Gene Summary

Gene:ERBB4; erb-b2 receptor tyrosine kinase 4
Aliases: HER4, ALS19, p180erbB4
Summary:This gene is a member of the Tyr protein kinase family and the epidermal growth factor receptor subfamily. It encodes a single-pass type I membrane protein with multiple cysteine rich domains, a transmembrane domain, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins and other factors and induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment. Mutations in this gene have been associated with cancer. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:receptor tyrosine-protein kinase erbB-4
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ERBB4 (cancer-related)

Yan T, Cui H, Zhou Y, et al.
Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma.
Nat Commun. 2019; 10(1):1670 [PubMed] Free Access to Full Article Related Publications
Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1/2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort (n = 508). Furthermore, knockdown of BRCA1/2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment.

Zhang X, Bai Q, Xu Y, et al.
Molecular profiling of the biphasic components of hepatic carcinosarcoma by the use of targeted next-generation sequencing.
Histopathology. 2019; 74(6):944-958 [PubMed] Related Publications
AIMS: To better understand the tumourogenesis and molecular features of hepatic carcinosarcoma (HCS).
METHODS AND RESULTS: We selected 13 cases of HCS, including the clinicopathological and immunohistochemical features, and analysed the molecular alterations in separately microdissected carcinomatous and sarcomatous components in eight cases by using targeted next-generation sequencing with a panel of 329 cancer-related genes. As a result, transitional areas were observed between the two components of HCS in all cases. Concordance and overlap in genetic alterations were identified in the two histological components of the eight HCS patients, indicating the clonal relatedness of the two tumour components. The most common gene alterations found in both components were TP53 (75%, 6/8) and NF1/2 (38%, 3/8) mutations and VEGFA amplification (25%, 2/8), which may be strongly associated with HCS tumorigenesis. Unique mutations and amplifications found only in one component were also identified. Amplifications involving MET (38%, n = 3/8) and PDGFRA (25%, n = 2/8) were present only in the sarcomatous components, whereas mutation affecting ERBB4 (25%, n = 2/8) and amplifications of CCND1 and FGF3/4/19 (38%, n = 3/8) were present only in the carcinomatous components, indicating their involvement in the clonal evolution of HCS. Furthermore, multiple potential therapeutic targets were identified for HCS.
CONCLUSIONS: Our findings indicate that HCS could have been of monoclonal origin, and that the diverse clonal evolution might be driven by special molecular alterations in each tumour component. Our results also identify multiple therapeutic targets of HCS, which are valuable for the personalised treatment of HCS.

Gao XH, Yu GY, Hong YG, et al.
Clinical significance of multiple gene detection with a 22-gene panel in formalin-fixed paraffin-embedded specimens of 207 colorectal cancer patients.
Int J Clin Oncol. 2019; 24(2):141-152 [PubMed] Related Publications
BACKGROUND: Simultaneous detection of multiple molecular biomarkers is helpful in the prediction of treatment response and prognosis for colorectal cancer (CRC) patients.
METHODS: A 22-gene panel consisting of 103 hotspot regions was utilized in the formalin-fixed paraffin-embedded (FFPE) tissue samples of 207 CRC patients, using the next-generation sequencing (NGS)-based multiplex PCR technique. Those 22 genes included AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, and TP53.
RESULTS: Of the 207 patients, 193 had one or more variants, with 170, 20, and 3 having one, two, and three mutated genes, respectively. Of the total 414 variants identified in this study, 384, 25, and 5 were single-nucleotide variants, deletion, and insertion. The top four frequently mutated genes were TP53, KRAS, PIK3CA, and FBXW7. There was high consistency between the results of NGS-PCR technique and routine ARMS-PCR in KRAS and BRAF mutation detection. Univariate and multivariate analyses demonstrated that advanced TNM stage, elevated serum CEA, total variants number ≥ 2, AKT1 and PTEN mutation were independent predictors of shorter DFS; poor differentiation, advanced TNM stage, total variants number ≥ 2, BRAF, CTNNB1 and NRAS mutation were independent predictors of shorter OS.
CONCLUSIONS: It is feasible to detect multiple gene mutations with a 22-gene panel in FFPE CRC specimens. TNM stage and total variants number ≥ 2 were independent predictors of DFS and OS. Detection of multiple gene mutations may provide additional prognostic information to TNM stage in CRC patients.

Koutras A, Lazaridis G, Koliou GA, et al.
Evaluation of the prognostic value of all four HER family receptors in patients with metastatic breast cancer treated with trastuzumab: A Hellenic Cooperative Oncology Group (HeCOG) study.
PLoS One. 2018; 13(12):e0207707 [PubMed] Free Access to Full Article Related Publications
In the current study, we performed a complete analysis, with four different methods, of all four HER family receptors, in a series of patients with metastatic breast cancer treated with trastuzumab-based regimens and evaluated their prognostic value. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 227 patients, considered to be HER2-positive when assessed at the local laboratories. We evaluated gene amplification, copy number variations (CNVs), mRNA and protein expression of all four HER family members. In addition, our analysis included the evaluation of several other factors by immunohistochemistry (IHC), such as pHER2Tyr1221/1222, pHER2Tyr877 and PTEN. Central review of HER2 status by IHC and fluorescence in situ hybridization revealed that of the 227 patients, only 139 (61.2%) were truly HER2-positive. Regarding the 191 patients treated with trastuzumab as first-line therapy, median time to progression (TTP) was 15.3 and 10.4 months for HER2-positive and HER2-negative participants, respectively, whereas median survival was 50.4 and 38.1 months, respectively. In HER2-positive patients, high HER3 mRNA expression was of favorable prognostic significance for TTP and survival (HR = 0.43, 95% CI 0.21-0.88, Wald's p = 0.022 and HR = 0.43, 95% CI 0.21-0.88, p = 0.021, respectively), while EGFR copy gain and EGFR protein expression were associated with higher risk for disease progression in HER2-negative patients (HR = 3.53, 95% CI 1.19-10.50, p = 0.023 and HR = 3.37, 95% CI 1.12-10.17, p = 0.031, respectively). Positive HER3 protein expression was a favorable factor for TTP in HER2-negative patients (HR = 0.43, 95% CI 0.22-0.84, p = 0.014). In the multivariate analysis, only EGFR copy gain retained its prognostic significance for TTP in the HER2-negative population (HR = 3.96, 95% CI 1.29-12.16, p = 0.016), while high HER3 mRNA expression retained its favorable prognostic significance for TTP in the HER2-positive subgroup (HR = 0.47, 95% CI 0.23-0.99, p = 0.048). The present study suggests that EGFR copy gain represents a negative prognostic factor for TTP in HER2-negative patients with metastatic breast cancer treated with trastuzumab. In addition, high HER3 mRNA expression appears to be of favorable prognostic significance for TTP in HER2-positive patients. Given the small number of patients included in the current analysis and the retrospective nature of the study, our findings should be validated in larger cohorts.

