Extrachromosomal DNA is associated with chromothripsis events and diverse prognoses in gastric cardia adenocarcinoma

Zhao, X.; Xing, P.; Song, X.; Zhao, M.; Zhao, L.; Dang, Y.; Lei, L.-L.; Xu, R.-H.; Han, W.-L.; Wang, P.-P.; Yang, M.-M.; Hu, J.-F.; Zhong, K.; Zhou, F.-Y.; Han, X.-N.; Meng, C.-L.; Ji, J.-J.; Chen, X.; Wang, L.-D.

doi:10.1101/2021.07.02.450861

bioRxiv · 10.1101/2021.07.02.450861

Extrachromosomal DNA is associated with chromothripsis events and diverse prognoses in gastric cardia adenocarcinoma

Zhao, X.·Xing, P.·Song, X.·Zhao, M.·Zhao, L.·Dang, Y.·Lei, L.-L.·Xu, R.-H.·Han, W.-L.·Wang, P.-P.·Yang, M.-M.·Hu, J.-F.·Zhong, K.·Zhou, F.-Y.·Han, X.-N.·Meng, C.-L.·Ji, J.-J.·Chen, X.·Wang, L.-D.

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Abstract

Extrachromosomal DNA plays an important role in oncogene amplification in tumour cells and poor outcomes across multiple cancers. However, the function of extrachromosomal DNA in gastric cardia adenocarcinoma (GCA) is very limited. Here, we investigated the availability and function of extrachromosomal DNA in GCA from a Chinese cohort of GCA using whole-genome sequencing (WGS), whole-exome sequencing (WES), and immunohistochemistry. For the first time, we identified the ecDNA amplicons present in most GCA patients, and found that some oncogenes are present as ecDNA amplicons in these patients. We found that oncogene ecDNA amplicons in the GCA cohort were associated with the chromothripsis process and may be induced by accumulated DNA damage due to local dietary habits in the geographic region. Strikingly, we observed diverse correlations between the presence of ecDNA oncogene amplicons and prognosis, where ERBB2 ecDNA amplicons correlated with good prognosis, EGFR ecDNA amplicons correlated with poor prognosis, and CCNE1 ecDNA amplicons did not correlate with prognosis. Large-scale ERBB2 immunohistochemistry results from 1668 GCA patients revealed that there was a positive correlation between the presence of ERBB2 and prognosis in 2-7-year survival; however, there was a negative correlation between the presence of ERBB2 and prognosis in 0-2-year survival. Our observations indicate that the presence of ERBB2 ecDNA in GCA patients may represent a good prognosis marker.

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Zhao, X., Xing, P., Song, X., Zhao, M., Zhao, L., Dang, Y., Lei, L.-L., Xu, R.-H., Han, W.-L., Wang, P.-P., Yang, M.-M., Hu, J.-F., Zhong, K., Zhou, F.-Y., Han, X.-N., Meng, C.-L., Ji, J.-J., Chen, X., Wang, L.-D.. 2021-07-04. Extrachromosomal DNA is associated with chromothripsis events and diverse prognoses in gastric cardia adenocarcinoma. https://doi.org/10.1101/2021.07.02.450861

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