The stomach cancer proteome

Stomach cancer, also termed gastric cancer or gastric carcinoma, is the fifth most common cancer in the world and the fourth leading cause of cancer-related mortality. The global 5-year survival rate is 20%. Stomach cancer occurs most often in men over the age of 40 and is common in Japan, Chile, and Iceland. The main risk factor for developing this type of cancer is Helicobacter pylori infection. Other risk factors include a history of adenomatous gastric polyps, chronic atrophic gastritis or pernicious anemia as well as smoking and consumption of salted, cured or smoked foods. A genetic component is present in approximately 10% of all cases.

Stomach cancer originates from the mucosa of the stomach and consist of adenocarcinoma of varying architecture, grade of differentiation and mucin content. Clinical classification into different stages is necessary for determining the most suitable therapy. Tumors restricted to the stomach and with no metastasis are treated with a combination of surgery, chemotherapy, radiotherapy and/or target therapy. Metastasized tumors are not curable and associated with more dismal prognosis.

Here, we explore the stomach cancer proteome using TCGA transcriptomics data and antibody-based protein data. 299 genes are suggested as prognostic based on transcriptomics data from 354 patients; 171 genes are associated with unfavorable prognosis and 128 genes are associated with favorable prognosis.

TCGA data analysis

In this metadata study, we used data from TCGA where transcriptomics data was available from 354 patients in total, 125 females and 229 males. Most patients (208 patients) were still alive at the time of data collection. The stage distribution was stage i) 48 patients, stage ii) 110 patients, stage iii) 146 patients, stage iv) 35 patients and 15 patients with missing stage information.

Unfavorable prognostic genes in stomach cancer

For unfavorable genes, higher relative expression levels at diagnosis give significantly lower overall survival for the patients. There are 171 genes associated with an unfavorable prognosis in stomach cancer. In Table 1, the top 20 most significant genes related to an unfavorable prognosis are listed.

AK4 is a gene associated with an unfavorable prognosis in stomach cancer. The best separation is achieved by an expression cutoff at 6.1 fpkm which divides the patients into two groups with 25% 5-year survival for patients with high expression versus 41% for patients with low expression, p-value: 4.87e-4. Immunohistochemical staining using an antibody targeting AK4 (HPA049461) shows a differential expression pattern in stomach cancer samples.

p<0.001
AK4 - survival analysis
AK4 - high expression
AK4 - low expression

Table 1. The 20 genes with highest significance associated with an unfavorable prognosis in stomach cancer.

Gene	Description	Predicted location	mRNA (cancer)	p-value
OPN1SW	opsin 1, short wave sensitive	Membrane	1.4	5.98e-8
ITGAV	integrin subunit alpha V	Membrane, Intracellular	20.4	1.05e-6
ZNF883	zinc finger protein 883	Intracellular	1.3	2.89e-6
SERPINE1	serpin family E member 1	Secreted	37.4	3.27e-6
CGB5	chorionic gonadotropin subunit beta 5	Secreted	1.7	1.18e-5
CAST	calpastatin	Intracellular	17.3	1.20e-5
NRP1	neuropilin 1	Secreted, Membrane, Intracellular	7.3	1.22e-5
AKR1B1	aldo-keto reductase family 1 member B	Intracellular	12.0	2.44e-5
RNF152	ring finger protein 152	Membrane, Intracellular	1.3	2.85e-5
SLC2A3	solute carrier family 2 member 3	Membrane	7.4	2.89e-5
CYTL1	cytokine like 1	Secreted	1.2	3.00e-5
DUSP1	dual specificity phosphatase 1	Intracellular	106.2	3.11e-5
MATN3	matrilin 3	Secreted	2.3	4.74e-5
GJA1	gap junction protein alpha 1	Membrane	18.3	4.99e-5
CCPG1	cell cycle progression 1	Membrane, Intracellular	2.7	5.02e-5
PPP1R3B	protein phosphatase 1 regulatory subunit 3B	Intracellular	7.8	6.03e-5
GPR176	G protein-coupled receptor 176	Membrane	2.0	6.84e-5
RNF144A	ring finger protein 144A	Membrane, Intracellular	3.4	7.32e-5
CD109	CD109 molecule	Membrane	2.7	7.96e-5
SPRED1	sprouty related EVH1 domain containing 1	Membrane, Intracellular	6.8	8.29e-5
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Favorable prognostic genes in stomach cancer

For favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 128 genes associated with a favorable prognosis in stomach cancer. In Table 2, the top 20 most significant genes related to a favorable prognosis are listed.

