Prognostic impact of gene copy number instability and tumor mutation burden in patients with resectable gastric cancer

Purpose Previous studies have highlighted the importance of an appropriate human epidermal growth factor receptor 2 (HER2) evaluation for the proper identification of patients eligible for treatment with anti-HER2 targeted therapies. Today, the relationship remains unclear between the level of HER2 amplification and the outcome of HER2-positive gastric cancer treated with first-line chemotherapy with trastuzumab. The aim of this study was to determine whether the level of HER2 gene amplification determined by the HER2/CEP17 ratio and HER2 gene copy number could significantly predict some benefit in overall survival and response to therapy in advanced gastric cancer treated with trastuzumab-based chemotherapy. Patients and Methods Ninety patients with metastatic gastric cancer treated with first-line trastuzumab-based chemotherapy were studied. The optimal cutoff values for HER2/CEP17 ratio and HER2 gene copy number (GCN) for discriminating positive results in terms of response and prolonged survival were determined using receiver operating characteristic curves analyses. Results In this study, a median HER2/CEP17 ratio of 6.11 (95% CI, 2.27 to 21.90) and a median HER2 gene copy number of 11.90 (95% CI, 3.30 to 43.80) were found. A mean HER2/CEP17 ratio of 4.7 was identified as the optimal cutoff value discriminating sensitive and refractory patients (P = .005). Similarly, the optimal cutoff for predicting survival longer than 12 months was 4.45 (P = .005), and for survival longer than 16 months was 5.15 (P = .004). For HER2 GCN, the optimal cutoff values were 9.4, 10.0, and 9.5, respectively (P = .02). Conclusion The level of HER2 gene amplification significantly predicts sensitivity to therapy and overall survival in advanced gastric cancer treated with trastuzumab-based chemotherapy.

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Prognostic impact of RUNX1 and ETV6 gene copy number on pediatric B-cell precursor acute lymphoblastic leukemia with or without hyperdiploidy

International Journal of Hematology ◽

10.1007/s12185-016-2034-y ◽

2016 ◽

Vol 104 (3) ◽

pp. 368-377 ◽

Cited By ~ 1

Author(s):

Nuket Yurur Kutlay ◽

Esra Pekpak ◽

Sule Altıner ◽

Talia Ileri ◽

Arzu Nedime Vicdan ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Copy Number ◽

Lymphoblastic Leukemia ◽

Gene Copy Number ◽

Gene Copy ◽

Prognostic Impact ◽

Cell Precursor

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SOX2 and FGFR1 gene copy number in surgically resected non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.7061 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 7061-7061

Author(s):

Luca Toschi ◽

Giovanna Finocchiaro ◽

Teresa T. Nguyen ◽

Margaret Skokan ◽

Laura Giordano ◽

...

Keyword(s):

Lung Cancer ◽

Gene Amplification ◽

Squamous Cell ◽

Cell Lung Cancer ◽

Copy Number ◽

Gene Copy Number ◽

Gene Copy ◽

Prognostic Impact ◽

Prognostic Relevance ◽

Fgfr1 Gene

7061 Background: SOX2 is a member of the SRY-related HMG-box family of transcription factors and has been shown to be frequently amplified and overexpressed in squamous cell lung cancer, with conflicting results regarding its prognostic relevance. Similarly, FGFR1, a transmembrane tyrosine kinase receptor belonging to the fibroblast growth factor receptor family, has been recently reported to be amplified in squamous cell lung carcinomas, suggesting a potential role for FGFR1 as a therapeutic target in NSCLC. Aim of the present study is to evaluate SOX2 and FGFR1 gene copy number in surgically resected NSCLCs, to investigate their prognostic relevance and their association with clinico-pathological characteristics. Methods: SOX2 and FGFR1 gene copy number was assessed by fluorescence in situ hybridization (FISH) in tissue microarray cores from 447 surgically resected NSCLCs. Each patient was given a score ranging from 1 to 6 according to increasing mean copy number per cell of each gene, with 6 indicating true gene amplification. Results: SOX2 and FGFR1 FISH was successfully performed in 445 patients (pts), which were grouped as + (score 5-6) and - (score 1-4). Using this scoring system 105 (23.6%) pts tested SOX2+, while 74 (16.6%) pts resulted FGFR1+. True gene amplification for SOX2 and FGFR1 was observed in 19 (4.3%) and 37 (8.3%) cases, respectively. SOX2+ and FGFR1+ status was significantly associated with squamous histology (p<.001). Additionally, SOX2+ pts had a significantly higher chance of being former/current smokers, male and FGFR1+. FGFR1 gene status had no prognostic impact in the whole population and in the squamous cell carcinoma subgroup. Conversely, SOX2+ pts had significantly longer overall survival compared with SOX2- pts (HR 0.68, p=.020). When restricting survival analysis to squamous cell histology, stage I-II SOX2+ pts had a significant survival advantage compared with SOX2- group (HR 0.38, p=.006), while no difference was observed in stage III-IV pts. Conclusions: Increased SOX2 and FGFR1 gene copy number is a common event in lung cancer pts with squamous cell histology. SOX2 gene gain is a favorable prognostic factor in surgically resected pts, particularly in early stage squamous cell cancers.

