Abstract
Patterns of somatic mutations in cancer genes provide information about their functional role in tumourigenesis, and thus indicate their potential for therapeutic exploitation. Yet, the classical distinction between oncogene and tumour suppressor may not always apply. For instance, TP53 has been simultaneously associated with tumour suppressing and promoting activities. Here, we uncover a similar phenomenon for GATA3, a frequently mutated, yet poorly understood, breast cancer gene. We identify two functional classes of frameshift mutations that are associated with distinct expression profiles in tumours, differential disease-free patient survival and gain- and loss-of-function activities in a cell line model. Furthermore, we find an estrogen receptor-independent synthetic lethal interaction between a GATA3 frameshift mutant with an extended C-terminus and the histone methyltransferases G9A and GLP, indicating perturbed epigenetic regulation. Our findings reveal important insights into mutant GATA3 function and breast cancer, provide the first potential therapeutic strategy and suggest that dual tumour suppressive and oncogenic activities are more widespread than previously appreciated.
Highlights
High-throughput genome sequencing has allowed the systematic analysis of the complex mutational landscape of tumours and has provided key insights into tumour evolution and cancer etiology [1,2,3]
We describe the frequently mutated, but poorly studied, breast cancer gene GATA3 as a rare exception: We discover that two different functional classes of mutations in this gene can lead to either gain- or loss-of-function activities
Mutation positions in breast cancer genes are associated with differentially expressed genes
Summary
High-throughput genome sequencing has allowed the systematic analysis of the complex mutational landscape of tumours and has provided key insights into tumour evolution and cancer etiology [1,2,3]. It is typically assumed that all mutations within an individual gene have the same downstream consequences for tumourigenesis. Distinct mutations in the TP53 gene (encoding p53) lead to both loss-of-function and gain-of-function, impinging on multiple different pathways [7,8,9,10]. It is unclear if this type of dual activity of mutant p53 represents an exceptional case or is more common. We hypothesised that mutations in different positions in a cancer gene may result in different downstream consequences. We developed an unbiased computational approach and applied it to breast cancer, as large publicly available data sets are available for this cancer type
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