HER2 Gene Amplification and Protein Expression in Pancreatic Ductal Adenocarcinomas

Aumayr, Klaus; Soleiman, Afschin; Sahora, Klaus; Schindl, Martin; Werba, Gregor; Schoppmann, Sebastian F.; Birner, Peter

doi:10.1097/pai.0b013e31828dc392

Cited by 27 publications

(10 citation statements)

References 27 publications

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“…Te Velde et al reported that neither membranous overexpression nor gene amplification of HER2 was seen in pancreatic cancer [28]. A study by Aumayr, et al observed positive HER2 expression, as determined by IHC staining, in 10% of pancreatic cancer cases, and of these, 7% demonstrated HER2 gene amplification [29]. In our study we observed positive HER2 expression in 60.0% of cases, which is significantly higher than that observed by others.…”

Section: Discussioncontrasting

confidence: 68%

The prognostic significance of human epidermal growth factor receptor family protein expression in operable pancreatic cancer

Zhang

et al. 2016

BMC Cancer

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BackgroundPrognostic factors aid in the stratification and treatment of cancer. This study evaluated the prognostic significance of human epidermal growth factor receptor (HER) family members (HER1–4) expression in patients with operable pancreatic cancer.MethodsThe expression of individual HER proteins in patient tissue specimens was detected by immunohistochemistry staining. Patient follow-up time was between 1.0 and 78.1 months.ResultsPositive expression of HER1, HER2, HER3 and HER4 was detected in 41.4, 60.0, 24.3 and 65.7% of cases, respectively. Kaplan–Meier analysis revealed that HER3 positive expression was associated with decreased median survival time (12.0 vs. 25.6 months for HER3 positive and negative groups, respectively; P = 0.013). Cox’s regression confirmed that positive HER3 expression was an independent predictor of poor survival (RR = 3.684, P = 0.001). In contrast, HER4 negative patients had a significantly decreased median survival time when compared with HER4 positive patients (11.4 vs. 25.6 months, respectively; P = 0.027). However, HER4 was not an independent predictor of survival. No significant association between HER1 or HER2 expression and survival was observed (P = 0.626 & P = 0.859, respectively).ConclusionsHER3 is an independent prognostic marker for patients with operable pancreatic cancer. HER4 may also be of potential prognostic value in this disease and deserves further attention.

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Section: Discussioncontrasting

confidence: 68%

The prognostic significance of human epidermal growth factor receptor family protein expression in operable pancreatic cancer

Zhang

et al. 2016

BMC Cancer

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“…4A and Supplementary Figure S7 ). Amplifications of CCND1 and ERBB2 genes are observed in PDAC 22 and are potentially targetable 33 34 . Focusing on 27 patients with high percentages of ctDNA, high amplification could also be detected in our NGS platform.…”

Section: Discussionmentioning

confidence: 99%

Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer

Takai

Totoki

Nakamura

et al. 2015

Sci Rep

172

146

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect and monitor molecular characteristics of tumors. In the present study, we determined the mutational status of KRAS in plasma cfDNA using multiplex picoliter-droplet digital PCR in 259 patients with PDAC. We constructed a novel modified SureSelect-KAPA-Illumina platform and an original panel of 60 genes. We then performed targeted deep sequencing of cfDNA and matched germline DNA samples in 48 patients who had ≥1% mutant allele frequencies of KRAS in plasma cfDNA. Importantly, potentially targetable somatic mutations were identified in 14 of 48 patients (29.2%) examined by targeted deep sequencing of cfDNA. We also analyzed somatic copy number alterations based on the targeted sequencing data using our in-house algorithm, and potentially targetable amplifications were detected. Assessment of mutations and copy number alterations in plasma cfDNA may provide a prognostic and diagnostic tool to assist decisions regarding optimal therapeutic strategies for PDAC patients.

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“…Since ERK is part of the canonical MAPK pathway, which is initiated by epidermal growth factor (EGF) receptors, we tested whether loss of Dsg2 modulates the activities of EGF receptors. Indeed, HER2, which can be overexpressed in PDACs, 23 was activated as demonstrated by increased levels of HER2 autophosphorylated at Tyr1196 (Fig. 5D).…”

Section: Inhibition Of Perk Activation Prevents Enhanced Migration mentioning

confidence: 96%

Loss of desmoglein 2 promotes tumorigenic behavior in pancreatic cancer cells

Hütz

Zeiler

Sachs

et al. 2017

Molecular Carcinogenesis

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The ability to maintain cell-cell adhesion is crucial for tissue integrity and organization. Accordingly, loss of cohesiveness plays a critical role in cancer invasion and metastasis. Desmosomes are cell junctions providing strong intercellular adhesive strength and dysregulation of desmosomal constituents contributes to cancer progression through altered cell signaling pathways. Here, we focused on the desmosomal adhesion molecules Desmoglein 2 (Dsg2) and Desmocollin 2 (Dsc2), and their contribution to migration and invasion in pancreatic cancer cells. Silencing of Dsg2 but not Dsc2 resulted in loss of cell cohesion and enhanced migration, and invasion of pancreatic adenocarcinoma cells. To identify potential pathways regulated by Dsg2, we performed kinase arrays and detected the activity of ERK and growth factor receptors to be significantly enhanced in Dsg2-deficient cells. Consequently, inhibition of ERK phosphorylation in Dsg2 knockdown cells normalized migration. Loss of Dsg2 resulted in reduced levels of the desmosomal adapter protein and transcriptional regulator Plakoglobin (PG) in an ERK-dependent manner, whereas other desmosomal molecules were not altered. Overexpression of PG rescued enhanced migration induced by silencing of Dsg2. These results identify a novel pro-migratory pathway of pancreatic cancer cells in which loss of Dsg2 reduces the levels of PG via deregulated MAPK signaling.

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HER2 Gene Amplification and Protein Expression in Pancreatic Ductal Adenocarcinomas

Abstract: HER2 is overexpressed in a subset of PDACs, identifying them as possible candidates for a targeted therapy. For assessment of HER2 status in PDAC, the scoring system originally developed for gastric cancer is recommend.

Cited by 27 publications

References 27 publications

The prognostic significance of human epidermal growth factor receptor family protein expression in operable pancreatic cancer

The prognostic significance of human epidermal growth factor receptor family protein expression in operable pancreatic cancer

Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer

Loss of desmoglein 2 promotes tumorigenic behavior in pancreatic cancer cells

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