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Gene copy number gain of EGFR is a poor prognostic biomarker in gastric cancer: evaluation of 855 patients with bright-field dual in situ hybridization (DISH) method

Gastric Cancer ◽

10.1007/s10120-014-0449-9 ◽

2014 ◽

Vol 19 (1) ◽

pp. 63-73 ◽

Cited By ~ 15

Author(s):

Eiji Higaki ◽

Takeshi Kuwata ◽

Akiko Kawano Nagatsuma ◽

Yasunori Nishida ◽

Takahiro Kinoshita ◽

...

Keyword(s):

Gastric Cancer ◽

In Situ Hybridization ◽

Copy Number ◽

Prognostic Biomarker ◽

Gene Copy Number ◽

Copy Number Gain ◽

Gene Copy ◽

Bright Field ◽

Gene Copy Number Gain

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Integrated gene copy number and expression microarray analysis of gastric cancer highlights potential target genes

International Journal of Cancer ◽

10.1002/ijc.23574 ◽

2008 ◽

Vol 123 (4) ◽

pp. 817-825 ◽

Cited By ~ 48

Author(s):

Samuel Myllykangas ◽

Siina Junnila ◽

Arto Kokkola ◽

Reija Autio ◽

Ilari Scheinin ◽

...

Keyword(s):

Gastric Cancer ◽

Microarray Analysis ◽

Copy Number ◽

Target Genes ◽

Gene Copy Number ◽

Gene Copy ◽

Expression Microarray ◽

Potential Target

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The prognostic impact of high MET gene copy number on non-small cell lung cancer: A meta-analysis of eight studies.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e22049 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e22049-e22049

Author(s):

Anastasios Dimou ◽

Lemuel Non ◽

Kostas N Syrigos

Keyword(s):

Lung Cancer ◽

Primary Tumor ◽

Copy Number ◽

Fixed Effects ◽

Meta Analysis ◽

Gene Copy Number ◽

Gene Copy ◽

Prognostic Impact ◽

Fixed Effects Model ◽

Cross Sectional

e22049 Background: The risk stratification of NSCLC on the basis of molecular information is a key approach in the clinical management of patients with the disease. MET is the receptor for HGF and is present in the membrane of NSCLC cells. The most common genetic alteration associated with MET is the gene amplification. Methods: Two independent investigators applied parallel search strategies with the terms "MET" AND "lung cancer", "MET" AND "NSCLC", "met gene copy number" AND "prognosis" in PubMed through November 2012. We selected the studies that investigated the association of MET gene copy number with prognosis. A quality score that assessed the lab methods, the generalizability and the analysis, was assigned to each study that was finally included in the analysis. Results: Among 791 studies that were identified in the initial search, we retrieved 8 cross sectional studies on retrospective cohorts with adequate data regarding the prognostic impact of MET gene copy number on the survival of patients with NSCLC. Among the studies, 5 used FISH and the remaining 3 used RT PCR to assess the MET gene copy number in the primary tumor. All 8 studies used tissue from surgically resected specimens. MET gene copy number predicted worse overall survival when all studies were combined in a fixed effects model (HR=1.35, 95% CI 1.17-1.57). We calculated the I2 statistic to assess heterogeneity (I2=44%, p=0.09). There were four studies where a higher gene copy number predicted a better outcome and four in which the opposite was true. The Egger’s regression intercept showed no significant publication bias (p=0.38). Conclusions: Higher MET gene copy number in the primary tumor at the time of diagnosis predicts worse outcome in patients with NSCLC.

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