Mutational inactivation of TGFBR2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor β resistant cells

Swati Biswas, Patricia Trobridge, Judith Romero-Gallo, Dean Billheimer, Lois L. Myeroff, James K V Willson, Sanford D. Markowitz, William M. Grady

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

The mutational inactivation of transforming growth factor β receptor type II (TGFBR2) occurs in ∼30% of colon cancers and promotes the formation of colon cancer by inhibiting the tumor suppressor activity of the TGFB signaling pathway. TGFBR2 mutations occur in >90% of microsatellite unstable (MSI) colon cancers and affect a polyadenine tract in exon 3 of TGFBR2, called BAT-RII, which is vulnerable to mutation in the setting of DNA mismatch repair (MMR) system deficiency. In light of the vulnerable nature of the BAT-RII tract in the setting of MMR inactivation and the favorable effects of TGFBR2 inactivation in colon cancer, analysis of TGFBR2 inactivation provides an opportunity to assess the roles of genomic instability vs. clonal selection in cells acquiring TGFBR2 BAT-RII tract mutations in MSI colon cancer formation. The contribution of genomic instability and/or clonal evolution to the mutational inactivation of TGBFR2 in MSI colon cancers has not been studied in a systematic way that would allow a determination of the relative contribution of these two mechanisms in the formation of MSI colon cancer. It has not been demonstrated whether the BAT-RII tract mutations are strictly a consequence of the BAT-RII region being hypermutable in the setting of MMR deficiency or if the mutations are rather a consequence of clonal selection pressure against the TGFB receptor. Through the use of defined cell line systems, we show that both genomic instability and clonal selection of TGFB resistant cells contribute to the high frequency of TGFBR2 mutations in MSI colon cancer.

Original languageEnglish (US)
Pages (from-to)95-106
Number of pages12
JournalGenes Chromosomes and Cancer
Volume47
Issue number2
DOIs
StatePublished - Feb 2008

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Genomic Instability
Transforming Growth Factors
Microsatellite Repeats
Colonic Neoplasms
Mutation
DNA Mismatch Repair
Clonal Evolution
Growth Factor Receptors
Mutation Rate
Exons
Pressure
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

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Mutational inactivation of TGFBR2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor β resistant cells. / Biswas, Swati; Trobridge, Patricia; Romero-Gallo, Judith; Billheimer, Dean; Myeroff, Lois L.; Willson, James K V; Markowitz, Sanford D.; Grady, William M.

In: Genes Chromosomes and Cancer, Vol. 47, No. 2, 02.2008, p. 95-106.

Research output: Contribution to journalArticle

Biswas, Swati ; Trobridge, Patricia ; Romero-Gallo, Judith ; Billheimer, Dean ; Myeroff, Lois L. ; Willson, James K V ; Markowitz, Sanford D. ; Grady, William M. / Mutational inactivation of TGFBR2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor β resistant cells. In: Genes Chromosomes and Cancer. 2008 ; Vol. 47, No. 2. pp. 95-106.
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