Distinctive Genomic Characteristics in -mutant Cancers Can Potentially Predict Beneficial Clinical Outcomes in Patients Who Receive Immune Checkpoint Inhibitor

Background: Mutations in proofreading domain can cause deficiencies in DNA repair, conferring ultramutated cancer phenotypes. Preliminary clinical studies have revealed an association between mutations and beneficial clinical outcomes to immune checkpoint inhibitor (ICI) therapy This study aims to investigate the genomic characteristics of mutant tumors and the prognostic value of mutation for ICI treatment.

Methods: Genomic data of 21,074 patients with 23 cancer types were retrieved from Burning Rock variant database (BR VarDB). The prevalence and spectra of and mutations were assessed and compared with that in The Cancer Genome Atlas (TCGA) samples. The correlations of mutation with tumor mutational burden (TMB) and microsatellite instability (MSI) were investigated. The prognostic value of mutations was also explored in 2,487 ICI-treated patients from published studies.

Results: BR VarDB samples displayed a similar mutational prevalence of (3.2% 3.2%) and (1.4% 1.6%, P=0.248) versusTCGA samples, but a slightly lower frequency of and co-mutations (0.21% 0.43%, P<0.001). -mutant tumors harbored increased TCT→TAT and TCG→TTG transversions, and genomic signatures associated with DNA mismatch repair (MMR) deficiency and ultra-hypermuation. Furthermore, tumors with proofreading mutation showed a significantly higher TMB than tumors with non-proofreading mutations (P<0.01), although both possessed a higher TMB than wild-type (WT) tumors (P<0.0001 and P<0.0001, respectively). MSI was commonly observed in tumors harboring dominant clone of mutation (10.2%), but occurred rarely in WT tumors (0.5%) and tumors with accumulating sub-cloned mutation (0%). Survival analysis revealed that mutation was not independently correlated with longer survival after adjusting for TMB and other factors (HR =0.86, P=0.372). However, patients harboring mutation demonstrated a higher response rate than patients with WT tumors (35.2% 19.6%, P=0.0165).

Conclusions: We delineated distinctive genomic characteristics in -mutant tumors, suggesting the potential predictive role of mutations, especially those in the proofreading domain, for beneficial outcomes of immunotherapy. Our results also suggest that MSI caused by a loss-of-function mutation in the MMR pathway tends to result from proofreading deficiency in mutant tumors with MSI.