TRKA expression and NTRK1 gene copy number across solid tumours

AimsNeurotrophic Tropomyosin Kinase Receptor 1 (NTRK1) gene encodes for the protein Tropomyosin-related kinase A (TRKA). Deregulated activity of TRKA has been shown to have oncogenic potential. We present here the results of an immunohistochemical (IHC) observational cohort study of TRKA expression together with gene copy number (GCN) assessment in various solid tumours.MethodsFormalin-fixed, paraffin-embedded consecutive samples of different tumour types were tested for TRKA expression. Samples showing TRKA IHC staining in at least 10% of cells were analysed by fluorescence in situ hybridisation to assess NTRK1 gene rearrangements and/or individual GCN gain. All patients underwent this molecular assessment within the phase I ALKA-001 clinical trial.Results1043 samples were tested and annotation for histology was available in 1023. Most of the samples were colorectal adenocarcinoma (CRC) (n=550, 52.7%) and lung adenocarcinoma (n=312, 29.9%). 24 samples (2.3%) were biliary tract carcinoma (BTC). Overall, 17 (1.6%) samples were characterised by TRKA IHC expression (four weak, eight moderate, five strong): 9/17 lung adenocarcinoma, 3/17 CRC, 3/17 BTC, 1/17 thyroid cancer and 1/17 cancer of unknown primary. Of these, 1/17 with strong TRKA IHC staining displayed NTRK1 gene rearrangement and 15/17 NTRK1 GCN gain by FISH. No correlation was found between intensity of TRKA IHC staining and number of copies of NTRK1.ConclusionsTRKA expression can be found in 1.6% of solid tumours and can be paralleled by NTRK1 gene rearrangements or mostly GCN gain. The prognostic and translational therapeutic impact of the latter remains to be established.

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Prognostic impact of HER-2/neu gene copy number determination by fluorescence in situ hybridisation (FISH) versus immunohistochemically detected overexpression in node positive primary breast cancer

European Journal of Cancer ◽

10.1016/s0959-8049(98)80123-8 ◽

1998 ◽

Vol 34 ◽

pp. S30

Author(s):

H. Bojar ◽

C. Bente ◽

K. Martin ◽

K. Struse ◽

C. Schmoor ◽

...

Keyword(s):

Breast Cancer ◽

Primary Breast Cancer ◽

Copy Number ◽

In Situ Hybridisation ◽

Gene Copy Number ◽

Gene Copy ◽

Prognostic Impact ◽

Fluorescence In Situ Hybridisation ◽

Her 2

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Clinical significance of ESR1 gene copy number changes in breast cancer as measured by fluorescence in situ hybridisation

Journal of Clinical Pathology ◽

10.1136/jclinpath-2012-200929 ◽

2012 ◽

Vol 66 (2) ◽

pp. 140-145 ◽

Cited By ~ 14

Author(s):

Ching-Hung Lin ◽

Jacqueline M Liu ◽

Yen-Shen Lu ◽

Chieh Lan ◽

Wei-Chung Lee ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Significance ◽

Copy Number ◽

In Situ Hybridisation ◽

Gene Copy Number ◽

Disease Free Survival ◽

Gene Copy ◽

Fluorescence In Situ Hybridisation ◽

Copy Number Changes

AimsThe ESR1 gene encodes for oestrogen receptor (ER) α, which plays a crucial role in mammary carcinogenesis and clinical outcome in patients with breast cancer. However, the clinical significance of the ESR1 gene copy number change for breast cancer has not been clarified.MethodsESR1 gene copy number was determined by fluorescence in situ hybridisation (FISH) on tissue sections. A minimum of 20 tumour cells were counted per section, and a FISH ratio of ESR1 gene to CEP6 ≥2.0 was considered ESR1 amplification. A ratio >1.2 but <2.0 was considered ESR1 gain. The ESR1 copy number was further measured by quantitative real-time PCR (Q-PCR) with ASXL2 as a reference.ResultsFISH revealed ESR1 amplification in six cases (4.0%) and ESR1 gain in 13 cases (8.7%) from a total of 150 cases. ESR1 gain and amplification were more common in older patients (p<0.001), and correlated well with ER protein expression (p=0.03) measured by immunohistochemistry, and ESR1 copy number (p<0.001) measured by Q-PCR. Furthermore, the multivariate analysis revealed that ESR1 amplification was associated with a shorter disease-free survival (HR=5.56, p=0.03) and a shorter overall survival (HR=5.11, p=0.04).ConclusionsIn general, the frequency of ESR1 amplification in breast cancer is low when measured by FISH in large sections. ESR1 gain and amplification in breast cancer may be associated with older age and poorer outcomes.