Roskoski R
Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers.
Pharmacol Res. 2019; 139:395-411 [PubMed] Related Publications
The EGFR family is among the most investigated receptor protein-tyrosine kinase groups owing to its general role in signal transduction and in oncogenesis. This family consists of four members that belong to the ErbB lineage of proteins (ErbB1-4). The ErbB proteins function as homo and heterodimers. These receptors contain an extracellular domain that consists of four parts: domains I and III are leucine-rich segments that participate in growth factor binding (except for ErbB2) and domains II and IV contain multiple disulfide bonds. Moreover, domain II participates in both homo and heterodimer formation within the ErbB/HER family of proteins. Seven ligands bind to EGFR including epidermal growth factor and transforming growth factor-α, none bind to ErbB2, two bind to ErbB3, and seven ligands bind to ErbB4. The extracellular domain is followed by a single transmembrane segment of about 25 amino acid residues and an intracellular portion of about 550 amino acid residues that contains (i) a short juxtamembrane segment, (ii) a protein kinase domain, and (iii) a carboxyterminal tail. ErbB2 lacks a known activating ligand and ErbB3 is kinase impaired. Surprisingly, the ErbB2-ErbB3 heterodimer complex is the most active dimer in the family. These receptors are implicated in the pathogenesis of a large proportion of lung and breast cancers, which rank first and second, respectively, in the incidence of all types of cancers (excluding skin) worldwide. On the order of 20% of non-small cell lung cancers bear activating mutations in EGFR. More than 90% of these patients have exon-19 deletions (

Wege AK, Chittka D, Buchholz S, et al.
HER4 expression in estrogen receptor-positive breast cancer is associated with decreased sensitivity to tamoxifen treatment and reduced overall survival of postmenopausal women.
Breast Cancer Res. 2018; 20(1):139 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The sensitivity of estrogen receptor-positive breast cancers to tamoxifen treatment varies considerably, and the molecular mechanisms affecting the response rates are manifold. The human epidermal growth factor receptor-related receptor HER2 is known to trigger intracellular signaling cascades that modulate the activity of coregulators of the estrogen receptor which, in turn, reduces the cell sensitivity to tamoxifen treatment. However, the impact of HER2-related receptor tyrosine kinases HER1, HER3, and, in particular, HER4 on endocrine treatment is largely unknown.
METHODS: Here, we retrospectively evaluated the importance of HER4 expression on the outcome of tamoxifen- and aromatase inhibitor-treated estrogen receptor-positive breast cancer patients (n = 258). In addition, we experimentally analyzed the efficiency of tamoxifen treatment as a function of HER4 co-expression in vitro.
RESULTS: We found a significantly improved survival in tamoxifen-treated postmenopausal breast cancer patients in the absence of HER4 compared with those with pronounced HER4 expression. In accordance with this finding, the sensitivity to tamoxifen treatment of estrogen and HER4 receptor-positive ZR-75-1 breast cancer cells can be significantly enhanced by HER4 knockdown.
CONCLUSION: We suggest an HER4/estrogen receptor interaction that impedes tamoxifen binding to the estrogen receptor and reduces treatment efficiency. Whether the sensitivity to tamoxifen treatment can be enhanced by anti-HER4 targeting needs to be prospectively evaluated.

Mansouri Bidkani M, Tabatabaeian H, Parsafar S, et al.
ErbB4 receptor polymorphism 2368A>C and risk of breast cancer.
Breast. 2018; 42:157-163 [PubMed] Related Publications
PURPOSE: A number of single nucleotide polymorphisms (SNPs) in EebB4 gene have been studied, which has clarified their impact on breast cancer in different populations. Nevertheless, the importance of rs13423759 in breast cancer has not been studied and its effect remained almost unclear. In this paper, we evaluated the frequency of rs13423759 different alleles in Iranian population and statistically analyzed their association with breast cancer risk.
MATERIALS AND METHODS: Allele-specific Primer PCR (ASP-PCR) was recruited in this study to genotype rs13423759 position in 172 breast cancer and 148 healthy control subjects. The genotypes of control and cases were analyzed statistically to find the association between rs13423759 alleles and breast cancer incidence and its clinicopathological characteristics. In silico studies were performed in order to find the mechanistic viewpoint of rs13423759 alleles in breast cancer.
RESULTS: rs13423759 allele C was shown to be significantly associated with breast cancer risk, HER2 positivity and increased risk of metastasis. Reciprocally, allele A was correlated with the lowered risk of breast cancer. The in silico studies showed that rs13423759 allele C is capable to strengthen the interaction between miR-548as, an oncomiRNA, and ErbB4 mRNA, leading to its lowered concentration in the cells.
CONCLUSION: rs13423759 allele C is significantly associated with the enhanced risk of breast cancer, elevated metastasis and HER2 positivity.

