The landscape of ACVR2A mutations in Chinese solid tumor patients.

Abstract

e14523 Background: ACVR2A (activin A receptor type 2A) encodes a receptor that mediates the functions of activins, and it contains two polyadenine (A8) microsatellite loci, which are located in exon 3 and exon 10. Recent studies have shown that ACVR2A mutant was associated with microsatellite instability-high (MSI-H) and high tumor mutational burden(TMB-H) in gastrointestinal cancers. However, this association remains unclear in other solid tumors. Methods: We retrospectively analyzed the ACVR2A mutations from comprehensive 539-gene profiling of 10434 Chinese patients with pan-cancer. Somatic mutations in tumor tissue were assessed. We screened out ACVR2A mutations, calculated the mutation frequency, TMB in different types of cancer. Results: ACVR2A mutants were detected in 340 (2.9%) samples. The top 5 frequently cancers were colorectal cancer (98, 28.8%), lung carcinoma (68, 20%), hepatocellular carcinoma (64, 18.8%), gastric cancer (48, 14.1%) and biliary tract cancers (19, 5.6%). And 12.7% were other cancers (e.g., pancreatic cancer, small bowel adenocarcinoma, brain cancer). ACVR2A variants included truncation (50%), splicing site variant (9.0%), and other mutant types(41.1%). Truncation was the most common type, recurring in a few hot spots (K437Rfs*5/ K437Rfs*19, D96Tfs*54/ D96Rfs*4, V433del, R438Efs*19). The TMB in ACVR2A mutation group was significantly higher than that in ACVR2A wild-type group (p < 0.001). In addition, TMB ≥10 muts/Mb was seen in 76.7% tumors with ACVR2A truncation or splicing site mutant(INACT) and 20.6% tumors with other mutant types(VUS)(p = 0.002). The median TMB of INACT group and VUS group was 35.46 muts/Mb (0.74-344.12) and 6.62 muts/Mb(0.5-598.53), respectively. Conclusions: We analyzed the distribution of ACVR2A mutants in Chinese patients with solid tumors. Our data shows that ACVR2A truncation or splice site mutant type is significantly associated with TMB-H, and this may be potential molecular marker of immunotherapy.