Association Of The Atm Mrna, Protein Expression And The Somatic Mutation Counts In Human Cancers And Its Impact On Overall Survival In Breast And Gastric Cancer

Abstract Background: ATM is a tumor suppressor gene, and involves in DNA damage repair and cell cycle checkpoint activation. We aim to investigate the relationship between mRNA and protein expression levels of ATM gene and the somatic mutation count using whole exome sequencing data derived from TCGA database in various cancer types, including breast and stomach cancer. Materials and Methods: mRNA expression, protein expression, and somatic mutation data of 22 cancer types were collected from the TCGA data portal in April 2017, and their association with overall survival (OS) was analyzed. Considering the heterogeneous nature of the tumors, subgroups for breast cancer (luminal A, luminal B, HER2, and triple-negative) and for stomach cancer (microsatellite-instability [MSI] status) were applied. To validate the survival outcome in an independent cohort, MTCI Breast Cancer Survival Analysis Tool (http://glados.ucd.ie/BreastMark/) was used for survival analysis in breast cancer. Results: Out of 22 cancer types from the TCGA database, we found that mRNA expression levels of ATM exhibited significant inverse correlation with somatic mutation counts in 4 cancer types (adenoid cystic carcinoma, breast cancer, stomach cancer, and thyroid carcinoma). Tumors with higher somatic mutation counts above the median value had shorter OS compared to those with lower somatic mutation count (p=0.001) in these cancer types. mRNA expression and protein level of ATM showed positive correlation in breast and stomach cancer (p<0.001 and p=0.001, respectively). Regarding the subgroups of breast cancer, low ATM mRNA expression (the bottom 25% expression level) was associated with high somatic mutation count (p=0.023), and trends to shorter OS (median 114 months vs. 123 months, p=0.071) in luminal A subtype. Median OS was significantly shorter in tumors with low ATM mRNA compared to high in the MTCI validation cohort (n=609, HR 0.54, 95% CI 0.33-0.86, p=0.009). In contrast, ATM mRNA expression was not associated with somatic mutation count in TNBC, and the high somatic mutation count above the median was associated with longer OS (median not reached vs. 114 months, p=0.037). In stomach cancer, ATM mRNA expression level was not significantly associated with OS. However, MSI-high tumors had higher somatic mutation counts and lower ATM mRNA expression level compared to microsatellite stable (MSS) or MSI-low tumors, and low ATM mRNA level was associated with trend to better survival in MSI-high tumors (median OS 55 months vs. 31 months, p=0.136). Conclusion: These results suggest that the ATM mRNA expression is associated with somatic mutation count and prognosis in some types of cancers. However, these associations need to be assessed in the contexts of molecular subtypes and MSI status. Further studies are warranted to confirm the findings in our study. Citation Format: Koung Jin Suh, Kwangsoo Kim, Seongmin Choi, Kyung-Hun Lee, Jin Won Kim, Keun-Wook Lee, Jee Hyun Kim, Seongyeong Kim, Ahrum Min, Tae-Yong Kim, Seock-Ah Im. Association of the ATM mRNA, protein expression and the somatic mutation counts in human cancers and its impact on overall survival in breast and gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1370.