Virtual Library
Start Your Search
Ruiqi Liu
Author of
-
+
P60 - Tumor Biology and Systems Biology - Basic and Translational Science - Immune Bio (ID 198)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
-
+
P60.13 - Association of KMT2C/D Mutations with Tumor Mutation Burden and Response to Immune Checkpoint Inhibitors in NSCLC (ID 3698)
00:00 - 00:00 | Presenting Author(s): Ruiqi Liu
- Abstract
Introduction
Histone lysine methyltransferases (HMTs) comprise a subclass of epigenetic regulators and dysregulation of these enzymes may lead to tumorigenesis. The KMT2C/D proteins belong to the mixed-lineage leukemia (MLL) family of HMTs which methylate the histone 3 lysine 4 (H3K4) as part of mammalian COMPASS complexes. KMT2C/D mutations lead to dysregulated expression of DNA damage response and DNA repair genes and increased levels of genomic instability. We hypothesized that KMT2C/D mutations may associate with higher tumor mutation burden (TMB) and be a predictor of immune checkpoint inhibitors (ICIs) efficacy. Therefore, we explored the correlation between KMT2C/D mutations and benefit from ICIs in non-small cell lung cancer (NSCLC).
Methods
A total of 1821 Chinese NSCLC patients were enrolled from January 2017 to January 2020 in our center. Targeted next-generation sequencing (NGS) was used to determine mutations in genes and TMB. Clinicopathologic and genomic data were also collected from NSCLC patients at the Memorial Sloan Kettering Cancer Center (MSKCC) treated with PD-(L)1 inhibitors or PD-1 plus CTLA-4 blockade. Correlations of KMT2C/D mutations and TMB were calculated by student's t-test. Progression-free survival (PFS) was estimated with the Kaplan-Meier method.
Results
In our cohort, the somatic mutations of KMT2C/D included missense mutations (145/208), indels (inframe (2/208) and frameshift (30/208)), nonsense mutations (43/208), and splicing variants (13/208) in 11.4% of NSCLC tumors. The median TMB was significantly higher in the KMT2C/D mutations (MT) group compared to the wild type (WT) group (17.4 vs 9 muts/Mb, P < 0.0001). About 82.7% (172/208) of patients in the KMT2C/D MT group and 44.5% (718/1613) in the WT group had high TMB respectively (> 9.9 muts/Mb, P < 0.0001). In MSKCC cohort, KMT2C/D mutations were also associated with higher TMB (11.3 vs 6.1 muts/Mb, P < 0.0001). Furthermore, the median predicted neoantigen burden was dramatically higher in the MT group compared with the WT group (641 vs 302, P = 0.0046). Compared to the WT group, patients in the MT group had a significantly longer median PFS (5.4 vs 3.6 months, HR: 0.69 [95%CI: 0.51-0.92], P = 0.024) with PD-(L)1 therapy or combination PD-1 and CTLA-4. The data from the MSKCC cohort also revealed that PD-L1 expression and fraction of copy number-altered genome did not have any associations with KMT2C/D mutations.
Conclusion
Our results indicate that KMT2C/D mutations are frequent in NSCLC and are associated with higher TMB and improved clinical outcomes in NSCLC patients treated with ICIs. Further studies are required to explore the association of KMT2C/D mutations and ICIs clinical benefit in pan-cancer.
