Loss of activin receptor type 2 protein expression in microsatellite unstable colon cancers.
OBJECTIVE
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.
Jung
Barbara
B
Departmentof Medicine, University of California, San Diego, USA.
Doctolero
Ryan T
RT
Tajima
Akihiro
A
Nguyen
Alexie K
AK
Keku
Temitope
T
Sandler
Robert S
RS
Carethers
John M
JM
D030301:Activin Receptors, Type II / Q000235:genetics* / Q000378:metabolism*; D000483:Alleles; D002874:Chromosome Mapping; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D016368:Frameshift Mutation; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030301:Activin Receptors, Type II; D000077294:Receptor, Transforming Growth Factor-beta Type II