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Evaluation of the Oncomine Comprehensive Assay v3 panel for the detection of 1p/19q codeletion in oligodendroglial tumours

Journal of Clinical Pathology ◽

10.1136/jclinpath-2021-207876 ◽

2021 ◽

pp. jclinpath-2021-207876

Author(s):

Rola H Ali ◽

Mona Alateeqi ◽

Hiba Jama ◽

Noor Alrumaidhi ◽

Ali Alqallaf ◽

...

Keyword(s):

Copy Number ◽

In Situ Hybridisation ◽

Fluorescence In Situ Hybridisation ◽

Ion Torrent ◽

Robust Detection ◽

Targeted Next Generation Sequencing ◽

Formalin Fixed Paraffin ◽

Custom Made ◽

Formalin Fixed Paraffin Embedded ◽

Diffuse Gliomas

AimsAccurate assessment of 1p/19q codeletion status in diffuse gliomas is of paramount importance for diagnostic, prognostic and predictive purposes. While targeted next generation sequencing (NGS) has been widely implemented for glioma molecular profiling, its role in detecting structural chromosomal variants is less well established, requiring supplementary informatic tools for robust detection. Herein, we evaluated a commercially available amplicon-based targeted NGS panel (Oncomine Comprehensive Assay v3) for the detection of 1p/19q losses in glioma tissues using an Ion Torrent platform and the standard built-in NGS data analysis pipeline solely.MethodsUsing as little as 20 ng of DNA from formalin-fixed paraffin-embedded tissues, we analysed 25 previously characterised gliomas for multi-locus copy number losses (CNLs) on 1p and 19q, including 11 oligodendrogliomas (ODG) and 14 non-oligodendroglial (non-ODG) controls. Fluorescence in-situ hybridisation (FISH) was used as a reference standard.ResultsThe software confidently detected combined contiguous 1p/19q CNLs in 11/11 ODGs (100% sensitivity), using a copy number cut-off of ≤1.5 and a minimum of 10 amplicons covering the regions. Only partial non-specific losses were identified in non-ODGs (100% specificity). Copy number averages of ODG and non-ODG groups were significantly different (p<0.001). NGS was concordant with FISH and was superior to it in distinguishing partial from contiguous losses indicative of whole-arm chromosomal deletion.ConclusionsThis commercial NGS panel, along with the standard Ion Torrent algorithm, accurately detected 1p/19q losses in ODG samples, obviating the need for specialised custom-made informatic analyses. This can easily be incorporated into routine glioma workflow as an alternative to FISH.

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Comprehensive Profiling of Gene Copy Number Alterations Predicts Patient Prognosis in Resected Stages I–III Lung Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2019.00556 ◽

2019 ◽

Vol 9 ◽

Cited By ~ 3

Author(s):

Xiaohong Han ◽

Qiaoyun Tan ◽

Sheng Yang ◽

Junling Li ◽

Jianping Xu ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Copy Number ◽

Gene Copy Number ◽

Gene Copy ◽

Copy Number Alterations ◽

Patient Prognosis

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EGFR gene copy number alterations are not a useful screening tool for predicting EGFR mutation status in lung adenocarcinoma

Pathology ◽

10.1097/pat.0000000000000027 ◽

2014 ◽

Vol 46 (1) ◽

pp. 32-36

Author(s):

Prudence A. Russell ◽

Y.U. Yong ◽

D.O. Hongdo ◽

Timothy D. Clay ◽

Melissa M. Moore ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Copy Number ◽

Screening Tool ◽

Egfr Mutation ◽

Gene Copy Number ◽

Gene Copy ◽

Copy Number Alterations ◽

Mutation Status ◽

Egfr Gene

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Comprehensive Screening of Gene Copy Number Aberrations in Formalin-Fixed, Paraffin-Embedded Solid Tumors Using Molecular Inversion Probe–Based Single-Nucleotide Polymorphism Array

Journal of Molecular Diagnostics ◽

10.1016/j.jmoldx.2016.03.008 ◽

2016 ◽

Vol 18 (5) ◽

pp. 676-687 ◽

Cited By ~ 8

Author(s):

Rajesh R. Singh ◽

Meenakshi Mehrotra ◽

Hui Chen ◽

Alaa A. Almohammedsalim ◽

Ayesagul Sahin ◽

...

