Abstract 5155
Background
Disruption of epigenetic regulation in CRC, particularly aberrant histone methylation, has been shown to correlate with poorer survival rates in mCRC. We aimed to highlight the molecular differences between CRC harboring pathological mutations in genes involved in histone modification (KMT family).
Methods
Tumors were examined by NextGen sequencing, protein expression, and gene amplification. Tumor mutational burden (TMB) was calculated based on somatic missense mutations (TMB-high ≥ 17 mt/MB) and microsatellite instability (MSI) was evaluated on known MSI loci in the target regions. Chi-square and t-tests were used for comparative analyses.
Results
In total, 3621 CRC were examined, and 224 (6.2%) showed a pathological mutation in KMT2A, KMT2C, or KMT2D. Demographics were as follow: F/M 47%/53%, median age 60. KMT mutations were strongly associated with MSI-H (66.5% vs 2.5%, P<.0001), TMB-high (72% vs 3%, P<.0001), BRAF mutation (24.7% vs 7.5%, P<.0001), PD-L1 overexpression (14.2% vs 2.7%, P<.0001), right-sided (11.7% vs 3.4% in left-sided tumors, P = 0.001) and POLE mutations (6.7% vs 0.1%, P<.0001). Furthermore, the rate of mutations among several genes such as ATM, ATRX, BRCA1/2, MLH1, MSH2/6, PMS2 (all P < 0.001) were more frequently seen in the KMT mutated tumors. All remained significant after multiple test correction. When we analyzed MSS tumors and POLE non-mutant tumors excluding MSI-H or POLE mutation, TMB-H remains more frequent in tumors with KMT mutations (8.3% vs 0.9%, P = 0.004), as well as several genes were more frequently mutated in KMT mutated tumors compared to WT tumors (CDC73, 1.7% vs 0.0%, P=.003; KDR, 1.7% vs 0.03%, P=.011; SDHB, 1.7% vs 0.1%, P=.023; PRKDC, 1.7% vs. 0.1%, P=.046; CHEK2, 5.6% vs 1.4%, P=.049).
Conclusions
Our findings provide the first exploratory data on KMT genes mutations and their association with clinical and molecular features in CRC, in a large population of patients. Further investigations are warranted to elucidate the association between TMB-H and histone modifications, potentially leading to a better understanding of epigenetic alterations in CRC and to identify novel targets for therapeutic options for CRC patients.
Clinical trial identification
Legal entity responsible for the study
Heinz-Josef Lenz.
Funding
Has not received any funding.
Editorial Acknowledgement
Disclosure
K. Poorman, M. Winerip, W.M. Korn: Employee: Caris Life Sciences. J.L. Marshall: Consultant: Caris Life Sciences. All other authors have declared no conflicts of interest.