Jing Wang, Ajaz Ahmad Bhat, Punita Dhawan, Ming Li, Bing Zhang, Daniel C. Liebler, Robbert J.C. Slebos

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

A growing body of genomic data on human cancers poses the critical question of how genomic variations translate to cancer phenotypes. We used standardized shotgun proteomics and targeted protein quantitation platforms to analyze a panel of 10 colon cancer cell lines differing by mutations in DNA mismatch repair (MMR) genes. In addition, we performed transcriptome sequencing (RNA-seq) to enable detection of protein sequence variants from the proteomic data. Biologic replicate cultures yielded highly consistent proteomic inventories with a cumulative total of 6,513 protein groups with a protein false discovery rate of 3.17% across all cell lines. Networks of coexpressed proteins with differential expression based on MMR status revealed impact on protein folding, turnover and transport, on cellular metabolism and on DNA and RNA synthesis and repair. Analysis of variant amino acid sequences suggested higher stability of proteins affected by naturally occurring germline polymorphisms than of proteins affected by somatic protein sequence changes. The data provide evidence for multisystem adaptation to MMR deficiency with a stress response that targets misfolded proteins for degradation through the ubiquitin-dependent proteasome pathway. Enrichment analysis suggested epithelial-to-mesenchymal transition in RKO cells, as evidenced by increased mobility and invasion properties compared with SW480. The observed proteomic profiles demonstrate previously unknown consequences of altered DNA repair and provide an expanded basis for mechanistic interpretation of MMR phenotypes.

Original languageEnglish
Pages (from-to)387-397
Number of pages11
JournalCancer Research
Volume74
Issue number1
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

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DNA Mismatch Repair
Colorectal Neoplasms
Proteomics
Proteins
RNA Sequence Analysis
Phenotype
Cell Line
Epithelial-Mesenchymal Transition
Protein Stability
Protein Folding
Protein Sequence Analysis
Firearms
Protein Transport
Proteasome Endopeptidase Complex
Ubiquitin
Proteogenomics
Transcriptome
DNA Repair
Colonic Neoplasms
Proteolysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Proteogenomic analysis reveals unanticipated adaptations of colorectal tumor cells to deficiencies in DNA mismatch repair. / Halvey, Patrick J.; Wang, Xiaojing; Wang, Jing; Bhat, Ajaz Ahmad; Dhawan, Punita; Li, Ming; Zhang, Bing; Liebler, Daniel C.; Slebos, Robbert J.C.

In: Cancer Research, Vol. 74, No. 1, 01.01.2014, p. 387-397.

Research output: Contribution to journalArticle

Halvey, Patrick J. ; Wang, Xiaojing ; Wang, Jing ; Bhat, Ajaz Ahmad ; Dhawan, Punita ; Li, Ming ; Zhang, Bing ; Liebler, Daniel C. ; Slebos, Robbert J.C. / Proteogenomic analysis reveals unanticipated adaptations of colorectal tumor cells to deficiencies in DNA mismatch repair. In: Cancer Research. 2014 ; Vol. 74, No. 1. pp. 387-397.
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