Youssef O, Knuuttila A, Piirilä P, et al.
Hotspot Mutations Detectable by Next-generation Sequencing in Exhaled Breath Condensates from Patients with Lung Cancer.
Anticancer Res. 2018; 38(10):5627-5634 [PubMed] Related Publications
BACKGROUND: Genetic alterations occurring in lung cancer are the basis for defining molecular subtypes and essential for targeted therapies. Exhaled breath condensate (EBC) is a form of non-invasive sample that, amongst components, contains DNA from pulmonary tissue. Next-generation sequencing (NGS) was herein used to analyze mutations in EBC from patients with lung cancer.
MATERIALS AND METHODS: EBC was collected from 26 patients with cancer and 20 healthy controls. Amplicon-based sequencing using Ion Ampliseq Colon and Lung Cancer gene panel v2 was applied.
RESULTS: The sequencing was successful in 17 patients and 20 controls. EBC from patients revealed 39 hotspot mutations occurring in: adenomatous polyposis coli (APC), v-raf murine sarcoma viral oncogene homolog B (BRAF), discoidin domain receptor tyrosine kinase 2 (DDR2), epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 4 (ERBB4), F-box and WD repeat domain containing 7 (FBXW7), fibroblast growth factor receptor 1 (FGFR1), FGFR3 (fibroblast growth factor receptor 3), Kirsten rat sarcoma viral oncogene homolog (KRAS), mitogen-activated protein kinase kinase 1 (MAP2K1), met proto-oncogene (MET), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), ret proto-oncogene (RET), SMAD family member 4 (SMAD4), serine/threonine kinase 11 (STK11), and tumor protein p53 (TP53) genes. EBC from controls revealed 35 hotspot mutations. The average mutant allele fraction was higher in patients than controls.
CONCLUSION: NGS can identify mutations in EBCs from patients with lung cancer. This could provide a promising non-invasive method for the assessment of gene mutations in lung cancer.

Samadi P, Saki S, Dermani FK, et al.
Emerging ways to treat breast cancer: will promises be met?
Cell Oncol (Dordr). 2018; 41(6):605-621 [PubMed] Related Publications
BACKGROUND: Breast cancer (BC) is the most common cancer among women and it is responsible for more than 40,000 deaths in the United States and more than 500,000 deaths worldwide each year. In previous decades, the development of improved screening, diagnosis and treatment methods has led to decreases in BC mortality rates. More recently, novel targeted therapeutic options, such as the use of monoclonal antibodies and small molecule inhibitors that target specific cancer cell-related components, have been developed. These components include ErbB family members (HER1, HER2, HER3 and HER4), Ras/MAPK pathway components (Ras, Raf, MEK and ERK), VEGF family members (VEGFA, VEGFB, VEGFC, VEGF and PGF), apoptosis and cell cycle regulators (BAK, BAX, BCL-2, BCL-X, MCL-1 and BCL-W, p53 and PI3K/Akt/mTOR pathway components) and DNA repair pathway components such as BRCA1. In addition, long noncoding RNA inhibitor-, microRNA inhibitor/mimic- and immunotherapy-based approaches are being developed for the treatment of BC. Finally, a novel powerful technique called CRISPR-Cas9-based gene editing is emerging as a precise tool for the targeted treatment of cancer, including BC.
CONCLUSIONS: Potential new strategies that are designed to specifically target BC are presented. Several clinical trials using these strategies are already in progress and have shown promising results, but inherent limitations such as off-target effects and low delivery efficiencies still have to be resolved. By improving the clinical efficacy of current therapies and exploring new ones, it is anticipated that novel ways to overcome BC may become attainable.

Forget A, Martignetti L, Puget S, et al.
Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling.
Cancer Cell. 2018; 34(3):379-395.e7 [PubMed] Related Publications
The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.

Nye A, Collins JD, Porter CL, et al.
Predictive genetic profiles for regional lymph node metastasis in primary cutaneous melanoma: a case-matched pilot study.
Melanoma Res. 2018; 28(6):555-561 [PubMed] Related Publications
Melanoma confers an estimated lifetime risk of one in 50 for 2016. Clinicopathologic staging and sentinel lymph node biopsy (SLNB) have been the standard of care for T2 and T3 lesions. Molecular biomarkers identified in the primary lesion suggestive of metastatic potential may offer a more conclusive prognosis of these lesions. Our purpose was to investigate molecular mutations in primary melanoma that were predictive for micrometastasis as defined by a positive sentinel lymph node (SLN) in a case-controlled manner: nine patients with negative SLN and nine with positive SLN. The two cohorts were statistically identical as shown by a t-test for age (P=0.17), race (P=0.18), Breslow depth (P=0.14), Clark level (P=0.33), host response (P=0.17), ulceration (P=0.50), satellite nodules (P=0.17), lymphovascular invasion (P=0.50), and mitotic activity (P=0.09). While no single gene was significantly associated with SLN status, multivariate analysis using classification and regression tree assessment revealed two unique gene profiles that completely represented regional metastases in our cohort as defined by a positive SLN: PIK3CA (+) NRAS (-) and PIK3CA (-) ERBB4 (-) TP53 (+) SMAD4 (-). These profiles were identified in 89% of the patients with positive SLN; none of these profiles were identified in the SLN-negative cohort. We identified two unique gene profiles associated with positive SLN that do not overlap other studies and highlight the genetic complexity that portends the metastatic phenotype in cutaneous melanoma.

Yokota T, Serizawa M, Hosokawa A, et al.
PIK3CA mutation is a favorable prognostic factor in esophageal cancer: molecular profile by next-generation sequencing using surgically resected formalin-fixed, paraffin-embedded tissue.
BMC Cancer. 2018; 18(1):826 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Practical and reliable genotyping procedures with a considerable number of samples are required not only for risk-adapted therapeutic strategies, but also for stratifying patients into future clinical trials for molecular-targeting drugs. Recent advances in mutation testing, including next-generation sequencing, have led to the increased use of formalin-fixed paraffin-embedded tissue. We evaluated gene alteration profiles of cancer-related genes in esophageal cancer patients and correlated them with clinicopathological features, such as smoking status and survival outcomes.
METHODS: Surgically resected formalin-fixed, paraffin-embedded tissue was collected from 135 consecutive patients with esophageal cancer who underwent esophagectomy. Based on the assessment of DNA quality with a quantitative PCR-based assay, uracil DNA glycosylase pretreatment was performed to ensure quality and accuracy of amplicon-based massively parallel sequencing. Amplicon-based massively parallel sequencing was performed using the Illumina TruSeq® Amplicon Cancer Panel. Gene amplification was detected by quantitative PCR-based assay. Protein expression was determined by automated quantitative fluorescent immunohistochemistry.
RESULTS: Data on genetic alterations were available for 126 patients. The median follow-up time was 1570 days. Amplicon-based massively parallel sequencing identified frequent gene alterations in TP53 (66.7%), PIK3CA (13.5%), APC (10.3%), ERBB4 (7.9%), and FBXW7 (7.9%). There was no association between clinicopathological features or prognosis with smoking status. Multivariate analyses revealed that the PIK3CA mutation and clinical T stage were independent favorable prognostic factors (hazard ratio 0.34, 95% confidence interval: 0.12-0.96, p = 0.042). PIK3CA mutations were significantly associated with APC alterations (p = 0.0007) and BRAF mutations (p = 0.0090).
CONCLUSIONS: Our study provided profiles of cancer-related genes in Japanese patients with esophageal cancer by next-generation sequencing using surgically resected formalin-fixed, paraffin-embedded tissue, and identified the PIK3CA mutation as a favorable prognosis biomarker.

