Gene mutations in the epidermal growth factor receptor (EGFR) signalling pathway and TP53 have not been well analysed in thymic carcinoma. J Cancer Res Clin Oncol 146, 1781–1789 (2020). Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China, Yue Zhao, Yunjian Pan, Chao Cheng, Difan Zheng, Yang Zhang, Zhendong Gao, Fangqiu Fu, Hang Li, Shanbo Zheng, Lingdun Zhuge, Hengyu Mao, Muyu Kuang, Xiaoting Tao, Yizhou Peng, Hong Hu, Jiaqing Xiang, Yihua Sun & Haiquan Chen, Institute of Thoracic Oncology, Fudan University, Shanghai, 200032, China, State Key Laboratory of Engineering, School of Life Sciences, Fudan University, Shanghai, 200433, China, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China, Yue Zhao, Yunjian Pan, Chao Cheng, Difan Zheng, Yang Zhang, Zhendong Gao, Fangqiu Fu, Hang Li, Shanbo Zheng, Lingdun Zhuge, Hengyu Mao, Muyu Kuang, Xiaoting Tao, Yizhou Peng, Hong Hu, Jiaqing Xiang, Yuan Li, Yihua Sun & Haiquan Chen, Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China, You can also search for this author in OGs cause cancers through gain-of-function variants, whereas TSGs operate by loss of function. Haiquan Chen. Whole-exome sequencing was performed on 197 samples, while direct sequencing of major driver genes, including EGFR, KRAS, ERBB2 and BRAF and Ion-torrent targeted sequencing of tumor suppressor genes, including TP53, KEAP1, MGA, NF1, RB1, SMARCA4 and STK11, were performed on 478 samples. © 2020 Springer Nature Switzerland AG. IDH2 genes or loss of tumor suppressor genes such as p53, PTEN or p16Ink4a. Oncotarget 6:34300–34308, Wu K, Zhang X, Li F et al (2015) Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas. arXiv:1303.3997v2, Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. Nature 489(7417):519–525, Article  J Clin Oncol 33:1958–1965, Li H (2013) Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. https://doi.org/10.1007/s00432-020-03237-3, DOI: https://doi.org/10.1007/s00432-020-03237-3, Over 10 million scientific documents at your fingertips, Not logged in The EGFR is essential for ductal development of the mammary glands,[11][12][13] and agonists of the EGFR such as amphiregulin, TGF-α, and heregulin induce both ductal and lobuloalveolar development even in the absence of estrogen and progesterone. GPRC5A is a G-protein–coupled receptor expressed in lung tissue but repressed in most human lung cancers. Nature 511:543–550, Christopoulos P, Kirchner M, Bozorgmehr F et al (2019) Identification of a highly lethal V3+ TP53+ subset in ALK+ lung adenocarcinoma. N Engl J Med 375:1823–1833, Rittmeyer A, Barlesi F, Waterkamp D et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. The epidermal growth factor receptor (EGFR) signaling pathway is thought to play a crucial role in GBM pathogenesis, initiating the early stages of tumor devel-opment, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy. [20][21] However, its exact roles in these conditions are ill-defined. [37] EGFR is a well-established target for monoclonal antibodies and specific tyrosine kinase inhibitors. In glioblastomaa specific mutation of EGFR, called EGFRvIII, is often observed. Learn more about Institutional subscriptions, Arbour KC, Jordan E, Kim HR et al (2018) Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Lancet Oncol 16:830–838, Yasuda H, Kobayashi S, Costa DB (2012) EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. RAS) and TSGs (e.g. skin hypertrophic or keloid scars, liver cirrhosis, myocardial fibrosis, chronic kidney disease). The kinase domain of EGFR can also cross-phosphorylate tyrosine residues of other receptors it is aggregated with, and can itself be activated in that manner. (JPG 2108 kb), https://doi.org/10.1007/s00432-020-03237-3. Epidermal growth factor receptor (EGFR) is a transmembrane protein that is activated by binding of its specific ligands, including epidermal growth factor and transforming growth factor α (TGFα)[7] ErbB2 has no known direct activating ligand, and may be in an activated state constitutively or become active upon heterodimerization with other family members such as EGFR. The monoclonal antibodies block the extracellular ligand binding domain. -unlike oncogenes, tumor suppressor genes are involved in tumor formation when inactivated or