Prevalence and influence on outcome of HER2/neu, HER3 and NRG1 expression in patients with metastatic colorectal cancer

Stahler, Arndt; Heinemann, Volker; Neumann, Jens; Crispin, Alexander; Schalhorn, Andreas; Stintzing, Sebastian; Gießen-Jung, Clemens; Weikersthal, Ludwig Fischer von; Vehling-Kaiser, Ursula; Stauch, Martina; Quietzsch, D.; Holch, Julian Walter; Krüger, Stephan; Haas, Michael; Michl, Marlies; Einem, J von; Kirchner, Thomas; Jung, Andreas; Modest, Dominik Paul

doi:10.1097/cad.0000000000000510

Cited by 15 publications

(13 citation statements)

References 29 publications

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“…No evidence has convinced that HER2 gene amplification is a prognostic factor for CRC. Laurentpuig et al (2016) and Stahler et al (2017) demonstrated patients with HER2 amplification tumor had a worse survival, but some recent studies (Pietrantonio et al, 2017;Richman et al, 2016) argued no meaningful relationships between this marker and survival. Several studies had reported the frequency of BRAF mutation in Chinese CRC patients, but the number of samples was limited in most of the studies (Li et al, 2011a; Mao et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Li et al (2011b) reported an association between HER2 expression and tumor size and distant metastases, and a recent meta-analysis showed HER2 amplification was associated with lymph node metastasis and advanced tumors stage (Sun et al, 2016). The number of studies suggests that HER2 may play some role in tumor progression and would be a valuable prognostic factor for CRC patients (Laurentpuig et al, 2016;Stahler et al, 2017). But in other studies, HER2 gene amplification was higher in patients with more advanced stage or distant metastases, and no significant difference in prognosis for CRC patients (Pietrantonio et al, 2017;Wang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, information about HER2 amplification in Chinese CRC patients was limited (Li et al, 2011b). Some studies (Laurentpuig et al, 2016;Stahler et al, 2017) demonstrated patients with HER2 amplification tumor had a worse survival, but other studies (Pietrantonio et al, 2017;Richman et al, 2016) argued no meaningful relationships between this marker and survival. Therefore, in the present study, we analyzed the HER2 amplification and BRAF V600E mutation status of CRC patients to evaluate possible associations between HER2 and BRAF V600E mutation and the clinicopathological characteristics in primary stage I-III CRC, and we also attempted to explore the prognostic role of HER2 and BRAF V600E mutation.…”

Section: Introductionmentioning

confidence: 99%

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HER2 and BRAF mutation in colorectal cancer patients: a retrospective study in Eastern China

Zhang

Wang

et al. 2020

PeerJ

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Objective To investigate the frequency and prognostic role of the human epidermal growth factor receptor 2 gene (HER2) and BRAF V600E gene mutation in Chinese patients with colorectal cancer (CRC). Methods Clinicopathological and survival information from 480 patients with stage I–III CRC were reviewed and recorded. HER2 amplification was analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), BRAF V600E mutation was tested by IHC and Sanger sequencing. The relationship between HER2 and BRAF V600E mutation status and clinicopathological characteristics and outcomes were determined. Results The amplification of HER2 and BRAF V600E mutation were identified in 27 of 480 (5.63%) and 19 of 480 (3.96%) CRC patients, respectively. HER2 amplification significantly correlated with greater bowel wall invasion (P = 0.041) and more advanced TNM stage (I vs. II vs. III; 0 vs 5.78% vs. 7.41%, P = 0.013). Patients suffering from tumors with poor differentiation had a higher incidence rate of BRAF V600E mutation than those with moderate/well differentiation (7.77% vs 2.92%, P = 0.04). HER2 amplification was an independent prognostic factor for worse disease-free survival (DFS) (HR = 2.53, 95% CI: 1.21–5.30, P = 0.014). Conclusion The prevalence of HER2 amplification and BRAF V600E mutation in stage I–III CRC patients in Chinese was 6% and 4%, respectively, and HER2 amplification appeared to be associated with a worse DFS. More comprehensive molecular classification and survival analysis are needed to validate our findings.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HER2 and BRAF mutation in colorectal cancer patients: a retrospective study in Eastern China

