HER2 Prognostic Significance and Therapeutic Implications in Gastric Cardia Adenocarcinoma: Insights from Multi-Omics Profiling

Wang, L.; Xing, p.; Zhao, X.; Song, X.; Wei, M.; Lei, L.; Xu, R.; Wang, R.; Ma, L.; You, D.; Chen, P.; Xie, M.; Zhao, M.; Zhang, H.; Lv, H.; Li, A.; Wang, X.; Zhou, F.; Gao, S.; Chen, X.

doi:10.1101/2024.03.02.583089

bioRxiv · 10.1101/2024.03.02.583089

HER2 Prognostic Significance and Therapeutic Implications in Gastric Cardia Adenocarcinoma: Insights from Multi-Omics Profiling

Wang, L.·Xing, p.·Zhao, X.·Song, X.·Wei, M.·Lei, L.·Xu, R.·Wang, R.·Ma, L.·You, D.·Chen, P.·Xie, M.·Zhao, M.·Zhang, H.·Lv, H.·Li, A.·Wang, X.·Zhou, F.·Gao, S.·Chen, X.

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Abstract

Therapeutic targets for Gastric Cardia Adenocarcinoma (GCA), particularly for HER2- negative patients, are lacking. Here, we conducted multi-omics profiling on 128 GCA patients using mass spectrometry, whole-exome sequencing, RNA-Seq, and metabolomics. We found HER2 to be a favorable prognostic marker for GCA. Employing molecular counting, we categorized patients into HER2-high, -low, and -negative groups. We uncovered an enrichment of DNA repair features in the HER2-high group, while HER2-low and -negative groups exhibited strong inflammation. We found that tumor mutation burden may not be the distinguishing factor among these three groups. We revealed that the HER2-negative and -low groups have a tumor-suppressive immune microenvironment, and HER2 expression is associated with fatty acid metabolic profiles and inflammation in the blood of patients. Our study revealed anti-inflammatory and immune checkpoint inhibition, targeting PD-L2 and the CD47/SIRPA pair, as therapeutic strategies for HER2-negative GCA patients. These findings highlight promising avenues for personalized treatment for GCA.

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Wang, L., Xing, p., Zhao, X., Song, X., Wei, M., Lei, L., Xu, R., Wang, R., Ma, L., You, D., Chen, P., Xie, M., Zhao, M., Zhang, H., Lv, H., Li, A., Wang, X., Zhou, F., Gao, S., Chen, X.. 2024-03-06. HER2 Prognostic Significance and Therapeutic Implications in Gastric Cardia Adenocarcinoma: Insights from Multi-Omics Profiling. https://doi.org/10.1101/2024.03.02.583089

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