HRR–MMR Co-Mutations Merit Further Investigation As Lung Cancer Biomarker

Author: By Laura Cowen, medwireNews Reporter 

medwireNews: The presence of mutations in both homologous recombination repair (HRR) and mismatch repair (MMR) genes may be associated with higher levels of tumour mutational burden (TMB) and tumour neoantigen burden (TNB) in people with lung cancer, Chinese study findings indicate. 

Speaking at the European Lung Cancer Congress 2022, Jun Li, from Shandong Provincial Hospital in China, explained that “co-mutations in DDR [DNA damage repair-]related pathways may serve as potential predictors for immune checkpoint blockade therapy.” 

To investigate, Jun Li and colleagues performed next-generation sequencing on samples from 1309 patients with lung cancer. Of these, 691 (52.7%) carried at least one variant in a DDR pathway gene. 

They found that the genes with the highest frequency of mutations were EGFR (42.2%), TP53 (41.6%), FAT3 (28.2%), PDE4DIP (25.6%), and KMT2C (25.5%), followed by FAT1 (21.5%), OBSL1 (20.8%), KMT2D (20.3%), SYNE1 (16.3%) and ROS1 (15.5%). 

When the researchers grouped the patients according to whether they had a HRR mutation, a MMR mutation or both in the DDR pathway genes, they found that co-mutation status was associated with significantly higher TMB and TNB in the 462 tissue samples they analysed. 

Specifically, mean TMB was 8.0 mutations/Mb in samples taken from individuals with both a HRR mutation and a MMR mutation, and was significantly lower, at 6.0 and 5.3 mutations/Mb in samples from individuals with only a HRR mutation or a MMR mutation, respectively. 

The corresponding mean TNBs in tissue samples were 5.9, 4.7 and 4.1 mutations/Mb, with the difference between the groups statistically significant. 

In 225 blood samples, mean TMB was 4.7 mutations/Mb in the co-mutated group versus 4.0 and 3.3 mutations/Mb in the groups with either a HRR mutation or a MMR mutation, respectively. The difference between the groups was again statistically significant. 

There were no significant differences, however, in mean TNB detected in blood samples, at 2.7, 2.4 and 2.5 mutations/Mb in participants with both HRR and MMR mutations, an HRR mutation and a MMR mutation, respectively. 

Jun Li concluded: “Our study suggested that mutations in DDR related pathways were worthy for further study in its potential for lung cancer.” 

Reference  

Li J, Xu J, Xia PR, et al. 172MO - Analysis of comutations in DNA damage repair (DDR) related pathways with immunotherapeutic biomarkers in Chinese lung cancer patients. Ann Oncol 2022;.33(suppl_2):S111–S116. DOI: 10.1016/annonc/annonc866