Keyword(s):

Copy Number ◽

Single Nucleotide Polymorphism Array ◽

Gene Copy Number ◽

Gene Copy ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Formalin Fixed Paraffin ◽

Formalin Fixed Paraffin Embedded ◽

Molecular Inversion Probe ◽

Formalin Fixed

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EGFR Gene Copy Number Gain is Related to High Tumor SUV and Frequent Relapse after Adjuvant Chemotherapy in Resected Lung Adenocarcinoma

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyq248 ◽

2011 ◽

Vol 41 (4) ◽

pp. 548-554 ◽

Cited By ~ 4

Author(s):

Y. Koh ◽

B. Jang ◽

Y. K. Jeon ◽

T. M. Kim ◽

S.-H. Lee ◽

...

Keyword(s):

Adjuvant Chemotherapy ◽

Lung Adenocarcinoma ◽

Copy Number ◽

Gene Copy Number ◽

Copy Number Gain ◽

Gene Copy ◽

Egfr Gene ◽

Gene Copy Number Gain ◽

Frequent Relapse

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Heterogeneous MET gene copy number and EGFR mutation elicit discordant responses to crizotinib between primary and metastatic lesions in erlotinib-resistant lung adenocarcinoma

Lung Cancer ◽

10.1016/j.lungcan.2018.03.016 ◽

2018 ◽

Vol 124 ◽

pp. 317-319 ◽

Cited By ~ 3

Author(s):

Katsuhiro Yoshimura ◽

Masato Karayama ◽

Yusuke Inoue ◽

Tomoaki Kahyo ◽

Naoki Inui ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Copy Number ◽

Egfr Mutation ◽

Gene Copy Number ◽

Gene Copy ◽

Metastatic Lesions

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Copy number variation of MDM2 and p53 genes in extracellular DNA as potential marker for lung adenocarcinoma diagnostics.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e23094 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e23094-e23094

Author(s):

Denis S. Kutilin ◽

Yaroslav S. Enin ◽

Dmitriy I. Vodolazhsky ◽

Vyacheslav A. Sustretov ◽

Tamara G. Ayrapetova ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Copy Number ◽

Gene Copy Number ◽

P53 Gene ◽

Extracellular Dna ◽

Gene Copy ◽

Mdm2 Gene ◽

Healthy Donors ◽

Number Variation ◽

P53 Genes

e23094 Background: Today, the problem of early diagnostics of lung cancer remains unsolved as every fourth patient diagnosed with the disease already has distant metastases. Studying gene copy number variation (CNV) in extracellular DNA in the blood plasma can become a basis for a new effective and low invasive method for predictive diagnostics and disease prognosis. The purpose of the study was to examine the copy number of the MDM2 and p53 genes in extracellular DNA of patients with metastatic and non-metastatic lung cancer and healthy donors. Methods: The blood samples of 30 patients with lung adenocarcinoma (collected before surgery) and 30 healthy donors (without cancer) were studied. Each sample was centrifuged to obtain blood plasma. DNA was isolated from plasma using a phenol-chloroform extraction method. Detection of relative copy number of the MDM2 and p53 genes (reference gene - GAPDH) was performed by RT-qPCR using CFX96 thermocycler (Bio-Rad, USA). The groups were compared by the Mann-Whitney U- test. Results: Reduction of the p53 gene copy number by 57% (p < 0.05), as well as increasing of the MDM2 gene copy number by 160% (p < 0.05), were found in the extracellular DNA of patients with lung adenocarcinoma compared with healthy donors. As a result, the ratio of copy number of pro-/anti-apoptotic genes p53:MDM2 in extracellular DNA of patients with lung adenocarcinoma (1:23 ratio) was different from that of healthy donors (1:4 ratio). The MDM2 gene copy number in extracellular DNA of patients with metastases exceeded the value in non-metastatic patients two-fold (p < 0.05). The p53 gene copy number in extracellular DNA of patients with metastatic and non-metastatic cancer did not differ significantly. Conclusions: CNV of the p53 and MDM2 genes in extracellular DNA has a high potential for low invasive diagnostics and prognosis of lung adenocarcinoma.

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