Abstract 497P
Background
KMT2C and KMT2D usually forms a complex and are responsible for methylation at H3K4. According to our previous results, KMT2C/2D mutations in CRC were usually accompanied by DNA damage repair genes mutations and microsatellite instability high (MSI-H), both of which reported have tightly related with immunotherapy. We hypothesized that KMT2C/2D mutations may cause genomic instability in CRC and may be a predictor of ICI efficacy. Therefore, we investigated the relationship between the mutations of KMT2C/2D and immunotherapy, and analyzed the potential clinical benefit from ICI for patients with KMT2C/2D mutations.
Methods
CRC data from our cohort (N=2,824) and DFCI (Cell Reports 2016) cohort (N=619) were used to analyze MSI status. CRC Data from MSKCC ICI (Nat Genet 2019) cohort (N=110) were used to evaluate the tumor mutation burden (TMB) and overall survival (OS). Characteristics compared between KMT2C/2D mutant (MT) and wild type groups (WT) were analyzed with t-test. OS analyses were conducted through Kaplan-Meier analysis/log-rank test.
Results
In our cohort, MSI-H was observed in 49% (32/65) of KMT2C/2D MT group, whereas, it was only in 7% (99/1376) of WT group. Similarly, in DFCI cohort, MSI-H was found in 47% (55/118) of MT group, and only in 9% (36/411) of WT group. Both cohorts proved that the mutations of KMT2C/2D and MSI-H were closely related, suggesting a potential correlation between KMT2C/2D mutations and higher genomic instability. Further analyzing the MSKCC ICI cohort, we found the median TMB score (69.08 vs.14.37) was significantly different between KMT2C/2D MT and WT group (R squared 0.5527, 95% CI -73.8 to -35.63, p<0.0001), and the median OS differed widely (34 vs. 13 months) in KMT2C/2D MT and WT group (HR 0.46, 95% CI 0.24 to 0.88, p<0.05) ; the results supported that mutations in KMT2C/2D was associated with higher TMB and OS with ICI treatment.
Conclusions
In present study, we found KMT2C/2D mutations were tightly associated with MSI-H and higher TMB. The CRC patients with KMT2C/2D mutations could benefit from ICI therapy. Further prospective studies are warranted to comprehensively consider the mutations of KMT2C/2D, MSI-H and TMB, all of which may contribute to ICI clinical benefit.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
X. Zhang, T. Ma, X. Zhang, H. Zhu: Full/Part-time employment: Genetron Health (Beijing) Technology, Co. Ltd. All other authors have declared no conflicts of interest.