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 About Gastric Cancer (Biomarkers) Knowledgebase |
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Overview >>
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Gastric adenocarcinoma is the second leading cause of cancer death worldwide. It is particularly common in Asia and especially in
China and Japan. In Singapore it is the fourth most common cancer in males who have a 1:50 lifetime risk of developing gastric
cancer. Gastric cancer traditionally carries a poor prognosis with 79% of tumors diagnosed at stage IV and five year survival
less than 5%. Advanced gastric cancer is generally refractory to chemotherapy, which leads to poor prognosis. It has been shown
that if it is diagnosed at an early stage, it is a curable disease. Therefore it is most important to be able to identify
clinically useful early markers that can detect gastric cancer at an early stage.
Aims
This knowledgebase integrates available information from various sources to help
- find out the genes responsible for the formation of gastric cancers
- identify better diagnostic and prognostic biomarkers for gastric cancers
Gastric cancer prognostic factors used in clinical practice
- depth of invasion through the gastric wall
- the presence or absence of regional lymph node involvement
Molecular biomarkers for diagnosis and prognosis of gastric cancer
- Carcinoembryonic antigen (CEA)
- CA 125, CA 19-9, CA 72-4 and alpha-fetoprotein (useful for prognosis)
- Serum pepsinogen I (predictor of stomach cancer)
- proteases (pepsinogen C, plasminogen activator, matrix metalloproteinases and their inhibitors)
- cadherins, mucins and CD44 splicing variants (related to invasion/metastasis and extracellular matrix adhesion and
degradation)
Genetic changes associated with gastric cancer oncogenesis
- genetic instability represented by microsatellite instability (CA repeats)
- re-activation of telomerase activity
- inactivation of tumour suppressor genes
- activation of oncogenes
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Major classes of genes associated with the progression of gastric cancer
| Genes related to cell cycle regulation |
Genes related to growth signal transduction |
Cyclins
(cyclin E was found to serve as a useful prognostic indicator for gastric cancer progression)
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Epithelial growth factor (EGF)
transforming growth factor α
(TGF-α) and TGF-β
They serve as autocrine growth factors and associated with gastric cancer progression.
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p53
(Mutated p53 isoforms can generate an autoimmune response. Serum anti-p53 antibodies can serve as a diagnostic and
prognostic marker in gastric cancer patients.
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Vascular endothelial growth factor (VEGF)
independent prognostic marker in gastric cancer patients. Together with platelet-derived endothelial cell growth
factors (PD-ECGFs), it has become a novel gastric cancer prognostic marker.
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Cdks
(Regulators cyclin-dependent kinases (CDKs 1, 2, 4 and 6) and their inhibitors (p15, p16, p21waf1/cip1
and p27kip1) are also expressed in gastric cancer tissues.
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Protein tyrosine kinases (PTKs)
Receptors for the growth factors and they are key molecules in signaling pathways such as
phosphoinositide 3-kinase, 70 kDa S6 kinase, mitogen-activated protein kinase (MAPK), phospholipase C-gamma, and the
Jak/STAT pathways. PTKs are good candidates to examine genes within a biochemical pathway, or groups of genes with
similar functions and under differential regulation (i.e. gene families), as they are involved in the growth regulation
of normal cells, as well as the oncogenesis of cancer cells.
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| Oncogenic receptor PTKs which have been studied in gastric cancers
| c-Met [hepatocyte growth factor (HGF) receptor] |
Amplification of the c-met gene has been demonstrated in scirrhous-type gastric cancers.
c-met is overexpressed or amplified in advanced gastric cancers of both the well-differentiated
and poorly differentiated types. c-Met immunoreactivity was observed at a high positive rate (40–80%).
Simultaneous detection of c-met gene expression and c-Met protein immunoreactivity has also been
noted in the majority of gastric cancer specimens.
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| k-Sam (fibroblast growth factor receptor 2) |
k-sam activation is more specific to the poorly differentiated variants. k-Sam protein was detected in ~50%
of poorly differentiated gastric cancers, and not in differentiated-type gastric cancers.
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| ErbB2/Neu [EGF receptor (EGFR) 2] |
By contrast, amplification of the erbB2/neu gene is often detected in well-differentiated gastric carcinomas. EGFR
antibodies was demonstrated in 30–50% of human gastric cancers and correlated with a poor prognosis. ErbB2
immunoreactivity was seen in 10–50% of all human gastric cancers, and was more common in well-differentiated-type
gastric cancers. The expression of the ErbB2 protein is a significant independent prognostic factor for long-term
survival, disease recurrence and lymph-node metastasis Targeting erbB2-expressing cells with conjugated
immunoliposomes containing chemotherapeutic reagents might prove useful.
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| Src |
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| VEGF receptor (KDR) |
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| Hek5 (Erk) |
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| Abl, nerve growth factor receptor |
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| (TrkA) |
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| Stem cell factor receptor (c-Kit) |
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