Liang X, Vacher S, Boulai A, et al.
Targeted next-generation sequencing identifies clinically relevant somatic mutations in a large cohort of inflammatory breast cancer.
Breast Cancer Res. 2018; 20(1):88 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer. Using a custom-made breast cancer gene sequencing panel, we investigated somatic mutations in IBC to better understand the genomic differences compared with non-IBC and to consider new targeted therapy in IBC patients.
METHODS: Targeted next-generation sequencing (NGS) of 91 candidate breast cancer-associated genes was performed on 156 fresh-frozen breast tumor tissues from IBC patients. Mutational profiles from 197 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as non-IBC controls for comparison analysis. The mutational landscape of IBC was correlated with clinicopathological data and outcomes.
RESULTS: After genotype calling and algorithmic annotations, we identified 392 deleterious variants in IBC and 320 variants in non-IBC cohorts, respectively. IBC tumors harbored more mutations than non-IBC (2.5 per sample vs. 1.6 per sample, p < 0.0001). Eighteen mutated genes were significantly different between the two cohorts, namely TP53, CDH1, NOTCH2, MYH9, BRCA2, ERBB4, POLE, FGFR3, ROS1, NOTCH4, LAMA2, EGFR, BRCA1, TP53BP1, ESR1, THBS1, CASP8, and NOTCH1. In IBC, the most frequently mutated genes were TP53 (43.0%), PIK3CA (29.5%), MYH9 (8.3%), NOTCH2 (8.3%), BRCA2 (7.7%), ERBB4 (7.1%), FGFR3 (6.4%), POLE (6.4%), LAMA2 (5.8%), ARID1A (5.1%), NOTCH4 (5.1%), and ROS1 (5.1%). After grouping 91 genes on 10 signaling pathways, we found that the DNA repair pathway for the triple-negative breast cancer (TNBC) subgroup, the RTK/RAS/MAPK and cell cycle pathways for the HR
CONCLUSIONS: Breast cancer-specific targeted NGS uncovered a high frequency of deleterious somatic mutations in IBC, some of which may be relevant for clinical management.

Krol I, Castro-Giner F, Maurer M, et al.
Detection of circulating tumour cell clusters in human glioblastoma.
Br J Cancer. 2018; 119(4):487-491 [PubMed] Related Publications
Human glioblastoma (GBM) is a highly aggressive, invasive and hypervascularised malignant brain cancer. Individual circulating tumour cells (CTCs) are sporadically found in GBM patients, yet it is unclear whether multicellular CTC clusters are generated in this disease and whether they can bypass the physical hurdle of the blood-brain barrier.  Here, we assessed CTC presence and composition at multiple time points in 13 patients with progressing GBM during an open-label phase 1/2a study with the microtubule inhibitor BAL101553. We observe CTC clusters ranging from 2 to 23 cells and present at multiple sampling time points in a GBM patient with pleomorphism and extensive necrosis, throughout disease progression. Exome sequencing of GBM CTC clusters highlights variants in 58 cancer-associated genes including ATM, PMS2, POLE, APC, XPO1, TFRC, JAK2, ERBB4 and ALK. Together, our findings represent the first evidence of the presence of CTC clusters in GBM.

Molnár B, Galamb O, Péterfia B, et al.
Gene promoter and exon DNA methylation changes in colon cancer development - mRNA expression and tumor mutation alterations.
BMC Cancer. 2018; 18(1):695 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: DNA mutations occur randomly and sporadically in growth-related genes, mostly on cytosines. Demethylation of cytosines may lead to genetic instability through spontaneous deamination. Aims were whole genome methylation and targeted mutation analysis of colorectal cancer (CRC)-related genes and mRNA expression analysis of TP53 pathway genes.
METHODS: Long interspersed nuclear element-1 (LINE-1) BS-PCR followed by pyrosequencing was performed for the estimation of global DNA metlyation levels along the colorectal normal-adenoma-carcinoma sequence. Methyl capture sequencing was done on 6 normal adjacent (NAT), 15 adenomatous (AD) and 9 CRC tissues. Overall quantitative methylation analysis, selection of top hyper/hypomethylated genes, methylation analysis on mutation regions and TP53 pathway gene promoters were performed. Mutations of 12 CRC-related genes (APC, BRAF, CTNNB1, EGFR, FBXW7, KRAS, NRAS, MSH6, PIK3CA, SMAD2, SMAD4, TP53) were evaluated. mRNA expression of TP53 pathway genes was also analyzed.
RESULTS: According to the LINE-1 methylation results, overall hypomethylation was observed along the normal-adenoma-carcinoma sequence. Within top50 differential methylated regions (DMRs), in AD-N comparison TP73, NGFR, PDGFRA genes were hypermethylated, FMN1, SLC16A7 genes were hypomethylated. In CRC-N comparison DKK2, SDC2, SOX1 genes showed hypermethylation, while ERBB4, CREB5, CNTN1 genes were hypomethylated. In certain mutation hot spot regions significant DNA methylation alterations were detected. The TP53 gene body was addressed by hypermethylation in adenomas. APC, TP53 and KRAS mutations were found in 30, 15, 21% of adenomas, and in 29, 53, 29% of CRCs, respectively. mRNA expression changes were observed in several TP53 pathway genes showing promoter methylation alterations.
CONCLUSIONS: DNA methylation with consecutive phenotypic effect can be observed in a high number of promoter and gene body regions through CRC development.

