Characterization Of GATA3 Mutation In Breast Tumors

Background:With the rapid advances in high-throughput sequencing technologies and well-devoloped bioinformatics tools,our understanding of molecular biology of breast cancer has been greatly improved.As a critical transcription factor,GATA-binding protein 3(GATA3)is one of the most frequently mutated genes in breast cancer.However,the GATA3 mutational spectra in Chinese breast cancer patients are still largely unknownObjective:The objective of this study was to investigate GATA3 mutational profile and its association with clinicopathologic characteristics in breast cancer patients.Method:A total of 589 consecutive treatment-naive Chinese patients with invasive breast cancer at Guangdong Provincial People’s Hospital(GDPH)were recruited in this study.Mutations in GATA3 were detected using the method of capture-based targeted sequencing.Correlations between GATA3 mutations and clinicopathologic features were analysed using Chi-square test.Then,we compared the results between Chinese and western population by using publicly available datasets,including Molecular Taxonomy of Breast Cancer International Consortium(METABRIC)cohort(n=1981)and The Cancer Genome Atlas(TCGA)cohort(n=960),and further performed survival analysis in these cohorts.Finally,we uesd the Kyoto Encyclopedia of Genes and Genomes(KEGG)database to analyze the pathways that are distinct between GATA3 wild-type and mutant groups in the GDPH database.Results:GATA3 is mutated in 13.8%(n=81)of 589 cases in our GDPH cohort,and there are 85 GATA3 mutations totally detected.90.5%(77/85)of GATA3 mutations are clusterd in the C-terminal region and ZnF2 domain.And the majority of mutation types are frameshift mutations and splice mutations in GDPH cohort.Our results suggests that GATA3 mutaions mainly occur in ER-positive(18.4%vs.0.6%,P<0.001),PR-positive(18.2%vs.3.8%,P<0.001),HER2-negative(17.5%vs 6.3%,P<0.001),HR+/HER2-(HR+/HER2-20.9%vs.HR+/HER2+9.9%vs HR-/HER2+ 0.0%vs.HR-/HER2-1.5%,P<0.001),negative lymph nodes(18.2%vs 10.4%,P=0.007),lower expression of Ki67 protein(22.6%vs.10.9%,P<0.001),and early stage breast cancer(15.7%vs.6.5%,P=0.009).The prevalence of GATA3 mutation in METABRIC and TCGA cohort is 11.6%(230/1981)and 9.7%(93/960),respectively.And the hotspot mutation region and major mutation types are similar to that in GDPH cohort.GATA3 mutation is also significantly associated with ER-positive,PR-positive and HR+/HER2-subtype in these cohorts(P<0.05)Moreover,GATA3 is more likely to be mutated in patients younger than 50 years old(13.7%vs.7.9%,P=0.005)and premenopausal patients(16.2%vs.7.1%,P<0.001)in TCGA cohort.Furthermore,cox multivariate analysis demonstrates that GATA3 is of independent prognosis significance in METABRIC cohort,and patients with GATA3 mutations have a significantly better overall survival than wild-type group(HR,0.587;95%CI 0.428-0.806;P=0.001).In addition,the KEGG pathway analysis results shows that the variation rate in GATA3 wild-type tumors in cell cycle(37.9%vs.21.2%,P=0.036)is signifiantly higher compared to the GATA3 wild-type group.Conclusion:GATA3 mutation spectra in Chinese and western breast cancer populations are similar in terms of GATA3 mutaion prevalence,mutation sites and major mutation types.GATA3 mutation is closely associated with clinicopathological characteristics suggesting favorable prognosis,and it may be a promising prognostic biomarker in breast cancer.