ACVR2A

Overview

ACVR2A encodes Activin A receptor type 2A, a serine/threonine kinase receptor in the TGF-beta superfamily signaling pathway. In cancer genomics, ACVR2A is notable as the most frequently mutated gene in hypermutated colorectal adenocarcinomas, where microsatellite instability-driven frameshift mutations in its coding region inactivate TGF-beta/activin pathway signaling. Its extremely high mutation rate in MSI-H colorectal tumors reflects mutational slippage at repetitive coding sequences rather than positive selection alone, though loss of activin signaling may confer a growth advantage.

Alterations observed in the corpus

  • ACVR2A is the most frequently mutated gene in hypermutated (MSI-H) colorectal adenocarcinoma, altered in 63% of hypermutated tumors across 276 TCGA CRC cases; mutations are predominantly frameshift indels consistent with microsatellite instability-driven mutagenesis PMID:22810696
  • Mutated in HCC as part of the trunk-driver landscape (WES, n=1,289); listed as a non-actionable somatic alteration in the molecular landscape review PMID:24798001
  • Recurrently mutated TGF-β receptor newly implicated as an HCC driver (previously seen in chondrosarcoma); identified by MutSigCV exome sequencing of 243 HCC tumors PMID:25822088

Cancer types (linked)

  • COAD (colorectal adenocarcinoma): Mutation rate of 63% in hypermutated tumors; enrichment in the MSI-H subgroup with frameshift indels at repetitive sequences PMID:22810696

Co-occurrence and mutual exclusivity

  • Mutations co-occur with MSI-H status and MLH1 epigenetic silencing in hypermutated colorectal tumors PMID:22810696

Therapeutic relevance

  • No direct targeted therapy; hypermutated/MSI-H colorectal tumors harboring ACVR2A mutations may benefit from immune checkpoint inhibitors given their high mutational burden PMID:22810696

Open questions

  • Whether ACVR2A mutations are passenger events driven purely by MSI-H mutagenesis or provide selective advantage through TGF-beta pathway inactivation remains unresolved.

Sources

  • PMID:22810696 — TCGA CRC comprehensive molecular characterization (276 tumors)

This page was processed by crosslinker on 2026-05-14. - PMID:24798001

This page was processed by crosslinker on 2026-05-14. - PMID:25822088

This page was processed by crosslinker on 2026-05-14.