Cavalieri S, Perrone F, Miceli R, et al.
Efficacy and safety of single-agent pan-human epidermal growth factor receptor (HER) inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer.
Eur J Cancer. 2018; 97:7-15 [PubMed] Related Publications
BACKGROUND: In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial.
METHODS: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC.
RESULTS: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup.
CONCLUSIONS: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.

Liu M, Solomon W, Cespedes JC, et al.
Neuregulin-1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/AKT/STAT3 signaling.
J Neuroinflammation. 2018; 15(1):104 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human cerebral malaria (HCM) is a severe form of malaria characterized by sequestration of infected erythrocytes (IRBCs) in brain microvessels, increased levels of circulating free heme and pro-inflammatory cytokines and chemokines, brain swelling, vascular dysfunction, coma, and increased mortality. Neuregulin-1β (NRG-1) encoded by the gene NRG1, is a member of a family of polypeptide growth factors required for normal development of the nervous system and the heart. Utilizing an experimental cerebral malaria (ECM) model (Plasmodium berghei ANKA in C57BL/6), we reported that NRG-1 played a cytoprotective role in ECM and that circulating levels were inversely correlated with ECM severity. Intravenous infusion of NRG-1 reduced ECM mortality in mice by promoting a robust anti-inflammatory response coupled with reduction in accumulation of IRBCs in microvessels and reduced tissue damage.
METHODS: In the current study, we examined how NRG-1 treatment attenuates pathogenesis and mortality associated with ECM. We examined whether NRG-1 protects against CXCL10- and heme-induced apoptosis using human brain microvascular endothelial (hCMEC/D3) cells and M059K neuroglial cells. hCMEC/D3 cells grown in a monolayer and a co-culture system with 30 μM heme and NRG-1 (100 ng/ml) were used to examine the role of NRG-1 on blood brain barrier (BBB) integrity. Using the in vivo ECM model, we examined whether the reduction of mortality was associated with the activation of ErbB4 and AKT and inactivation of STAT3 signaling pathways. For data analysis, unpaired t test or one-way ANOVA with Dunnett's or Bonferroni's post test was applied.
RESULTS: We determined that NRG-1 protects against cell death/apoptosis of human brain microvascular endothelial cells and neroglial cells, the two major components of BBB. NRG-1 treatment improved heme-induced disruption of the in vitro BBB model consisting of hCMEC/D3 and human M059K cells. In the ECM murine model, NRG-1 treatment stimulated ErbB4 phosphorylation (pErbB4) followed by activation of AKT and inactivation of STAT3, which attenuated ECM mortality.
CONCLUSIONS: Our results indicate a potential pathway by which NRG-1 treatment maintains BBB integrity in vitro, attenuates ECM-induced tissue injury, and reduces mortality. Furthermore, we postulate that augmenting NRG-1 during ECM therapy may be an effective adjunctive therapy to reduce CNS tissue injury and potentially increase the effectiveness of current anti-malaria therapy against human cerebral malaria (HCM).

Shu X, Gu J, Huang M, et al.
Germline genetic variants in somatically significantly mutated genes in tumors are associated with renal cell carcinoma risk and outcome.
Carcinogenesis. 2018; 39(6):752-757 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies (GWAS) have identified 13 susceptibility loci for renal cell carcinoma (RCC). Additional genetic loci of risk remain to be explored. Moreover, the role of germline genetic variants in predicting RCC recurrence and overall survival (OS) is less understood. In this study, we focused on 127 significantly mutated genes from The Cancer Genome Atlas (TCGA) Pan-Cancer Analysis across 12 major cancer sites to identify potential genetic variants predictive of RCC risk and clinical outcomes. In a three-phase design with a total of 2657 RCC cases and 5315 healthy controls, two single nucleotide polymorphisms (SNPs) that map to PIK3CG (rs6466135:A, ORmeta = 0.85, 95% CI = 0.77-0.94, Pmeta = 1.4 × 10-3) and ATM (rs611646:T, ORmeta = 1.17, 95% CI = 1.05-1.31, Pmeta = 3.5 × 10-3) were significantly associated with RCC risk. With respect to RCC recurrence and OS, two separate datasets with a total of 661 stages I-III RCC patients (discovery: 367; validation: 294) were analyzed. The most significant association was observed for rs10932384:C (ERBB4) with both outcomes (recurrence: HRmeta = 0.52, 95% CI = 0.39-0.68, Pmeta = 3.81 × 10-6; OS: HRmeta = 0.50, 95% CI = 0.37-0.67, Pmeta = 6.00 × 10-6). In addition, six SNPs were significantly associated with either RCC recurrence or OS but not both (Pmeta < 0.01). Rs10932384:C was significantly correlated with mutation frequency of ERBB4 in clear cell RCC (ccRCC) patients (P = 0.003, Fisher's exact test). Cis-eQTL was observed for several SNPs in blood/transformed fibroblasts but not in RCC tumor tissues. In summary, we identified promising genetic predictors of recurrence and OS among RCC patients with localized disease.