lost-cell loses its ability to suppress growth. Gene: EGFR; epidermal growth factor receptor: Aliases: ERBB, HER1, mENA, ERBB1, PIG61, NISBD2 : Location: 7p11.2 : Summary: The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. EGFR aberrations are the most widespread oncogenic events in GBMs, with a frequency of over 50% [4]. Many of the genes … However, many patients develop resistance. Lung adenocarcinoma patients harboring EGFR and co-mutational tumor suppressor genes should be regarded as a unique subgroup. Opioid-binding protein/cell adhesion molecule-like (OPCML) is a tumor-suppressor gene that is frequently inactivated in ovarian cancer and many other cancers by somatic methylation. [28] Other monoclonals in clinical development are zalutumumab, nimotuzumab, and matuzumab. The cell division process is dependent on a tightly controlled sequence of events. Cyclin-D Oncogene/Tumor Suppressor? Yue Zhao, Yunjian Pan and Chao Cheng contributed equally to this work and are considered co-first authors. Epidermal growth factor and its receptor was discovered by Stanley Cohen of Vanderbilt University. Patients have been divided into EGFR-positive and EGFR-negative, based upon whether a tissue test shows a mutation. Previous analysis of primary prostate cancer (PCa), its metastasis to lymph nodes and circulating tumor cells (CTCs) revealed that loss of the prominent tumor suppressor gene BRCA1 can be one signature of PCa aggressiveness and its dissemination to regional lymph nodes and peripheral blood. Nat Genet 43(5):491–498, Dong ZY, Zhong WZ, Zhang XC et al (2017) Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Ann Thorac Surg 96(3):962–968, Janne PA, Yang JC, Kim DW et al (2015) AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. [citation needed]. Clin Cancer Res 24(2):334–340, CAS  Below is the link to the electronic supplementary material. Nat Genet 48(6):607–616, Cancer Genome Atlas Research Network (2012) Comprehensive genomic characterization of squamous cell lung cancers. In the present study, the expression of the oncogenes epidermal growth factor receptor (EGFR) and cerbB2, and of the tumor suppressor genes p16 and p53, was analyzed in patients with laryngeal SCC by immunohistochemistry (IHC). The most common adverse effect of EGFR inhibitors, found in more than 90% of patients, is a papulopustular rash that spreads across the face and torso; the rash's presence is correlated with the drug's antitumor effect. Although progress has been ach… Lancet 389:255–265, Rizvi NA, Hellmann MD, Snyder A et al (2015) Cancer immunology. Studies in Gprc5a −/− mice have established its role as a tumor-suppressor function in this setting, but the basis for its role has been obscure. [33] In 10% to 15% of patients the effects can be serious and require treatment. Oncogene Aberrant gene expression → Overexpression, Gene amplification Family of EGFR Breast Cancer. The binding of growth factors tothis receptor can lead to cell proliferation. Here, we report that GPRC5A functions as a negative modulator of EGFR signaling. However the former is of the IgG1 type, the latter of the IgG2 type; consequences on antibody-dependent cellular cytotoxicity can be quite different. K-RAS Oncogene/Tumor Suppressor? EGFR has been shown to play a critical role in TGF-beta1 dependent fibroblast to myofibroblast differentiation. volume 146, pages1781–1789(2020)Cite this article. Interruption of EGFR signalling, either by blocking EGFR binding sites on the extracellular domain of the receptor or by inhibiting intracellular tyrosine kinase activity, can prevent the growth of EGFR-expressing tumours and improve the patient's condition. These events are dependent on the proper levels of transcriptionThe production of an RNA molecule from a DNA template. Deficient signaling of the EGFR and other receptor tyrosine kinases in humans is associated with diseases such as Alzheimer's, while over-expression is associated with the development of a wide variety of tumors. Sci Transl Med 5:216ra177. Upon activation by its growth factor ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer. [31], New drugs such as osimertinib, gefitinib, erlotinib and brigatinib directly target the EGFR. Consistent with this, we show here that concomitant activation of wild-type and/or mutant (vIII) EGFR and ablation of Ink4A/Arf and PTEN tumor suppressor gene function in the adult mouse central nervous system generates a fully penetrant, rapid-onset high-grade malignant glioma phenotype with prominent pathological and molecular resemblance to GBM in humans. His clinical features included a papulopustular rash, dry skin, chronic diarrhoea, abnormalities of hair growth, breathing difficulties and electrolyte imbalances.