Abstract 1702P
Background
Biomarkers such as mutations, microsatellite instability (MSI), tumor mutational burden(TMB), and tumor mutational neoantigen(TNB) may represent tumor-intrinsic pathological feature and the immune microenvironment, which may serve as predictors for immune checkpoint inhibitors(ICIs). This study aimed to assess comutations in DNA Danamge Repair(DDR) pathway and its correlations with MSI, TMB and TNB in Chinese CRC patients, which helped to explore the potential use of immunotherapy biomarkers.
Methods
In brief, tumor tissue from 370 Chinese patients with CRC were performed by OncoDrug-SeqTM603-gene panel assay through next generation sequencing (NGS) using Illumina NovaSeq 6000. Genomic alterations were classified according to The American College of Medical Genetics and Genomics (ACMG) guidelines. Only pathogenic or likely pathogenic alterations included. We also investigate evaluated the association of DDR pathway alteration status with TMB, TNB level by different positive biomarker groups.
Results
MSI high (MSI-H) CRC accounts for 4.3% of all CRC. Alterations in DDR pathway were present in 86 (23.2%) of the 370 patients. The top 10 genes in DDR pathay with mutational incidence > 1% were MSH6(4.6%), ATM(4.3%), BRCA2(4.1%), ATR(3.5%), MLH1(2.4%), RAD54L(2.4%), RAD50(2.4%), CHEK2(1.9%), BRCA1(1.6%), MSH2(1.3%). There were twenty-nine alterations in DDR-related genes identified in total. Notably, the mutational incidence of DDR pathway in MSI-H CRC was 87.5%, while 20.3% in Microsatellite stability (MSS) CRC. We found that in patients with ≥2 alterations present in DDR pathway was correlated with higher levels of TMB or TNB. Particularly, in patients with ≥2 DDR alterations, the mean TMB level was significantly higher than those with ＜2 DDR alterations (32.0MUTS/Mb vs.5.6MUTS/Mb, respectively, P=0.0000004). In patients with ≥2 DDR alterations, the mean TNB level was significantly higher than those with ＜2 DDR alterations (32.6 MUTS /Mb vs.5.9 MUts /Mb, P =0.0000008).
Conclusions
Identification of comutations in DDR pathway are potentially applicable to predict the efficacy of ICIs, providing a potentially convenient approach for evaluation of TMB, TNB.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Zhejiang Shaoxing Topgen Biomedical Technology Co. Ltd.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.