188P - The landscape of SMARCA2 genomic alterations in Chinese cancer patients

Background

Alterations of the SMARCA2 gene primarily promote cell proliferation and tumorigenesis by impacting the function of the SWI/SNF complex and activating multiple oncogenic signaling pathways. Previous studies have shown that selective inhibition of SMARCA2 can induce death of tumor cells with SMARCA4 mutations, providing a theoretical basis for SMARCA2 as a therapeutic target for tumors. In addition, differences in mutation profiles in pan-cancer can help understand pathogenesis, identify targets for therapy and promote precision medicine.

Methods

We retrospectively analyzed genomic DNA alterations in tissue samples from 21206 patients by next-generation sequencing (NGS). The SMARCA2 alterations were divided into functional or unfunctional mutations according to the OncoKB database.

Results

In total, 2.79% (592/21206) of pan-cancer patients carried SMARCA2 mutations. A total of 710 SMARCA2 alterations were identified in 592 patients, including missense mutations (60.56%), nonsense (4.51%), frameshifts (1.83%), splicing (21.83%), copy number variations (7.04%), non frameshift mutations (4.23%). Compared the genomic landscape among the SMARCA2-functional (S-F), SMARCA2-unfunctional (S-UNF) and SMARCA2-wide type (S-WT) patients. The results showed the S-F group have higher TMB (55.82 vs. 27.78 vs. 6.33, p<0.05) and higher proportion of MSI-H patients (31.15% vs. 22.48% vs. 1.72%, p<0.05). Additionally, 13.34% (n=79) of patients carried 2 (n=57) or more than 2 (n=22) SMARCA2 mutations. Compared with carriers of single mutation, they presented significantly higher TMB (141.40 vs 27.18) and higher proportions of MSI-H (73.42% vs. 34.62%). It is worth noting that in the SMARCA2 mutation cohort, 24.16% of patients also carried SMARCA4 mutation, and patients with co-mutation have significantly higher TMB (105.52 vs. 21.78) and a higher proportion of MSI-H (59.44% vs. 22.80%). Based on our results, immunotherapy may be an alternative strategy, which needs more clinical explorations.

Conclusions

SMARCA2 mutations are diverse, and patients with multiple SMARCA2 mutations or both SMARCA2-SMARCA4 mutations tumors had higher TMB and a higher proportion of MSI-H may more sensitive to immunotherapy, which may enable new therapeutic options in the future.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.