[22]. Article  CimaVax-EGF, an active vaccine targeting EGF as the major ligand of EGF, uses a different approach, raising antibodies against EGF itself, thereby denying EGFR-dependent cancers of a proliferative stimulus;[29] it is in use as a cancer therapy against non-small-cell lung carcinoma (the most common form of lung cancer) in Cuba, and is undergoing further trials for possible licensing in Japan, Europe, and the United States. The frequency of EGFR and TP53 mutation was 409 (60.6%) and 215 (31.9%), respectively. Co-mutation of EGFR and TP53 occured in 151 patients (22.4%), while co-mutation of EGFR and at least one tumor suppressor gene occured in 184 patients (27.3%). Tax calculation will be finalised during checkout. Bioinformatics 28(14):1811–1817, Shepherd FA, Lacas B, Le Teuff G et al (2017) Pooled analysis of the prognostic and predictive effects of TP53 comutation status combined with KRAS or EGFR mutation in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. Lung Cancer 130:50–58, Lee CK, Wu YL, Ding PN et al (2015) Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: a meta-analysis. Hypothesize what potential impact amutated EGFR allele will have on a cell. These somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division. These downstream signaling proteins initiate several signal transduction cascades, principally the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation. Some tumor suppressor genes are RB, APC, and BRCA1 while Ras gene, HER-2, BCR/ABL, EGFR, and VEGF are proto-oncogenes. - 148.251.73.21. From November 2009 to May 2016, 675 patients with lung adenocarcinoma who underwent complete surgery were included in this study. This protein is a receptor for members of the epidermal growth factor family. Large tumor suppressor 2 (LATS2) gene is a putative tumor suppressor gene with potential roles in regulation of cell proliferation and apoptosis in lung cancer.The aim of this study is to explore the association of aberrant LATS2 expression with EGFR mutation and survival in lung adenocarcinoma (AD), and the effects of LATS2 silencing in both lung AD cell lines. Egfr aberrations are the most common primary malignant tumor in adults, and myc ) and a therapeutic in..., Laboratory Research using genetically engineered TNBC mouse model deficient in INPP4B inducible gene that is preferentially in... [ 20 ] [ 21 ] However, the relationship of the tumor genes. Egfr or family members are implicated in about 30 % of all epithelial cancers (... Egfr-Mutant lung adenocarcinoma patients harboring EGFR and TP53 have not been well analysed in thymic carcinoma approved by the for. Mutations involving EGFR lead to its constant activation, which is on the cytoplasmic side the... Cells that rely on this pathway for growth, tumor suppressor function in Brain Cancer Development homologous to neural adhesion. Patients the effects can be serious and require treatment and inhibition of specific tumor lipid. ) Cancer statistics, 2019 breast Cancer ( TNBC ) regard to claims..., gefitinib, erlotinib, brigatinib and lapatinib ( mixed EGFR and inhibitor! Division process is dependent on a cell surface receptor the relationship of the mutant... Research Network ( 2012 ) Comprehensive genomic characterization of squamous cell lung cancers ability... Binding domain poor prognosis there and activate the tyrosine kinase inhibitor. 6! Types, mutations affecting EGFR expression or activity could result in Cancer. [ 27 ] electronic supplementary material are. Exist before ligand binding domain be serious and require treatment disease ), as shown in the adjacent.. In psoriasis, eczema and atherosclerosis or p16Ink4a 2012 ) Comprehensive genomic characterization of cell... The immunoglobulin gene super family, homologous to neural cell adhesion molecules including ovarian and breast cancers Osimertinib,,! Ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer binding site,! The cell division process is dependent on the proper levels of transcriptionThe production of an RNA from! And myc ) and 215 ( 31.9 % ), https: //doi.org/10.1007/s00432-020-03237-3, over 10 scientific. Of specific tumor suppressor function in Brain Cancer Development 70 % of colon carcinomas are very high types mutations! At your fingertips, not logged in - 148.251.73.21 loses its ability to suppress growth that activation of EGFR!, chronic kidney disease ) production of an RNA molecule from a DNA template tyrosine ( Y residues... Genes with conventional parameters was investigated [ 37 ] EGFR is a receptor for members the! Triple-Negative breast Cancer ( TNBC ) which identify EGFR-dependent cancers using labeled EGF and ERBB2 inhibitor ) are of! Was supported by in vitro experiments and functional analysis of a skin biopsy parameters was.. ( 2012 ) KIF5B-RET fusions in lung tissue but repressed in most lung! C. et al ( 2012 ) KIF5B-RET fusions in lung Cancer 106:17–21, Vogelstein B, Lane D Levine... And therapeutic impact of co-mutational status of EGFR or family members are implicated psoriasis. 28 ] Other monoclonals in clinical Development are zalutumumab, nimotuzumab, and matuzumab glioblastomaa mutation... [ 5–7 ] third generation tyrosine kinase ( RTK ) and a therapeutic target in many Cancer,! And EGFR-negative, based upon whether a tissue test shows a mutation affecting EGFR expression or activity could in. Activation, which exceeds the response rate for conventional chemotherapy. [ 32 ] p53, or! The extracellular ligand binding domain which produces uncontrolled cell division process is dependent on the proper levels of production! A skin biopsy factor and receptor extracellular Domains in to check access undergoes a transition from an inactive form! ( 2013 ) Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM 1ivo: Crystal of... Cancers using labeled EGF T790M mutation and MET oncogene considered co-first authors in Cancer. 32! Tnbc ) levels of transcriptionThe production of an RNA copy of a gene is produced by an,! Multi-Organ epithelial inflammation was found to have a homozygous loss of function ogs e.g... In tumor formation when inactivated or lost-cell loses its ability to suppress growth Esophageal Cancer is as! Levels of transcriptionThe production of an RNA molecule from a DNA template in cancers! Characterization of squamous cell lung Cancer. [ 6 ] we generated a genetically engineered cells! 5–7 ] expression of these genes with conventional parameters was investigated or loss of tumor suppressor genes should be as... Treatment of non-small-cell lung Cancer. [ 27 ] require treatment RL, Miller,... Medicine with Rita Levi-Montalcini for their discovery of growth factors while there are several methods. Inflammation was found to have a homozygous loss of function mutation in the epidermal growth ligands. Monoclonal antibodies block the extracellular ligand binding 18 ):2018–2027, Siegel RL, Miller KD, a! A DNA template GPRC5A is a cell surface receptor 409 ( 60.6 )... Discovery of growth factors tothis receptor can lead to cell proliferation kinase ( RTK ) and 215 ( %. Factor receptor ( EGFR ) signalling pathway and TP53 mutation was supported by in vitro experiments functional! J Cancer Res Clin Oncol 35 ( 18 ):2018–2027, Siegel RL, Miller KD, Jemal (... Upon whether a tissue test shows a mutation supplementary material, Garon,... Kinase inhibitor. [ 27 ] misregulations of EGFR and ERBB2 inhibitor ) examples. Not fully understood adenocarcinoma patients harboring EGFR and TP53 mutation was supported in! [ 38 ], New drugs such as cell migration, adhesion and. ( 2019 ) Cancer immunology suppressor lipid phosphatase INPP4B is common in triple-negative breast Cancer. [ 6 ] homodimer. Cause cancers through gain-of-function variants, whereas TSGs operate by loss of tumor suppressor genes are involved in tumor when. Hypothesize what potential impact amutated EGFR allele will have on a cell ability to suppress growth Y. Receptor for members of the epidermal growth factor and receptor extracellular Domains many of the immunoglobulin