Abstract A097: Genomic and transcriptomic characterization of RNA methyltransferases in breast cancer

Abstract

Abstract Background: Methylations of RNA are catalyzed by RNA methyltransferases (RNMTs) which regulate the structure, stability, translation, and function of almost every major class of human RNA. To date, more than 50 human RNMTs have been identified. Previous studies revealed that mutation and dysregulation of several RNMTs is associated with various human diseases, notably developmental disorders and cancer. However, the genomic and transcriptomic alterations of RNMT genes as well as their functional roles in cancer initiation and progression remain poorly characterized. This study seeks to characterize genetic alterations of 58 RNMTs in human cancer with an enriched focus on breast cancer. Furthermore, we will determine the associations between recurrent genetic alterations and gene expression levels of each RNMT, clinicopathological features, disease-free survival and disparities in breast cancer. Methods: Comprehensive genomic and transcriptomic analyses of 58 RNMTs in more than 10,000 primary tumors was performed using TCGA and METABRIC datasets. Copy number and gene expression of RNMTs were assessed by clinicopathological features of breast cancer in approximate 2,000 METABRIC breast tumors with long-term clinical follow-up data. Loss-of-function analysis was performed to examine RNMT candidates with important roles in growth and viability of breast cancer cells. Additionally, one candidate RNMT, FTSJ3 (FtsJ RNA methyltransferase homolog 3), was further pursued in order to assess its impact on cancer cell phenotypes in a panel of breast cancer cell lines. Results: We identified that a subset of RNMT genes, including TRMT12, NSUN2, and FTSJ3, have high frequencies of genomic amplification in a spectrum of human cancers, particularly in breast cancer. Several RNMTs, notably FTSJ3 and EMG1, are highly amplified and over-expressed in breast cancers of African-American women compared with that of European-American women. Breast cancer has been classified into five intrinsic subtypes with distinct risks and underlying biology. We found that different subtypes of breast cancer had different patterns of copy number and expression of each RNMT. Furthermore, we revealed that FTSJ3 was associated with higher grade and advanced stage of breast cancer. A genome-wide loss-of-function shRNA screen in a large panel of tumor lines indicated that FTSJ3 was required for the survival of some tumor cell lines. FTSJ3 depletion using siRNA oligos caused apoptosis and suppressed breast cancer cell survival with minimal effect on normal-like breast cancer cell survival. Conclusion: We identified a subset of RNMTs, notably FTSJ3, that were significantly associated with cancer aggressiveness and poor prognosis. Loss-of-function analysis revealed that FTSJ3 had important roles in promoting breast cancer cell growth and survival. Our findings provide a framework for further study of the functional consequences of RNMT alterations in human cancer, and for developing therapies that target RNMTs in future. Citation Format: Morenci M. Manning, Yuanyuan Jiang, Rui Wang, Lanxin Liu, Madison Bonahoom, Shomita Rode, Zeng-Quan Yang. Genomic and transcriptomic characterization of RNA methyltransferases in breast cancer [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A097.