# Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability

Source: https://onco.cc/key-papers/paper-markowitz-tgfbr2-inactivation-msi-colon-science-1995/  
OnCo record `paper-markowitz-tgfbr2-inactivation-msi-colon-science-1995` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

When a cell loses its DNA spell-checker, short repeated stretches of DNA slip. This paper found that one of the genes destroyed that way is the brake that stops bowel cells growing, which is how a repair defect becomes a cancer.

## Summary

Human colon cancer cell lines with high rates of microsatellite instability were found to harbour mutations in the type II TGF-beta receptor gene. Eight such examples, from three different mutations, were identified. The mutations clustered within small repeated sequences in the gene, were accompanied by the absence of cell surface receptors, and were usually associated with small amounts of transcript. Receptor mutation, by allowing cells to escape TGF-beta-mediated growth control, links DNA repair defects to a specific pathway of tumour progression.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Science
- Year: 1995
- DOI: 10.1126/science.7761852
- Authors: Markowitz S, Wang J, Myeroff L, et al.
- Findings: TGFBR2 mutated in 8 microsatellite-unstable colon cancer lines, from three mutations clustered in short repeats.; Mutation abolished surface receptor and TGF-beta growth control.
- What it means: It showed how mismatch repair failure selects for cancer: coding microsatellites in tumour suppressors are the targets, which is why TGFBR2, ACVR2A, RNF43 and B2M frameshifts are the signature of MSI-high bowel cancer.
- Caveats: Cell lines; the frequency in patients came later.; Most panels do not report coding-microsatellite frameshifts as such.

## Sources

- Markowitz et al., Science 1995: TGF-beta receptor II inactivation in colon cancer cells with microsatellite instability: https://doi.org/10.1126/science.7761852
- PubMed: https://pubmed.ncbi.nlm.nih.gov/7761852/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- targets: [Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)](https://onco.cc/targets/mmr/), [TGFBR2](https://onco.cc/targets/tgfbr2/)
- institutions: [Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center](https://onco.cc/institutions/johns-hopkins/)
- pathways: [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/), [TGF-β signalling](https://onco.cc/pathways/tgf-beta/)
- terms: [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/)
- people: [Bert Vogelstein](https://onco.cc/people/bert-vogelstein/), [Kenneth W. Kinzler](https://onco.cc/people/kenneth-kinzler/)
- journals: [Science](https://onco.cc/journals/science/)

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