79P SETD2 a potential tissue-agnostic predictive biomarker for ICIs in solid tumors

In the past decade immune-checkpoint inhibitors (ICIs) has revolutionized the treatment of patients with multiple types of cancer, but the predictive biomarkers are limited. SETD2 is an essential gene related to DNA damage repair (DDR) and an IFN-α induced immune response, indicating a predictive role in immunotherapeutic efficacy. In our discovery cohort, we reviewed 6726 sequencing samples, among them 375 samples were detected with SETD2 mutation and 13 patients from 9 centers were ICIs treated. Validation cohort datas included the TCGA, the MSKCC and the POPLAR/OAK cohort and 10 public ICIs treated cohorts. PolyPhen-2 and SIFT were used to distinguish deleterious mutations from tolerated mutations. Comparisons of tumor mutation burden (TMB), MSIsensor, survival, immune gene expression were calculated. Our discovery cohort showed a high ORR for patients with SETD2 mutation which was 53.8% (7/13) for all patients with immunotherapy and 42.9% (3/7) for PD-1/PD-L1 monotherapy. The favored ICIs outcomes was validated by MSKCC-IO cohort (p<0.0001). A significantly higher TMB was found in SETD2 deleterious mutation group in our discovery cohort including colorectal cancer (p<0.0001), non-small cell lung cancer (p<0.0001), melanoma (p=0.0022) and glioma (p=0.0042). And the elevation of TMB and the favored ICIs outcomes were comparable to other molecular features including POLE/D1, MMRS genes deleterious mutation group. A significantly higher MSIsensor was found in SETD2 deleterious mutation group in three cancers with the highest frequency of mismatch repair protein deletions including gastric adenocarcinoma (p=0.0029), endometrial carcinoma (p<0.0001), and colorectal carcinoma (p=0.0006) and SETD2 was an independent factor influencing MSI-H in gastric adenocarcinoma (p=0.003) and colorectal carcinoma (p<0.0001). Transcriptomic analysis in seven solid tumors from the TCGA database showed features of inflammated tumor microenvironment in tumors with SETD2 deleterious mutation group especially in renal cell carcinoma, colorectal adenocarcinoma and endometrial carcinoma. We identified a new tissue agnosticpredictive biomarker for ICIs: SETD2 deleterious mutation.