Utility of a panel of gene mutations and amplifications for estimation of prognosis in patients with gastric cancer
Authors:
L. Benešová 1; P. Mináriková 2; T. Hálková 1; B. Belšánová 1; Š. Suchánek 2; F. Bělina 3; L. Dušek 4; J. Jarkovský 4; M. Zavoral 2; M. Minárik 1,2
Authors‘ workplace:
Genomac výzkumný ústav, s. r. o., Centrum aplikované genomiky solidních nádorů, Praha
1; Interní klinika 1. LF UK a ÚVN – VFN Praha
2; Chirurgická klinika 2. LF UK a ÚVN – VFN Praha
3; Institut biostatistiky a analýz, LF a PřF MU, Brno
4
Published in:
Gastroent Hepatol 2016; 70(3): 244-251
Category:
Gastrointestinal Oncology: Original Article
doi:
https://doi.org/10.14735/amgh2016244
Overview
Although the 5-year survival of patients with gastric cancer has improved only marginally over the past 20 years, some specific subgroups of patients survive significantly longer. Finding molecular markers for individualized prognosis has therefore become a major issue. The aim of this project was to profile somatic point mutations and gene amplifications to map their frequency in Czech gastric cancer patients and to identify potential prognostic markers.
Material and methods:
The group included 70 patients with histologically confirmed gastric cancer. FFPE samples were obtained from either endoscopic tissue biopsies or resections from patients undergoing surgery. The study included searching for somatic mutations in KRAS, BRAF, PIK3CA, EGFR, CTNNB1, TP53 and APC, and gene amplifications in a panel of 29 genes, including common (proto)oncogenes and tumor suppressors implicated in tumor initiation and progression. The results were correlated with clinical data including stage, localization, and histopathological subtype of carcinoma, as well as patient survival. Correlation with survival was evaluated by using the Kaplan-Meier method. The relative hazard ratios (HRs) were tested by means of multivariate analysis using Cox proportional hazards model.
Results:
Frequencies of aberrations were lower compared with those in the global gastric cancer population. Cluster analysis identified a group of profiles that correlated with poor survival (HR = 7.36; 95% CI 1.34– 40.4; p = 0.022). Analysis within this group characterized by amplifications of PDGFRB, ERBB2, RET, EGFR, CCND1 and CDKN1B (p27/Kip1) revealed an increased HR for patients with amplification of at least two of these genes (HR = 4.66; 95% CI 1.5–14.43; p = 0.008).
Conclusion:
In this study, the frequencies of somatic mutations and gene amplifications in Czech patients with gastric cancer were determined. Furthermore, a group of gene amplifications that could be used to determine prognosis was identified. The results should be validated in an expanded group of patients, possibly by combining typical smaller sample sets from multiple centers. If confirmed, tests employing these markers could have potential for arriving at rational decisions about patient treatment, resulting in an overall improvement in the survival of patients with gastric cancer.
Key words:
gastric cancer – gene amplifications – point mutations – cluster analysis
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for biomedical papers.
Submitted:
3. 5. 2016
Accepted:
9. 6. 2016
Sources
1. Ústav zdravotnických informací a statistiky ČR. Národní onkologický registr (NOR). [online]. Dostupné z: www.uzis.cz/ registry-nzis/ nor.
2. Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136(5): E359–E386. doi: 10.1002/ijc.29210.
3. Parsonnet J, Friedman GD, Vandersteen DP et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 1991; 325(16): 1127– 1131.
4. Hu B, El Hajj N, Sittler S et al. Gastric cancer: classification, histology and application of molecular pathology. J Gastrointest Oncol 2012; 3(3): 251– 261. doi: 10.3978/ j.issn.2078-6891.2012.021.
5. Yuasa Y. Control of gut differentiation and intestinal-type gastric carcinogenesis. Nat Rev Cancer 2003; 3(8): 592– 600.
6. Deng N, Goh LK, Wang H et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 2012; 61(5): 673– 684. doi: 10.1136/ gutjnl-2011-301839.
7. Cristescu R, Lee J, Nebozhyn M et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 2015; 21(5): 449– 456. doi: 10.1038/ nm.3850
8. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell2010; 141(7): 1117– 1134. doi: 10.1016/ j.cell2010.06.011.
9. Bang YJ, Van Cutsem E, Feyereislova A et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376(9742): 687– 697. doi: 10.1016/ S0140-6736 (10)61121-X.
10. Minarik M, Minarikova L, Hrabikova M et al. Application of cycling gradient capillary electrophoresis to detection of APC, K-ras, and DCC point mutations in patients with sporadic colorectal tumors. Electrophoresis 2004; 25(7– 8): 1016– 1021.
11. Forbes SA, Bindal N, Bamford S et al. COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in cancer. Nucleic Acids Res 2011; 39: D945– D950. doi: 10.1093/ nar/ gkq929.
12. Gajria D, Chandarlapaty S. HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther 2011; 11(2): 263– 275. doi: 10.1586/ era.10.226.
13. Ryška A, Hejduk K, Fabián P et al. Korekce populačních predikcí počtu HER-2/ neupozitivních karcinomů prsu u žen na základě analýzy dat histologického registru karcinomů prsu (MAGISTER). XXXVI. Brno: Brněnské onkologické dny a XX. Konference pro sestry a laboranty, 19.– 21. duben 2012. Abstrakt 013.
14. Jørgensen JT, Hersom M. HER2 as a prognostic marker in gastric cancer – a systematic analysis of data from the literature. J Cancer 2012; 3: 137– 144. doi: 10.7150/ jca.4090.
15. Ooi A, Oyama T, Nakamura R et al. Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. Mod Pathol 2015; 28(6): 861– 871. doi: 10.1038/ modpathol.2015.33.
16. Morishita A, Gong J, Masaki T. Targeting receptor tyrosine kinases in gastric cancer. World J Gastroenterol 2014; 20(16): 4536– 4545. doi: 10.3748/ wjg.v20.i16.4536.
17. Dai Y. Platelet-derived growth factor receptor tyrosine kinase inhibitors: a review of the recent patent literature. Expert Opin Ther Pat 2010; 20(7): 885– 897. doi: 10.1517/ 13543776.2010.493559.
18. Shaw AT, Hsu PP, Awad MM et al. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer 2013; 13(11): 772– 787. doi: 10.1038/ nrc3612.
19. Musgrove EA, Caldon CE, Barraclough Jet al. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 2011; 11(8): 558– 572. doi: 10.1038/ nrc3090.
20. Nickeleit I, Zender S, Kossatz U et al. p27kip1: a target for tumor therapies? Cell Div 2007; 2: 13.
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