Gastroenterologie
a hepatologie

Utility of a panel of gene mutations and amplifications for estimation of prognosis in patients with gastric cancer

Lucie Benešová¹, Petra Mináriková ^{Orcid.org  2}, Tereza Hálková¹, Barbora Belšánová ^{Orcid.org  3}, Štěpán Suchánek ^{Orcid.org  4}, František Bělina ^{Orcid.org  5}, Ladislav Dušek ^{Orcid.org  6,7}, Jaroslav Jarkovský⁸, Miroslav Zavoral ^{Orcid.org  4}, Marek Minárik ^{Orcid.org  1,4}

+ Affiliation
¹ Genomac výzkumný ústav, s. r. o., Centrum aplikované genomiky solidních nádorů, Praha
² Interní klinika 1. LF UK a ÚVN – VFN, Praha
³ Genomac International, s. r. o, Centrum aplikované genomiky solidních nádorů, Praha
⁴ Interní klinika 1. LF UK a ÚVN – VFN Praha
⁵ Chirurgická klinika 2. LF UK a ÚVN – VFN Praha
⁶ Ústav zdravotnických informací a statistiky ČR, Praha
⁷ Institut biostatistiky a analýz LF MU, Brno
⁸ Institut biostatistiky a analýz, LF a PřF MU, Brno

Summary

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.

Keywords

point mutations, gene amplifications, gastric cancer, cluster analysis

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