Oncotarget

Research Papers:

Working together for the family: determination of HER oncogene co-amplifications in breast cancer

Sergio Laurito, María Teresita Branham, Emanuel Campoy, Sebastián Real, Juan Cueto, Guillermo Urrutia, Francisco Gago, Olga Tello, Telma Glatstein, Paola De la Iglesia, Lilit Atanesyan, Suvi Savola and Maria Roqué _

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Oncotarget. 2020; 11:2774-2792. https://doi.org/10.18632/oncotarget.27671

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Abstract

Sergio Laurito1,2, María Teresita Branham1, Emanuel Campoy1,3, Sebastián Real1,3, Juan Cueto3, Guillermo Urrutia4, Francisco Gago5, Olga Tello5, Telma Glatstein6, Paola De la Iglesia7, Lilit Atanesyan8, Suvi Savola8 and Maria Roqué1,2

1 Institute of Histology and Embryology, National Council of Research, Consejo Nacional de Investigaciones Científicas y Técnicas, Mendoza, Argentina

2 Universidad Nacional de Cuyo, Facultad de Ciencias Exactas y Naturales, Mendoza, Argentina

3 Universidad Nacional de Cuyo, Facultad de Ciencias Médicas, Mendoza, Argentina

4 Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA

5 Instituto Gineco-Mamario, Mendoza, Argentina

6 CARPAT SA, Mendoza, Argentina

7 Hospital Italiano, Servicio de Anatomía Patológica, Buenos Aires, Argentina

8 MRC-Holland BV, Department of Oncogenetics, Amsterdam, The Netherlands

Correspondence to:

Maria Roqué,email: [email protected]

Keywords: HER oncogenes; breast cancer; MLPA; digital PCR; co-amplification

Received: March 06, 2020     Accepted: June 20, 2020     Published: July 14, 2020

Copyright: © 2020 Laurito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

HER2 is a well-studied tyrosine kinase (TK) membrane receptor which functions as a therapeutic target in invasive ductal breast carcinomas (IDC). The standard of care for the treatment of HER2-positive breast is the antibody trastuzumab. Despite specific treatment unfortunately, 20% of primary and 70% of metastatic HER2 tumors develop resistance. HER2 belongs to a gene family, with four members (HER1-4) and these members could be involved in resistance to anti-HER2 therapies. In this study we designed a probemix to detect the amplification of the four HER oncogenes in a single reaction. In addition, we developed a protocol based on the combination of MLPA with ddPCR to detect the tumor proportion of co-amplified HERs. On 111 IDC, the HER2 MLPA results were validated by FISH (Adjusted r2 = 0,91, p < 0,0001), CISH (Adjusted r2 = 0,938, p < 0,0001) and IHC (Adjusted r2 = 0,31, p < 0,0001). HER1-4 MLPA results were validated by RT-qPCR assays (Spearman Rank test p < 0,05). Of the 111 samples, 26% presented at least one HER amplified, of which 23% showed co-amplifications with other HERs. The percentage of cells with HER2 co-amplified varied among the tumors (from 2–72,6%). Independent in-silico findings show that the outcome of HER2+ patients is conditioned by the status of HER3 and HER4. Our results encourage further studies to investigate the relationship with patient’s response to single or combined treatment. The approach could serve as proof of principle for other tumors in which the HER oncogenes are involved.


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