GATA6 amplification is associated with improved survival of TP53-mutated pancreatic cancer

BackgroundMolecular profiling of pancreatic adenocarcinoma (PDAC) demonstrates that genomic and transcriptomic features are associated with prognosis and chemosensitivity. We evaluated treatment outcomes by genetic alterations in TP53 and GATA6 to determine the prognostic and predictive impact of co-mutations, among patients with pancreatic cancer in New Yorks largest healthcare system. MethodsRetrospective analysis was performed of patients at Northwell Health diagnosed with PDAC between 2014 to 2022. Surgical status was used to segregate patients into two groups: resected and unresected. TP53 genotype and GATA6 amplification status were compared for overall survival (OS) as measured from time of diagnosis. Additionally, patient survival by chemotherapy regimen administered was evaluated. The Kaplan-Meier method was used to determine overall survival (OS) and the Wilcoxon test was used to compare survival curves. Previously established and published patient-derived organoids [1] were used to investigate GATA6 expression, genetic status, and chemotherapy drug sensitivity. ResultsTumor mutation status was available for 128 patients. TP53 mutations were found in 104 patients (81.3%), GATA6 amplifications were found in 18 patients (14.0%), and 16 (12.5%) patients had mutations in both genes. Patients with TP53 mutations had worse OS compared to the wild-type TP53 population (n = 22) (median OS 22.4 months, 95% CI 12.5 to 41.1, vs. 44.3 months, 95% CI 24.0 to 82.0, HR 2.03, p = 0.038). Among patients with a TP53 mutation, a survival advantage was observed in those who had a GATA6 amplification (n=16) compared to those who did not (n=86) (median OS 25.5 months vs. 19.4 months, HR 1.82, p = 0.027). Among patients with unresected PDAC who were TP53-mutant, the presence of GATA6 amplification (n=11) was associated with a substantial survival advantage compared to GATA6 wildtype (n=52) (median OS 25.5 months, vs. 10.1 months, HR 0.35, p = 0.004). In the TP53 mutation group, among 33 patients who received gemcitabine and nab-paclitaxel as the first-line palliative chemotherapy, patients with GATA6 amplification (n = 8) had significantly improved survival compared to those without GATA6 amplification (n = 25) (mean OS 23.1 months vs 9.4 months, HR 0.52, p = 0.017). However, pancreatic cancer organoids with TP53 mutation (n=34) did not exhibit increased drug sensitivity to GnP with GATA6 amplification. ConclusionsGenetic mutations in TP53 were associated with shorter OS than wild-type TP53. We found that GATA6 amplification appeared to attenuate poor prognosis observed in TP53-mutant patients regardless of type of standard chemotherapy received.