Xu J, Gong L, Qian Z, et al.
ERBB4 promotes the proliferation of gastric cancer cells via the PI3K/Akt signaling pathway.
Oncol Rep. 2018; 39(6):2892-2898 [PubMed] Related Publications
ERBB4 is one of the members of the epidermal growth factor receptor (EGFR) family. ERBB4 is a large transmembrane glycoprotein and has tyrosine kinase activity. Once combined with epidermal growth factor (EGF), ERBB4 can activate the related genes in the nucleus, thus promoting cell division and proliferation. In the present study, we investigated the effect of ERBB4 in the proliferation of gastric cancer cells. We found that high ERBB4 levels were closely related to the poor prognosis of gastric cancer patients. Furthermore, ERBB4 was highly expressed in gastric cancer cell lines when compared to the normal stomach cell line, GES. Clinical samples provided the same results. Two gastric cancer cell lines, SGC‑7901 and MNK‑45 were used to study the underlying mechanism of ERBB4 in the promotion of cell proliferation in gastric cancer cells both in vitro and in vivo. It was observed that after the expression of ERBB4 was suppressed, the proliferation of gastric cancer cells was markedly inhibited both in vitro and in vivo. Moreover, treatment with lentiviral vector siRNA‑ERBB4 (Lv‑siRNA‑ERBB4) or the ERBB4 inhibitor AST‑1306, markedly inhibited gastric cancer cell proliferation. Further experiments revealed that inhibition of the expression of ERBB4 could inhibit the activation of the PI3K/Akt signaling pathway. In addition, the use of the PI3K/Akt signaling pathway inhibitor LY294002 demonstrated the aforementioned results. Therefore, we believe that ERBB4 regulates cell proliferation mainly through the PI3K signaling pathway. Finally, nude mice xenografted with gastric cancer cells with low expression of ERBB4 exhibited smaller tumors and longer survival than those engrafted with control gastric cancer cells. These data indicated that ERBB4 promoted cell proliferation and is thus a potential therapeutic target for the treatment of gastric cancer.

Takada K, Kashiwagi S, Goto W, et al.
Analysis of HER Family (HER1-4) Expression as a Biomarker in Combination Therapy with Pertuzumab, Trastuzumab and Docetaxel for Advanced HER2-positive Breast Cancer.
Anticancer Res. 2018; 38(4):2285-2294 [PubMed] Related Publications
BACKGROUND: Chemotherapy with trastuzumab, pertuzumab and docetaxel (TPD regimen) is now strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER)2-positive breast cancer. In this study, we analyzed the expression of HER 1-4 proteins, and investigated whether or not their expression was predictive of the response of advanced HER2-positive breast cancer to chemotherapy with the TPD regimen.
PATIENTS AND METHODS: The study consisted of 29 cases in which TPD regimen chemotherapy was carried out from September 2013 to November 2015. The expression levels of estrogen receptor (ER), progesterone receptor (PgR), Ki67, HER1, HER2, HER3 and HER4 were evaluated using immunostaining employing needle biopsy specimens.
RESULTS: The overall response rate (ORR) was significantly higher in the HER3-positive group than in the HER3-negative group (p=0.002). In prognostic analysis, the HER3-positive group showed a significant progression-free survival extension over the HER3-negative group (p=0.042, log-rank). In univariate analysis, objective response (p=0.004, hazard ratio(HR)=0.123) and positive HER3 expression (p=0.023, HR=0.279) significantly contributed to extension of progression-free survival interval.
CONCLUSION: HER3 expression may be a useful factor for predicting the response of HER2-positive breast cancer to chemotherapy with the TPD regimen.

Shi J, Li F, Yao X, et al.
The HER4-YAP1 axis promotes trastuzumab resistance in HER2-positive gastric cancer by inducing epithelial and mesenchymal transition.
Oncogene. 2018; 37(22):3022-3038 [PubMed] Free Access to Full Article Related Publications
Trastuzumab is the only target to be approved as the first-line treatment of HER2 positive metastatic gastric cancer, but ubiquitous resistance decreases its therapeutic benefit. In this study, we found HER4, phosphorylation HER4 (p-HER4) and the mesenchymal marker Vimentin increased in trastuzumab-resistant cells (MKN45TR and NCI-N87TR), while epithelial markers expressions in trastuzumab-resistant cell lines and animal models decreased. Additionally, silencing HER4 prevented the epithelial-mesenchymal transition and led to decreased proliferation and migration in vitro and in vivo. The expression of YAP1, a vital downstream interacted target of HER4, decreased when HER4 was knocked down. Interestingly, stimulation of NRG1 could compromise the inhibitory impact and rescue cell survival; whereas, transfection of siYAP1 sensitized trastuzumab-treated cells. Expression analysis of the proteins in patient-derived xenograft model (PDX) mice showed that HER4, p-HER4, YAP1, and Vimentin were clearly upregulated in the trastuzumab-resistant mice compared to mice without trastuzumab resistance. However, HER2 and E-cadherin were downregulated in response to continuous treatment with trastuzumab. These findings elucidated that the central role of the HER4-YAP1 axis in trastuzumab resistance of HER2-positive gastric cancer cells through induction of EMT. Hence, regulating the HER4-YAP1 axis might be a promising strategy for clinical interventions in patients with HER2-positive gastric cancer.

Wu F, Wu S, Gou X
Identification of biomarkers and potential molecular mechanisms of clear cell renal cell carcinoma.
Neoplasma. 2018; 65(2):242-252 [PubMed] Related Publications
Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer in adults. The aim of this study is to identify the biomarkers and potential molecular mechanisms of ccRCC. Three gene expression profiles and two miRNA expression profiles were downloaded from GEO database. A total of 330 up-regulated differentially expressed genes (DEGs), 545 down-regulated DEGs, 26 up-regulated differentially expressed miRNAs (DEMs) and 11 down-regulated DEMs were identified by GEO2R. The gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by KOBAS software. The results showed that GO terms of the up-regulated DEGs were mostly enriched in response to stimulus at BP level, cell periphery at CC level and binding at MF level, while the GO terms of down-regulated DEGs were enriched in single-organism process at BP level, extracellular exosome at CC level and catalytic activity at MF level. As for KEGG pathways, HIF-1 signaling pathway, focal adhesion, PI3K-Akt signaling pathway and metabolic pathways were significantly enriched. Then, protein-protein interaction (PPI) network and miRNA-gene network were constructed and analyzed by Cytoscape. A total of eight DEGs were identified as biomarkers, including VEGFA, PPARA, CCND1, FLT1, CXCL12, FN1, DCN and ERBB4. Expression validation and survival analysis were performed by GEPIA and OncoLnc, respectively. Four biomarkers were verified by quantitative real-time PCR (qPCR) in 786-O cell line and HK-2 cell line. All four genes had the same expression trend as predicted. Our study provides a series of biomarkers and molecular mechanisms for the deeper research of ccRCC.

