Abstract 1807P
Background
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4), encoding a subunit of the ATPase subunit of the SWI/SNF chromatin-remodeling complex, is correlated with the chromatin remodeling. Previous studies revealed that functional loss mutations of SMARCA4 result in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. The differences in mutation profiles in pan-cancer can help understand pathogenesis, prognosis, and identify targets for therapy.
Methods
Using commercial NGS assays, we retrospectively analyzed genomic DNA alterations in FFPE or surgical tissue samples from 3776 patients with malignancies between 2019 to 2020. SMARCA4 frameshift, nonsense, splice-site, copy nubmber loss mutations, and missense mutations if predicted to be deleterious by SHFTand Polyphen-2 were considered pathogenic.
Results
In total, 7% (247/3773) of pan-cancer patients harbored SMARCA4 mutation. A total 303 genetic alterations were identified in 247 patients, including missense mutations (63%), nonsense (12%), frameshift (10%), splicing (8%), copy number loss (5%), non frameshift mutations (2%). In our cohort, the top 5 highest SMARKCA4 mutation frequency tumor types were cervical cancer (18), melanoma (13%), bladder cancer (12%), colorectal cancer (9%) and gastric carcinoma (8%), respectively. While in TCGA cohort, SMARCA4 is altered in 5% of all cancers with cervical cancer (15%), lung cancer (14%), melanoma (12%), gastric carcinoma (7%) and bladder cancer (6%) having the greatest prevalence of alterations. In TCGA cohort with deleterious mutation of SMARCA4, the progression-free survival (PFS) of SMARCA4 mutation group were shorter than wildtype group (31 vs 63 months; P = 0.006), and a decreasing trend on overall survival (OS) without significant difference (65 vs 79 months; P = 0.065).
Conclusions
SMARCA4 deleterious mutations are highly diverse and present at low to moderate frequencies across many cancers. Therefore, cataloging and characterizing these diverse alterations has the potential to facilitate precision medicine.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Shanbo Cao.
Funding
Has not received any funding.
Disclosure
T. Yang, H. Wang, F. Lou, F. Ding, T. Zhou, S. Cao: Financial Interests, Personal, Full or part-time Employment: AcornMed Biotechnology Co., Ltd. All authors have declared no conflicts of interest.