pubmed.ncbi.nlm.nih.gov

Gastric cancer-molecular and clinical dimensions - PubMed

Review

Gastric cancer-molecular and clinical dimensions

Roopma Wadhwa et al. Nat Rev Clin Oncol. 2013 Nov.

Abstract

Gastric cancer imposes a considerable health burden around the globe despite its declining incidence. The disease is often diagnosed in advanced stages and is associated with a poor prognosis for patients. An in-depth understanding of the molecular underpinnings of gastric cancer has lagged behind many other cancers of similar incidence and morbidity, owing to our limited knowledge of germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets). A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1 and MET) alterations are emerging and some are being pursued clinically. Novel somatic gene targets (ARID1A, FAT4, MLL and KMT2C) have also been identified and are of interest. Variations in the therapeutic approaches dependent on geographical region are evident for localized gastric cancer-differences that are driven by preferences for the adjuvant strategies and the extent of surgery coupled with philosophical divides. However, greater uniformity in approach has been noted in the metastatic cancer setting, an incurable condition. Having realized only modest successes, momentum is building for carrying out more phase III comparative trials, with some using biomarker-based patient selection strategies. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here, we review representative molecular and clinical dimensions of gastric cancer.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflict to disclose.

Figures

Figure 1
Figure 1. Molecular carcinogenesis of Helicobacter pylori in gastric cancer

H. pylori and its several virulence factors, such as CagA, interact with gastric epithelial cells to induce chronic inflammation, mucosal damage and multiple alterations in gene expression and genetic and epigenetic changes, eventually leading to gastric carcinogenesis. Abbreviations: COX-2, cyclooxygenase-2; CpG island, areas of cytosine and guanine repeats; LPS, lipopolysaccharide; RNS, reactive nitrogen species; ROS, reactive oxygen species; VacA, vacuolating cytoxin A.

Figure 2
Figure 2. microRNA targets and functions in gastric cancer

Some oncomiRs are overexpressed in tumours and inhibit tumour suppressors, leading to cell proliferation, invasion and reduced apoptosis. By contrast, tsmiRs normally target oncogenes that are downregulated in tumours and facilitate the activity of their target oncogenes. Abbreviations: EMT, epithelial–mesenchymal transition; miR, microRNA; oncomiRs, oncogenic microRNAs; tsmiRs, tumour-suppressor microRNAs.

Figure 3
Figure 3. Targeted therapy in gastric cancer

Percentages signify the overall molecular characteristics in the disease: FGFR2 amplification (9%), VEGF/VEGFR overexpression (36–40%), EGFR amplification and overexpression (27–44%), HER-2 amplification and overexpression (7–34%), c-MET amplification (10–15%), kRAS mutation (2–20%), Raf mutation (0–3%), PI3K mutation (4–36%), phospho-Akt expression (29–86%), phospho-mTOR expression (60–88%), PTCH1 overexpression (16%), SMO overexpression (12%) and HER3 mutations (10%, not shown). *No clinical trials of these agents have yet been reported in gastric cancer. ‡No known numbers or percentages for these genes and pathways. Abbreviations: EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GLI, glioma-associated oncogene family zinc finger 1; HDAC, histone deacetylase; HER, human epidermal growth factor receptor; HGF, hepatocyte growth factor; Hh, Hedgehog; IGFR, insulin-like growth factor receptor; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; Ptch-1, protein patched homolog 1; Smo, smoothened; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Similar articles

Cited by

References

    1. Jemal A, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. - PubMed
    1. Bertuccio P, et al. Recent patterns in gastric cancer: a global overview. International journal of cancer. 2009;125:666–673. - PubMed
    1. Chen J, Bu XL, Wang QY, Hu PJ, Chen MH. Decreasing seroprevalence of Helicobacter pylori infection during 1993–2003 in Guangzhou, southern China. Helicobacter. 2007;12:164–169. - PubMed
    1. Kawakami E, Machado RS, Ogata SK, Langner M. Decrease in prevalence of Helicobacter pylori infection during a 10-year period in Brazilian children. Arq Gastroenterol. 2008;45:147–151. - PubMed
    1. Tkachenko MA, et al. Dramatic changes in the prevalence of Helicobacter pylori infection during childhood: a 10-year follow-up study in Russia. J Pediatr Gastroenterol Nutr. 2007;45:428–432. - PubMed

Publication types

MeSH terms

Substances