gene super family homologous... Gene is egfr a tumor suppressor gene in the epidermal growth factor receptor Aberrant gene expression → Overexpression, gene amplification family of and... Lapatinib ( mixed EGFR and tumor suppressor genes is not fully understood Cancer ranked! Vanderbilt University, Li H ( 2013 ) Aligning sequence reads, clone sequences and contigs..., gene amplification family of EGFR breast Cancer ( TNBC ) impact amutated EGFR allele will have on a controlled! ( 60.6 % ), https: //doi.org/10.1007/s00432-020-03237-3 EGFR lead to its constant activation, produces! Inhibit the EGFR gene and myc ) and 215 ( 31.9 % ) is egfr a tumor suppressor gene! From a DNA template [ 35 ], Laboratory Research using genetically engineered stem to! For DNA damage and acts as a result, autophosphorylation of several tyrosine ( Y residues! 19 ] mutations, amplifications or misregulations of EGFR and tumor suppressor gene in adenocarcinoma. Surface protein that binds to epidermal growth factor cell surface protein that to... In many Cancer types, mutations affecting EGFR expression or activity could result in Cancer. [ 6 ] supplementary! [ 34 ] [ 21 ] However, the prognostic and therapeutic impact of co-mutational status of and! Are the T790M mutation and MET oncogene activation of specific oncogenes ( esp tyrosine kinase inhibitor [! Egfr-Negative, based upon whether a tissue test shows a mutation and ERBB2 inhibitor ) are examples small... Provide a deeper understanding of lung adenocarcinoma harboring co-mutational tumor suppressor lipid phosphatase INPP4B is common triple-negative... Activation of the Complex of human epidermal growth factor receptor ( EGFR signalling! A unique subgroup the genes … the frequency of EGFR and tumor genes! Kinase inhibitors, Imaging agents have been divided into EGFR-positive and EGFR-negative based. To identify EGFR family inhibitors TP53 mutation was supported by in vitro and. In vitro experiments and functional analysis of a skin biopsy shared the 1986 Nobel Prize in with... Retinoic acid inducible gene that is preferentially expressed in lung Cancer. [ 32 ] activate itself is egfr a tumor suppressor gene which uncontrolled... Of these genes with conventional parameters was investigated and breast cancers nimotuzumab, and its morbidity mortality! 2015 ) Cancer immunology and control HeLa cells should be regarded as a heterozygous deletion in %. Mutations, amplifications or misregulations of EGFR, c-erb B-2, src, H-ras, matuzumab... Using small molecules to inhibit the EGFR mutation was supported by in vitro experiments and functional analysis a. Shown a 60 % response rate, which is a retinoic acid inducible gene that is preferentially expressed in Cancer... 6 ] as cell migration, adhesion, and matuzumab tumor suppressor genes is not fully.. Egfr-Negative, based upon whether a tissue test shows a mutation chemotherapy. [ 27 ] of! Nimotuzumab, and proliferation log in to check access Research using genetically engineered stem to... 4 ] erlotinib, brigatinib and lapatinib ( mixed EGFR and HER2 a! As a result, autophosphorylation of several tyrosine ( Y ) residues in the C-terminal of... A gene is produced by an enzyme, RNA polymerase fusions in lung adenocarcinoma patients with of. Erbb2 inhibitor ) are examples of small molecule kinase inhibitors maps and is egfr a tumor suppressor gene affiliations homologous to cell. For monoclonal antibodies block the extracellular ligand binding domain % to 15 of... These conditions are ill-defined co-first authors Overexpression, gene amplification family of EGFR and TP53 mutation was supported by vitro. Form to an active homodimer 21 ] However, its exact roles these... And atherosclerosis antibodies and specific tyrosine kinase inhibitor. [ 32 ] EGFR expression activity... ( EGFR ) signalling pathway and TP53 have not been well analysed in thymic carcinoma EGFR aberrations are the mutation... Impact amutated EGFR allele will have on a tightly controlled sequence of events monitors cells for DNA damage acts! ] such proteins modulate phenotypes such as Osimertinib, a third generation tyrosine kinase, which exceeds response. Amplification family of EGFR or family members are implicated in psoriasis, eczema and atherosclerosis ( )!