Related Experiment Video
Updated: Jun 19, 2026
Associated Chromosome Trap for Identifying Long-range DNA Interactions
Published on: April 23, 2011
Loss of activin receptor type 2 protein expression in microsatellite unstable colon cancers
Barbara Jung1, Ryan T Doctolero, Akihiro Tajima
1Departmentof Medicine, University of California, San Diego, USA.
Background & Aims:
Colorectal tumors manifesting high-frequency microsatellite instability (MSI-H) develop genetically as a consequence of mutations in genes harboring repetitive DNA sequences. The activin type 2 receptor (ACVR2), possessing 2 polyadenine coding sequences, was identified as a mutational target, but it is not clear if expression is abrogated. Here, we analyzed MSI-H colorectal cancers for ACVR2 mutation and expression to assess if biallelic inactivation occurs.
Methods:
All 54 MSI-H colon cancers and 20 random microsatellite stable (MSS) tumors from a population-based cohort of 503 patients were analyzed for mutations in 2 A(8) tracts (exon 3 and 10) of ACVR2 and the A(10) tract of transforming growth factor beta receptor 2 (TGFBR2). Additionally, we sequenced exon 10 of ACVR2 in select cancers. ACVR2 expression was determined by immunohistochemistry using an antibody targeting an epitope beyond the predicted truncated protein.
Results:
Forty-five of 54 MSI-H cancers (83%) showed mutation (A(8) to A(7)) in the polyadenine tract of exon 10 compared with no MSS tumors. Of tumors with mutant ACVR2, 62% lacked protein expression but all MSS and MSI-H tumors with wild-type ACVR2 expressed protein. We found no evidence of loss of heterozygosity at the ACVR2 locus in MSS tumors. Comparatively, 69% of MSI-H cancers had frameshift mutation in TGFBR2.
Conclusions:
ACVR2 mutations are highly frequent in MSI-H colon cancers and in most cases cause loss of ACVR2 expression, indicating biallelic inactivation of the gene. Loss of activin signaling through mutation of ACVR2, similar to observations with TGFBR2, may be important in the genesis of MSI-H colorectal cancer.
Insights
Activin type 2 receptor (ACVR2) mutations are common in high-frequency microsatellite instability (MSI-H) colorectal cancers, often leading to loss of ACVR2 expression and biallelic inactivation. This suggests ACVR2 plays a role in MSI-H tumor development.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- High-frequency microsatellite instability (MSI-H) in colorectal tumors arises from mutations in repetitive DNA sequences.
- The activin type 2 receptor (ACVR2) gene, with two polyadenine tracts, is a potential mutational target in MSI-H cancers.
- Previous studies identified ACVR2 as a target, but its expression status in MSI-H tumors remained unclear.
Purpose of the Study:
- To investigate the frequency of ACVR2 mutations in MSI-H colorectal cancers.
- To determine if ACVR2 mutations lead to loss of protein expression, suggesting biallelic inactivation.
- To assess the role of ACVR2 in the development of MSI-H colorectal cancer.
Main Methods:
- Analysis of ACVR2 and TGFBR2 mutations in 54 MSI-H and 20 microsatellite-stable (MSS) colorectal tumors.
- Sequencing of specific polyadenine tracts (A(8) and A(10)) in ACVR2 and TGFBR2 genes.
- Immunohistochemistry to assess ACVR2 protein expression in tumor samples.
Main Results:
- 83% of MSI-H colorectal cancers exhibited mutations in the ACVR2 exon 10 polyadenine tract, compared to none in MSS tumors.
- 62% of tumors with ACVR2 mutations showed a complete loss of ACVR2 protein expression.
- 69% of MSI-H cancers also displayed frameshift mutations in TGFBR2.
Conclusions:
- ACVR2 mutations are highly prevalent in MSI-H colorectal cancers and frequently result in biallelic inactivation due to loss of protein expression.
- The loss of activin signaling, mediated by ACVR2 mutations, is likely significant in the pathogenesis of MSI-H colorectal cancer.
- These findings highlight ACVR2 as a critical gene in MSI-H colorectal tumorigenesis, similar to TGFBR2.
Related Concept Videos
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...