A neonatal case of HDR syndrome and a vascular ring with a novel GATA3 mutation

HDR syndrome (OMIM #146255) is caused by haploinsufficiency of the GATA3 gene. A vascular ring has not been reported in patients with GATA3-associated HDR syndrome. We report a neonatal case of HDR syndrome and a vascular ring that were possibly due to a novel frameshift mutation in the GATA3 gene.

GATA3 mutation disrupts a functional network governed by estrogen receptor, FOXA1 and GATA3

Estrogen receptors (ER) are part of the nuclear receptor superfamily of transcription factors and are activated by the steroid hormone 17β-estradiol. ER forms a regulatory network in conjunction with other transcription factors, such as FOXA1 and GATA3. GATA3 has been identified as one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER. How GATA3 mutations impact this transcriptional network is unknown. Here we investigate the function of one of the recurrent patient-derived GATA3 mutations (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt the cooperative action of ER, FOXA1, and GATA3, and induce a change in chromatin localization of these factors. Relocalization of ER and FOXA1 is associated with altered chromatin architecture, which leads to differential gene expression in GATA3 mutant cells. These results suggest an active role for GATA3 mutants in ER positive breast tumors.

A class of GATA3 mutation reprograms the breast cancer transcriptional network through gain and loss of function

GATA3 is frequently mutated in breast cancer; these mutations are widely presumed to be loss of function. Here, we address molecular alterations downstream of a novel class of GATA3 mutations, revealing both gain and loss of function. Mutation of one allele of GATA3 led to loss of binding and decreased expression at a subset of genes, including Progesterone Receptor. At other loci, associated with epithelial to mesenchymal transition, gain of binding at a novel sequence motif correlated with increased gene expression. These results demonstrate that not all GATA3 mutations are equivalent and that these mutations impact breast cancer through gain and loss of function.

Prognostic implication of GATA3 gene mutation on survival in invasive ductal carcinoma of the breast.

e13114 Background: GATA3 encodes a transcription factor, which is involved in activation and suppression of genes involved in cell maturation. GATA3 is necessary in the adult mammary gland to maintain the integrity and function of the luminal epithelium. Methods: METABRIC project funded by cancer research UK, the British Columbia cancer foundation and the Canadian breast cancer foundation mapped 173 gene mutations and amplifications in 2,433 primary breast tumors. Retrospective analysis was done for patients with invasive ductal carcinoma of the breast in the age group 30-60; to study the effect of GATA3 mutation on survival. Median survival was obtained from Kaplan-Meier plot, and mortality between groups was compared by Odds ratio (OR). Results: A total of 1500 patients across all age groups had invasive ductal carcinoma. 650 were within the age group 30-60; of which 234 died due to the disease, 360 were alive and 55 died due to other causes. 398 patients (61.2%) tested positive for estrogen receptor (ER) and 521 patients (80.2%) were negative for HER2 (human epidermal growth factor receptor 2). TP53 (50%) and PIK3CA (36%) mutations were more prevalent. GATA3 mutation was found in 79 patients (12.34%); among which, all 79 patients tested positive for ER (100%) and 74 patients (94.9%) negative for HER2. 10 patients (12.7%) died due to the disease, 62 patients (78.5%) were alive and 7 patients (8.9%) died due to other causes. Hence, patients with GATA3 mutations were more likely to survive (OR 4.66; CI 2.33-9.29 p < 0.0001) than patients without the mutation. The median survival for patients with GATA3 mutation (300 months) was also greater than patients without the mutation (219 months). In addition, patients with GATA3 mutation were more likely to be ER positive and HER2 negative. Conclusions: In the mammary gland, GATA3 is required for luminal epithelial cell differentiation. Loss of GATA3 results in de-differentiation to stem cell phenotype. It is found that GATA3 mutation correlates with a better prognosis compared to more common TP53 and PIK3CA gene mutations.