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Molecular alterations in gastric cancer with special reference to the early-onset subtype.

ABSTRACT: Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.

SUBMITTER: Skierucha M

PROVIDER: S-EPMC4768192 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Molecular alterations in gastric cancer with special reference to the early-onset subtype.

Skierucha Małgorzata M Milne Anya Na AN Offerhaus G Johan A GJ Polkowski Wojciech P WP Maciejewski Ryszard R Sitarz Robert R

World journal of gastroenterology 20160201 8

Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenet ...[more]

PMID: 26937134

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Project description:Gastric cancer is the fourth most common cause of cancer-related death. Currently, it is broadly accepted that the molecular complexity and heterogeneity of gastric cancer, both inter- and intra-tumor, display important barriers for finding specific biomarkers for the early detection and diagnosis of this malignancy. Early-onset gastric cancer is not as prevalent as conventional gastric carcinoma, but it is a preferable model for studying the genetic background, as young patients are less exposed to environmental factors, which influence cancer development. The main objective of this study was to reveal age-dependent genotypic characteristics of gastric cancer subtypes, as well as conduct mutation profiling for the most frequent alterations in gastric cancer development, using targeted next-generation sequencing technology. The study group included 53 patients, consisting of 18 patients with conventional gastric cancer and 35 with an early-onset subtype. The DNA of all index cases was used for next-generation sequencing, employing a panel of 94 genes and 284 single nucleotide polymorphisms (SNPs) (TruSight Cancer Panel, Illumina), which is characteristic for common and rare types of cancer. From among the 53 samples processed for sequencing, we were able to identify seven candidate genes (STK11, RET, FANCM, SLX4, WRN, MEN1, and KIT) and nine variants among them: one splice_acceptor, four synonymous, and four missense variants. These were selected for the age-dependent differentiation of gastric cancer subtypes. We found four variants with C-Score ≥ 10, as 10% of the most deleterious substitutions: rs1800862 (RET), rs10138997 (FANCM), rs2230009 (WRN), and rs2959656 (MEN1). We identified 36 different variants, among 24 different genes, which were the most frequent genetic alterations among study subjects. We found 16 different variants among the genes that were present in 100% of the total cohort: SDHB (rs2746462), ALK (rs1670283), XPC (rs2958057), RECQL4 (rs4925828; rs11342077, rs398010167; rs2721190), DDB2 (rs326212), MEN1 (rs540012), AIP (rs4930199), ATM (rs659243), HNF1A (rs1169305), BRCA2 (rs206075; rs169547), ERCC5 (rs9514066; rs9514067), and FANCI (rs7183618). The technology of next-generation sequencing is a useful tool for studying the development and progression of gastric carcinoma in a high-throughput way. Our study revealed that early-onset gastric cancer has a different mutation frequency profile in certain genes compared to conventional subtype.

Project description:Lung cancer is a leading cause of cancer-related mortality in many countries. Although recent advances in targeted therapy against driver oncogenes have significantly improved patient outcome, cure of this disease is still exceptional. Although tobacco is a known cause of lung cancer, not all smokers develop lung cancer, and conversely many patients, especially Asian female patients with lung cancer, are lifetime never-smokers. Therefore, efforts to understand the basis for different susceptibilities to lung cancer among individuals with different genetic, biologic, ethnic, and social backgrounds are important to help develop effective preventive measures. Lung cancer in never-smokers has many different characteristics to lung cancer in smokers, such as adenocarcinoma predominance and high frequency of epidermal growth factor receptor (EGFR) mutation yet low number of genetic changes. Epidemiologic studies suggest that East Asians are more susceptible to smoking-unrelated lung cancer but less susceptible to smoking-related lung cancer compared with Caucasians. Mutations in the EGFR gene are more common in Asian females and never-smokers. Our case-control study suggests that EGFR mutation occurs independent of smoking, and that the apparent low frequency of EGFR mutations in smokers may be the result of dilution by smoking-related lung cancer. The frequencies of three EGFR gene polymorphisms associated with increased protein expression are significantly different between East Asians and Caucasians, favoring lower protein expression in East Asians. Although these may be associated with preferred expression of the EGFR mutant allele, it is difficult to explain the frequent EGFR mutation in Asian patients. Genome wide association studies (GWAS) revealed several loci related to lung cancer susceptibility. In the future, GWAS may identify loci that are specifically related to EGFR-targeted carcinogenesis, leading to identification of carcinogens that induce EGFR mutations and effective prevention measures.

Dataset Information

Molecular alterations in gastric cancer with special reference to the early-onset subtype.

Publications

Molecular alterations in gastric cancer with special reference to the early-onset subtype.

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