Zhang

Wang

et al. 2020

PeerJ

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“…Furthermore, many of the allele specific replication genes are reported to be cancerrelated (Supp Table 1). Notably, three genes that lose allelic replication in DKO1 cells, are also reported to be associated with colon cancer; NRG1 (Luraghi et al, 2017;Stahler et al, 2017), PCDH7 (Li et al, 2020;van Roy, 2014) and DLC1 (Durkin et al, 2007;Peng et al, 2013) (Fig. 5c,d and Supp Fig.…”

Section: Dna Hypomethylation Causes Loss Of Allelic Replicationmentioning

confidence: 93%

DNA methylation is required to maintain DNA replication timing precision and 3D genome integrity

Smith

Luu

et al. 2020

Preprint

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DNA replication timing and three-dimensional (3D) genome organisation are associated with distinct epigenome patterns across large domains during differentiation and cancer progression. However, it is unclear if alternations in the epigenome, in particular cancer-associated DNA hypomethylation, can directly promote higher order genome architectural alterations. Here, we use Hi-C and single cell Repli-Seq, in the colorectal cancer DNMT1 and DNMT3B DNA methyltransferases double knockout model, to determine the impact of DNA hypomethylation on replication timing and 3D genome organisation. First, we find that the hypomethylated cells show a striking loss of replication timing precision with gain of intra-population replication timing heterogeneity and loss of 3D genome compartmentalisation. Second, hypomethylated regions that undergo a large change in replication timing also show loss of allelic replication timing, including at cancer-related genes. Finally, we observe the striking formation of ectopic H3K4me3-H3K9me3 domains across hypomethylated regions where late replication is maintained, which we propose serve to prevent aberrant transcription and loss of genome organisation after DNA demethylation. Together, our results highlight a previously underappreciated role for DNA methylation in the maintenance of 3D genome architecture.

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“…HER-2/neu is a member of the transmembrane epidermal growth factor receptor (EGF-R) family and is physiological expressed in many epithelial cells. However, it is overexpressed and/or amplified in human tumor of distinct origin including mammary carcinoma [ 8 ] and colorectal cancer [ 9 ]. HER-2/neu transformation is associated with an increased cell proliferation, migration, enhanced cell cycle progression as well as a survival of patients [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Linking CREB function with altered metabolism in murine fibroblast-based model cell lines

et al. 2017

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The cAMP-responsive element binding protein CREB is frequently overexpressed and activated in tumors of distinct histology, leading to enhanced proliferation, migration, invasion and angiogenesis as well as reduced apoptosis. The de-regulated expression of CREB might be linked with transcriptional as well as post-transcriptional regulation mechanisms. We show here that altered CREB expression levels and function are associated with changes in the cellular metabolism. Using comparative proteome-based analysis an altered expression pattern of proteins involved in the cellular metabolism in particular in glycolysis was found upon CREB down-regulation in HER-2/neu-transfected cell lines. This was associated with diminished expression levels of the glucose transporter 1, reduced glucose uptake and reduced glycolytic activity in HER-2/neu-transfected cells with down-regulated CREB when compared to HER-2/neu+ cells. Furthermore, hypoxia-induced CREB activity resulted in changes of the metabolism in HER-2/neu transfected cells. Low pH values in the supernatant of HER-2/neu transformants were restored by CREB down-regulation, but further decreased by hypoxia. The altered intracellular pH values were associated with a distinct expression of lactate dehydrogenase, and its substrate lactate. Moreover, enhanced phosphorylation of CREB on residue Ser133 was accompanied by a down-regulation of pERK and an up-regulation of pAKT. CREB promotes the detoxification of ROS by catalase, therefore protecting the mitochondrial activity under oxidative stress. These data suggest that there might exists a link between CREB function and the altered metabolism in HER-2/neu-transformed cells. Thus, targeting these altered metabolic pathways might represent an attractive therapeutic approach at least for the treatment of patients with HER-2/neu overexpressing tumors.

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Prevalence and influence on outcome of HER2/neu, HER3 and NRG1 expression in patients with metastatic colorectal cancer

Cited by 15 publications

References 29 publications

HER2 and BRAF mutation in colorectal cancer patients: a retrospective study in Eastern China

HER2 and BRAF mutation in colorectal cancer patients: a retrospective study in Eastern China

DNA methylation is required to maintain DNA replication timing precision and 3D genome integrity

Linking CREB function with altered metabolism in murine fibroblast-based model cell lines

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