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. 2018 Oct;11(10):655-664.
doi: 10.1158/1940-6207.CAPR-18-0072. Epub 2018 Aug 13.

Germline and Somatic NF1 Alterations Are Linked to Increased HER2 Expression in Breast Cancer

Xia Wang  1 , Roope A Kallionpää  2 , Patrick R Gonzales  3 , Dhananjay A Chitale  4 , Renee N Tousignant  5 , Jacob P Crowley  6 , Zhihua Chen  7 , Sean J Yoder  7 , Jaishri O Blakeley  8 , Maria T Acosta  9 , Bruce R Korf  3 , Ludwine M Messiaen  3 , Michael A Tainsky  10
Affiliations

Germline and Somatic NF1 Alterations Are Linked to Increased HER2 Expression in Breast Cancer

Xia Wang et al. Cancer Prev Res (Phila). 2018 Oct.

Abstract

NF1 germline mutation predisposes to breast cancer. NF1 mutations have also been proposed as oncogenic drivers in sporadic breast cancers. To understand the genomic and histologic characteristics of these breast cancers, we analyzed the tumors with NF1 germline mutations and also examined the genomic and proteomic profiles of unselected tumors. Among 14 breast cancer specimens from 13 women affected with neurofibromatosis type 1 (NF1), 9 samples (NF + BrCa) underwent genomic copy number (CN) and targeted sequencing analysis. Mutations of NF1 were identified in two samples and TP53 were in three. No mutation was detected in ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, and STK11 HER2 (ErbB2) overexpression was detected by IHC in 69.2% (9/13) of the tumors. CN gain/amplification of ERBB2 was detected in 4 of 9 with DNA analysis. By evaluating HER2 expression and NF1 alterations in unselected invasive breast cancers in TCGA datasets, we discovered that among samples with ERBB2 CN gain/amplification, the HER2 mRNA and protein expression were much more pronounced in NF1-mutated/deleted samples in comparison with NF1-unaltered samples. This finding suggests a synergistic interplay between these two genes, potentially driving the development of breast cancer harboring NF1 mutation and ERBB2 CN gain/amplification. NF1 gene loss of heterozygosity was observed in 4 of 9 NF + BrCa samples. CDK4 appeared to have more CN gain in NF + BrCa and exhibited increased mRNA expression in TCGA NF1--altered samples. Cancer Prev Res; 11(10); 655-64. ©2018 AACR.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

J.O. Blakeley is a consultant/advisory board member for Abbvie. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1.
Figure 1.
Expression of ERBB2 mRNA and its protein product HER2 in TCGA breast-invasive carcinoma dataset. The samples are stratified by their NF1 gene status and the presence of HER2 amplification.
Figure 2.
Figure 2.
Protein and mRNA levels of selected signaling molecules in the TCGA breast-invasive carcinoma dataset. The samples are stratified by their NF1 gene status.
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