Clinical Implications of Sub-grouping HER2 Positive Tumors by Amplicon Structure and Co-amplified Genes

Myriam Maoz,Dana Sherill-Rofe,Michal Inbar,Michal Devir,David Edelman,Beatrice Uziely,Salah Azzam,Luna Kadouri,Amir Sonnenblick,Ofra Maimon,Karen Meir,Tamar Peretz,Ziva Inbar-Daniel,Amir Eden,Aviad Zick,Idit Bloch,Hovav Nechushtan

doi:10.1038/s41598-019-55455-6

Myriam Maoz, Dana Sherill-Rofe + Show 15 more

Open Access

https://doi.org/10.1038/s41598-019-55455-6

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Abstract

ERBB2 amplification is a prognostic marker for aggressive tumors and a predictive marker for prolonged survival following treatment with HER2 inhibitors. We attempt to sub-group HER2+ tumors based on amplicon structures and co-amplified genes. We examined five HER2+ cell lines, three HER2+ xenographs and 57 HER2+ tumor tissues. ERBB2 amplification was analyzed using digital droplet PCR and low coverage whole genome sequencing. In some HER2+ tumors PPM1D, that encodes WIP1, is co-amplified. Cell lines were treated with HER2 and WIP1 inhibitors. We find that inverted duplication is the amplicon structure in the majority of HER2+ tumors. In patients suffering from an early stage disease the ERBB2 amplicon is composed of a single segment while in patients suffering from advanced cancer the amplicon is composed of several different segments. We find robust WIP1 inhibition in some HER2+ PPM1D amplified cell lines. Sub-grouping HER2+ tumors using low coverage whole genome sequencing identifies inverted duplications as the main amplicon structure and based on the number of segments, differentiates between local and advanced tumors. In addition, we found that we could determine if a tumor is a recurrent tumor or second primary tumor and identify co-amplified oncogenes that may serve as targets for therapy.

Highlights

ERBB2 amplification is a prognostic marker for aggressive tumors and a predictive marker for prolonged survival following treatment with HER2 inhibitors
We find that inverted duplication is the amplicon structure in the majority of HER2+ tumors
We found that co-amplification of PPM1D, which encodes wildtype p53-induced phosphatase 1 (WIP1), could identify a sub-group of HER2+ cell lines that are sensitive to treatment with a WIP1 inhibitor

Summary

Introduction

ERBB2 amplification is a prognostic marker for aggressive tumors and a predictive marker for prolonged survival following treatment with HER2 inhibitors. Sub-grouping HER2+ tumors using low coverage whole genome sequencing identifies inverted duplications as the main amplicon structure and based on the number of segments, differentiates between local and advanced tumors. ERBB2 amplification, defined as multiple copies of a DNA segment containing the ERBB2 gene, is found in tumors[2] and ERBB2 amplified/ HER2 positive (HER2+) cancers are treated as a unique clinical entity due to course of disease and to treatment options. ERBB2 amplification is a prognostic marker for aggressive breast tumors[3] and a predictive marker for prolonged survival of breast[4], gastric[5] and colon[6] cancer patients treated with HER2 inhibitors. Three principal amplicon structures were described in tumor amplified DNA: inverted duplication (ID), tandem repeat (TR) and double minute (DM)[12]. In HER2+ breast cancer patients co-amplification of EGFR17, FGFR118 and MYC19 is a poor prognostic marker

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