SUN-LB132 Frequency and Impact of Mutations in Tumor Suppressor Gene CDC73 in General Population and Malignant Tumors

Background: CDC73 gene is a putative tumor suppressor gene, and somatic and germline mutations of this gene have been linked with parathyroid tumors. There are also some reports suggesting that germline CDC73 mutations may increase risk of jaw, kidney and uterine tumors. However, the incidence and significance of CDC73 somatic mutations is largely unknown in tumors other than parathyroid tumors. Methods/Design: 1) Assess CDC73 germline mutation frequency and genotypes in general population using ExAC (Exome Aggregation Consortium) and gnomAD (Genome Aggregation Database); 2) Assess CDC73 somatic mutation frequency in various type of tumors using the Cancer Genome Atlas (TCGA) and non-TCGA datasets; 3) Examine significance of CDC73 mutation in uterine endometrial carcinoma (UCEC). Overall survival, CDC73 mutation signature, gene expression profile (GEP) and tumor immune microenvironment were compared between the UCEC samples with and without CDC73 mutations. Results: In ExAC and gnomAD databases, most of CDC73 germline mutations were mapped to the intron regions of the CDC73 gene and nonsynonymous CDC73 mutations are very rare, with allele frequency ranging from 8.24e-06 to 9.92e-05 and 3.97e-06 to 7.43e-05, respectively. Missense mutations accounted for more than 95% of the nonsynonymous mutations in the CDC73 gene in both databases. 2) In 155 cancer genomics studies including both TCGA and non-TCGA datasets with no overlapping samples, CDC73 was mutated in 0.7% cases and missense mutations comprised 78% of the CDC73 mutations. CDC73 somatic mutations were undetected or rarely detected in endocrine tumors except for parathyroid tumors. 3) UCEC is the tumor type that has the second highest CDC73 somatic mutation rate (8%) after parathyroid tumors. The UCEC with CDC73 mutations had a significantly better overall survival with a logrank p-value of 0.033 compared to the tumors with CDC73 WT. GEP analysis revealed that the CDC73-mutated UCEC tumors had significant upregulation of immunological markers and enriched immunologic signature compared to the CDC73-WT tumors. In silico analysis of tumor immune microenvironment showed higher fractions of cytotoxic CD8 cells, T follicular helper cells and M1 macrophage in the CDC73-mutated UCEC tumors. The majority of the CDC73-mutated tumors were POLE ultra-mutated and microsatellite instability (MSI) subtypes, which likely account for a better survival and an increased immune-cell infiltrate of these tumors. Conclusion: CDC73 mutations is rare in general population and tumors except for parathyroid carcinoma and UCEC. CDC73 mutation is a marker for better prognosis in UCEC and is associated with increased immune cell infiltrate in tumor microenvironment, likely due to majority of the CDC73-mutated tumors were POLE ultra-mutated and microsatellite instability (MSI) subtypes.