Wang H, Sun W, Sun M, et al.
HER4 promotes cell survival and chemoresistance in osteosarcoma via interaction with NDRG1.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(5 Pt A):1839-1849 [PubMed] Related Publications
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. The abilities of chemotherapy resistance are major roadblock in the successful treatment of OS. The clarification of mechanism regarding cell survival during OS chemotherapy are important. Here, we examined HER4 expression by immunohistochemistry in a large series of OS tissues, and found HER4 expression correlated with tumor characteristics and patient survival rates. HER4 knockdown by shRNA inhibited OS cell growth and tumorigenesis, and induced cell senescence and apoptosis in vitro and in vivo. We demonstrated that HER4 expression upregulated in the adverse conditions, such as serum starvation and sphere culture. Moreover, HER4 knockdown cells became more sensitive in stressful conditions such as loss of attachment, cytotoxic agents or nutrition insufficiency. Mechanism studies revealed that HER4 interacted with NDRG1, and NDRG1 overexpression could antagonize HER4 knockdown-mediated cell growth and apoptosis in stressed conditions. There was a positive correlation between HER4 and NDRG1 immunoreactivity in OS patients. Together, our present study shows that HER4 and/or NDRG1 might play a critical role for the cell survival and chemo-resistance of OS, and could be used as potential therapeutic targets in OS.

Bustos-Carpinteyro AR, Magaña-Torres MT, González-García JR, et al.
Los receptores epidérmicos humanos en el cáncer gástrico: alteraciones moleculares y su papel como diana terapéutica.
Gac Med Mex. 2017; 153(7):830-840 [PubMed] Related Publications
Gastric cancer (GC) is the third leading cause of cancer death worldwide; both environmental and genetic factors are involved in the etiology of this neoplasia. The human epidermal receptor (HER) pathway is essential for proliferation and differentiation of normal cells; but it is also implicated in the growth of cancer cells. In this work we investigate the molecular alterations in genes that encodes for HER receptors reported in GC, as well the role as therapeutic targets. We reviewed the literature reported to date regarding overexpression of HER-receptors, amplification and somatic mutations in ERBB genes occurred in gastric tumors, as well as the anti-HER therapies tested for treatment of GC. In GC, the overexpression of HER family is reported in a range of 12-87% of cases; up to 67% of cases with amplification, and 90 somatic mutations in ERBB genes. The only drug anti-HER approved for using combined with chemotherapy, in treatment of patients with advanced GC is trastuzumab; however, other targeted therapies are being investigated. The role of the HER family as a therapeutic target has not shown significant improvements in recent years; hence, further studies are required to find better options for treatment of GC.

Rauf F, Festa F, Park JG, et al.
Ibrutinib inhibition of ERBB4 reduces cell growth in a WNT5A-dependent manner.
Oncogene. 2018; 37(17):2237-2250 [PubMed] Free Access to Full Article Related Publications
Alterations in ERBB family members have been associated with many tumor malignancies. EGFR and ERBB2 have been extensively explored in clinical oncology and several drugs currently target them therapeutically. However, the significance of ERBB4 as a potential therapeutic target remains mostly unexplored, even though ERBB4 is overexpressed or mutated in many solid tumors. Using a unique functional protein microarray platform, we found that ibrutinib inhibits ERBB4 activity in the same nM range as its canonical target, BTK. Cell-based assays revealed that ibrutinib treatment inhibited cell growth and decreased phosphorylation of ERBB4 and downstream targets MEK and ERK in cancer cell lines with high levels of endogenous ERBB4. In vivo, ibrutinib-responsive mouse xenograft tumors showed decreased tumor volumes with ibrutinib treatment. Interestingly, global gene expression comparisons between responsive and non-responsive cells identified a signature featuring the WNT pathway that predicts growth responsiveness to ibrutinib. Non-responsive ERBB4-expressing cell lines featured elevated activity of the WNT pathway, through the overexpression of WNT5A. Moreover, inhibition of WNT5A expression led to an ibrutinib response in non-responsive cell lines. Our data show that inhibiting ERBB4 reduces cell growth in cells that have low WNT5A expression and reveal a link between the ERBB4 and WNT pathways.

Yun S, Kwak Y, Nam SK, et al.
Ligand-Independent Epidermal Growth Factor Receptor Overexpression Correlates with Poor Prognosis in Colorectal Cancer.
Cancer Res Treat. 2018; 50(4):1351-1361 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Molecular treatments targeting epidermal growth factor receptors (EGFRs) are important strategies for advanced colorectal cancer (CRC). However, clinicopathologic implications of EGFRs and EGFR ligand signaling have not been fully evaluated. We evaluated the expression of EGFR ligands and correlation with their receptors, clinicopathologic factors, and patients' survival with CRC.
Materials and Methods: The expression of EGFR ligands, including heparin binding epidermal growth factor-like growth factor (HBEGF), transforming growth factor (TGF), betacellulin, and epidermal growth factor (EGF), were evaluated in 331 consecutive CRC samples using mRNA in situ hybridization (ISH). We also evaluated the expression status of EGFR, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 using immunohistochemistry and/or silver ISH.
RESULTS: Unlike low incidences of TGF (38.1%), betacellulin (7.9%), and EGF (2.1%), HBEGF expression was noted in 62.2% of CRC samples. However, the expression of each EGFR ligand did not reveal significant correlations with survival. The combined analyses of EGFR ligands and EGFR expression indicated that the ligands‒/EGFR+ group showed a significant association with the worst disease-free survival (DFS; p=0.018) and overall survival (OS; p=0.005). It was also an independent, unfavorable prognostic factor for DFS (p=0.026) and OS (p=0.007). Additionally, HER4 nuclear expression, regardless of ligand expression, was an independent, favorable prognostic factor for DFS (p=0.034) and OS (p=0.049), by multivariate analysis.
CONCLUSION: Ligand-independent EGFR overexpression was suggested to have a significant prognostic impact; thus, the expression status of EGFR ligands, in addition to EGFR, might be necessary for predicting patients' outcome in CRC.

