Upregulation of the histone γ-H2AX correlates with worse patient survival and basal-like subtype in pancreatic ductal adenocarcinoma

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2024年3月19日

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Karl Knipper,
Yussra Hussein,
Adrian Georg Simon,
Caroline Fretter,
Alexander I. Damanakis,
Yue Zhao,
Christiane J. Bruns,
Thomas Schmidt,
Felix C. Popp,
Alexander Quaas,
Su Ir Lyu,
Michael Heise,
Frank Marusch,
Marco Siech,
Tawfik Mosa,
Bodo Schniewind,
Jürgen Tepel,
Werner Hartwig,
Christoph Prinz,
Bettina M. Rau,
Marco Niedergethmann,
Rainer Kube,
George Saada,
Wolfgang Hiller,
Utz Settmacher

摘要

Purpose

Patients with pancreatic ductal adenocarcinoma (PDAC) have yet to experience significant benefits from targeted therapy. Olaparib is currently the only active substance in BRCA-mutated PDACs that successfully influences the DNA repair of carcinoma cells. H2AX belongs to the histone family and is known as a part of the DNA repair system. The inhibition of γ-H2AX could lead to the inhibition of mitotically active tumor cells. Therefore, we aimed to evaluate the predictive value of the γ-H2AX in patients with PDAC.

Methods

All included patients (n = 311) received a pancreatic resection with curative intention in one of our PANCALYZE study centers. Subsequently, they were enrolled in a standardized follow-up protocol. Immunohistochemical stainings for γ-H2AX were conducted on tissue microarrays.

Results

Patients exhibiting high levels of γ-H2AX expression experience more frequent R1 resections, indicating advanced tumor stages in this subgroup. Additionally, patients with high γ-H2AX expression demonstrated significantly poorer survival compared to those with low expression (median OS: 15 vs. 25 months, p < 0.001). In multivariate analyses, high γ-H2AX expression could be identified as an independent risk factor for worse patient survival. Moreover, high γ-H2AX expression could be more frequently observed in the more aggressive basal-like subtype.

Conclusion

γ-H2AX can be characterized as a predictive biomarker for poorer patient survival. Consequently, upcoming clinical trials focused on the efficacy of targeted therapies influencing the DNA repair system and radiotherapy should evaluate γ-H2AX as a potential biomarker for therapy response. Furthermore, γ-H2AX may serve as a viable target for treatment in the future.