GATA3 amplification is associated with high grade disease in non-invasive urothelial bladder cancer but unrelated to patient prognosis

Abstract

Purpose: We aimed to assess the impact of GATA3 binding protein (GATA3) gene copy number alterations on tumor aggressiveness, patient prognosis, and GATA3 protein expression in a large urothelial bladder cancer cohort.

Methods: A tissue microarray containing over 2,700 urothelial bladder cancers (pTa-pT4) was analyzed retrospectively using dual-labeling fluorescence in-situ hybridization (FISH) with probes for GATA3 (10p14) and centromere 10. GATA3 copy number gains were categorized as GATA3 elevation (ratio GATA3/centromere ≥ 2/≤4), low-level amplification (ratio > 4/≤12), and high-level amplification (ratio > 12) and deletions were divided between homozygous and heterozygous.

Results: GATA3 copy number gain was detected in 9.9% of 2,213 interpretable tumors, including 2.0% with GATA3 elevation, 3.2% with low-level amplification, and 4.7% with high-level amplification. The frequency of high-level amplification increased from pTa G2 low (0%) to pTa G3 tumors (12% [CI 0.07;0.21]; p < 0.0001 pTa G2 low vs. pTaG2 high) but decreased in advanced-stage carcinomas pT2-4 with 5.4% [CI 0.07;0.21] (p < 0.0001, pTa vs. pT2-4). In muscle-invasive carcinomas, GATA3 amplification was not linked to tumor aggressiveness or patient survival. Overall, no homozygous GATA3 deletion was detected and heterozygous GATA3 deletion was only observed in 1.1%; of 1,432 pT2-4 tumors without any association to cancer progression. While GATA3 copy number was significantly correlated with GATA3 expression (p < 0.0001), the relationship was not strong. Only 2.3% of GATA3-negative cancers had a deletion, and 42.1% of strong GATA3-expressing cancers exhibited high-level amplification.

Conclusion: High-level GATA3 amplification is common in urothelial bladder cancer and correlates with grade progression in pTa tumors, while GATA3 deletion is rare. Neither amplification nor deletion appears to be the primary driver of GATA3 expression dysregulation.

Clinical trial number: Not applicable.

Keywords: FISH; GATA3; Prognosis; Urothelial bladder cancer.

Fig. 1

Examples of GATA3copy numbers by fluorescence in-situhybridization. A) non-altered GATA3 copy number status with two orange GATA3 signals and two green centromere 10 signals, B) GATA3 heterozygous deletion with one orange GATA3 signal and two green centromere 10 signals, C) elevated GATA3 copy number status with a GATA3/centromere 10 ratio ≥ 2 and < 4, and D) high-level GATA3 amplification with a GATA3/centromere 10 ratio ≥ 12

Fig. 2

GATA3 copy number status and patient survival in muscle invasive pT2-4 UBC. A) non-altered vs. gain (ratio GATA3/centromere 10 ≥ 2, and B) non-altered vs. high-level amplification (ratio GATA3/centromere 10 ≥ 12). The dashed line represents the lower and upper 95% confidence interval

Fig. 3

Association GATA3copy number status vs. GATA3 immunostaining. A) GATA3 amplified (ratio GATA3 signal/centromere 10 signal ≥ 2) vs. GATA3 non-amplified (ratio GATA3 signal/centromere 10 signal < 2), B) detailed GATA3 copy number status (GATA3 deletion with GATA3/centromere 10 ratio < 0.5, GATA3 normal with GATA3/centromere 10 ratio ≥ 0.5 and < 2, GATA3 elevated with GATA3/centromere 10 ratio ≥ 2 and < 4, GATA3 low-level amplification with GATA3/centromere 10 ratio ≥ 4 and < 12, and GATA3 high-level amplification with GATA3/centromere 10 ratio ≥ 12