Liu Q, Cornejo KM, Cheng L, et al.
Next-Generation Sequencing to Detect Deletion of RB1 and ERBB4 Genes in Chromophobe Renal Cell Carcinoma: A Potential Role in Distinguishing Chromophobe Renal Cell Carcinoma from Renal Oncocytoma.
Am J Pathol. 2018; 188(4):846-852 [PubMed] Related Publications
Overlapping morphologic, immunohistochemical, and ultrastructural features make it difficult to diagnose chromophobe renal cell carcinoma (ChRCC) and renal oncocytoma (RO). Because ChRCC is a malignant tumor, whereas RO is a tumor with benign behavior, it is important to distinguish these two entities. We aimed to identify genetic markers that distinguish ChRCC from RO by using next-generation sequencing (NGS). NGS for hotspot mutations or gene copy number changes was performed on 12 renal neoplasms, including seven ChRCC and five RO cases. Matched normal tissues from the same patients were used to exclude germline variants. Rare hotspot mutations were found in cancer-critical genes (TP53 and PIK3CA) in ChRCC but not RO. The NGS gene copy number analysis revealed multiple abnormalities. The two most common deletions were tumor-suppressor genes RB1 and ERBB4 in ChRCC but not RO. Fluorescence in situ hybridization was performed on 65 cases (ChRCC, n = 33; RO, n = 32) to verify hemizygous deletion of RB1 (17/33, 52%) or ERBB4 (11/33, 33%) in ChRCC, but not in RO (0/32, 0%). In total, ChRCCs (23/33, 70%) carry either a hemizygous deletion of RB1 or ERBB4. The combined use of RB1 and ERBB4 fluorescence in situ hybridization to detect deletion of these genes may offer a highly sensitive and specific assay to distinguish ChRCC from RO.

Jones DC, Scanteianu A, DiStefano M, et al.
Analysis of copy number loss of the ErbB4 receptor tyrosine kinase in glioblastoma.
PLoS One. 2018; 13(1):e0190664 [PubMed] Free Access to Full Article Related Publications
Current treatments for glioblastoma multiforme (GBM)-an aggressive form of brain cancer-are minimally effective and yield a median survival of 14.6 months and a two-year survival rate of 30%. Given the severity of GBM and the limitations of its treatment, there is a need for the discovery of novel drug targets for GBM and more personalized treatment approaches based on the characteristics of an individual's tumor. Most receptor tyrosine kinases-such as EGFR-act as oncogenes, but publicly available data from the Cancer Cell Line Encyclopedia (CCLE) indicates copy number loss in the ERBB4 RTK gene across dozens of GBM cell lines, suggesting a potential tumor suppressor role. This loss is mutually exclusive with loss of its cognate ligand NRG1 in CCLE as well, more strongly suggesting a functional role. The availability of higher resolution copy number data from clinical GBM patients in The Cancer Genome Atlas (TCGA) revealed that a region in Intron 1 of the ERBB4 gene was deleted in 69.1% of tumor samples harboring ERBB4 copy number loss; however, it was also found to be deleted in the matched normal tissue samples from these GBM patients (n = 81). Using the DECIPHER Genome Browser, we also discovered that this mutation occurs at approximately the same frequency in the general population as it does in the disease population. We conclude from these results that this loss in Intron 1 of the ERBB4 gene is neither a de novo driver mutation nor a predisposing factor to GBM, despite the indications from CCLE. A biological role of this significantly occurring genetic alteration is still unknown. While this is a negative result, the broader conclusion is that while copy number data from large cell line-based data repositories may yield compelling hypotheses, careful follow up with higher resolution copy number assays, patient data, and general population analyses are essential to codify initial hypotheses prior to investing experimental resources.

Mezni F, Mlika M, Boussen H, et al.
About molecular profile of lung cancer in Tunisian patients.
J Immunoassay Immunochem. 2018; 39(1):99-107 [PubMed] Related Publications
BACKGROUND: Molecular profile of lung cancer is well known in developed countries. These countries reached the era of liquid biopsies, immunotherapy, and urine circulating tumor DNA. The discrepancies between developed countries and developing ones are becoming deeper. Because of a lack of data in Tunisia, we tried to analyze the molecular profile of non-small-cell carcinomas and to assess the morphologic subtype of adenocarcinomas according to their mutational profile.
METHODS: We performed molecular analyses in Tunisia and in France of 84 patients who were able to afford the cost of the diagnostic techniques carcinomas diagnosed between 2012 and 2015. The diagnosis was established in our Department of Pathology and the percentage of the tumor cells was estimated by the pathologists. The paraffin-embedded blocks were sent to France, in 41 cases and were analyzed in Tunisia in 43 cases. A next-generation sequencing was performed in France and a real-time polymerase chain reaction (PCR) was performed in our country.
RESULTS: During the period of study, 1122 lung cancers were diagnosed and 87 patients were able to afford the molecular analyses cost. The mean age of these patients was 53 years. The sex ratio reached 1.9. The molecular analyses were not performed in three cases because of a low tumor cell rate. EGFR mutations were present in 16 cases: 3 men and 13 women. The adenocarcinomas were classified as acinar in 11 cases and solid in 5 cases. ALK-EML4 translocation was present in six cases. Mutations of BRAF, KRAS, P53, and ERBB4 genes were, respectively, detected in two cases, five cases (3 codon 12), three cases, and one case.
CONCLUSION: This study made us wonder about the possibility of implementing molecular techniques in low-income countries and about the necessity of optimizing the financial resources.

Chen K, Liu MX, Mak CS, et al.
Methylation-associated silencing of
Theranostics. 2018; 8(2):423-436 [PubMed] Free Access to Full Article Related Publications
Human growth factor receptor-bound protein-7 (GRB7) is a pivotal mediator involved in receptor tyrosine kinase signaling and governing diverse cellular processes. Aberrant upregulation of GRB7 is frequently associated with the progression of human cancers. However, the molecular mechanisms leading to the upregulation of GRB7 remain largely unknown. Here, we propose that the epigenetic modification of GRB7 at the post-transcriptional level may be a crucial factor leading to GRB7 upregulation in ovarian cancers.

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