CLDN7 is a gene associated with a favorable prognosis in stomach cancer. The best separation is achieved by an expression cutoff at 48.5 fpkm which divides the patients into two groups with 42% 5-year survival for patients with high expression versus 19% for patients with low expression, p-value: 4.09e-4. Immunohistochemical staining using an antibody targeting CLDN7 (HPA014703) shows a differential expression pattern in stomach cancer samples.

p<0.001
CLDN7 - survival analysis
CLDN7 - high expression
CLDN7 - low expression

ANAPC2 is another gene associated with a favorable prognosis in stomach cancer. The best separation is achieved by an expression cutoff at 5.4 fpkm which divides the patients into two groups with 42% 5-year survival for patients with high expression versus 11% for patients with low expression, p-value: 2.87e-4. Immunohistochemical staining using an antibody targeting ANAPC2 (CAB018692) shows a differential expression pattern in stomach cancer samples.

p<0.001
ANAPC2 - survival analysis
ANAPC2 - high expression
ANAPC2 - low expression

Table 2. The 20 genes with highest significance associated with a favorable prognosis in stomach cancer.

Gene	Description	Predicted location	mRNA (cancer)	p-value
TIMM29	translocase of inner mitochondrial membrane 29	Intracellular	7.1	7.03e-7
CHAF1A	chromatin assembly factor 1 subunit A	Intracellular	6.5	4.15e-6
SLC52A3	solute carrier family 52 member 3	Membrane	8.7	5.51e-6
FAM83G	family with sequence similarity 83 member G	Intracellular	6.3	7.58e-6
TMEM259	transmembrane protein 259	Membrane, Intracellular	29.5	8.92e-6
BICDL1	BICD family like cargo adaptor 1	Intracellular	4.2	1.21e-5
PRR15L	proline rich 15 like	Intracellular	59.3	1.69e-5
TNFAIP2	TNF alpha induced protein 2	Intracellular	29.1	2.79e-5
MISP3	MISP family member 3	Intracellular	9.7	3.11e-5
C3orf62	chromosome 3 open reading frame 62	Intracellular	1.7	3.29e-5
EFNA4	ephrin A4	Secreted, Membrane	11.7	3.60e-5
FAAH	fatty acid amide hydrolase	Membrane	7.0	3.63e-5
TTC9C	tetratricopeptide repeat domain 9C	Intracellular	6.6	4.15e-5
PICK1	protein interacting with PRKCA 1	Intracellular	4.9	5.26e-5
MAP2K2	mitogen-activated protein kinase kinase 2	Intracellular	22.6	5.43e-5
MEN1	menin 1	Intracellular	11.4	6.31e-5
TAF5	TATA-box binding protein associated factor 5	Intracellular	2.3	7.39e-5
DPP9	dipeptidyl peptidase 9	Intracellular	13.6	7.72e-5
TSEN54	tRNA splicing endonuclease subunit 54	Intracellular	9.4	7.78e-5
NCLN	nicalin	Membrane, Intracellular	32.7	8.82e-5
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The stomach cancer transcriptome

The transcriptome analysis shows that 73% (n=14794) of all human genes (n=20162) are expressed in stomach cancer. All genes were classified according to the stomach cancer-specific expression into one of five different categories, based on the ratio between mRNA levels in stomach cancer compared to the mRNA levels in the other 16 analyzed cancer tissues.

Figure 1. The distribution of all genes across the five categories based on transcript abundance in stomach cancer as well as in all other cancer tissues.

211 genes show some level of elevated expression in stomach cancer compared to other cancers (Figure 1). The elevated category is further subdivided into three categories as shown in Table 3.

Table 3. The number of genes in the subdivided categories of elevated expression in stomach cancer.

		Distribution in the 17 cancers
		Detected in single	Detected in some	Detected in many	Detected in all	Total
Specificity	Cancer enriched	5	7	1	0	13
	Group enriched	0	41	70	2	113
	Cancer enhanced	14	28	36	7	85
	Total	19	76	107	9	211

Additional information

Stomach cancer is commonly diagnosed based on biopsy obtained through gastroscopy. Gastroscopy entails the insertion of a fiber optic camera into the stomach to examine the gastric mucosa and more easily collect biopsy samples. In Stage 0, the cancer is limited to the inner lining of the stomach and this early stage is treatable by endoscopic mucosal resection, or by gastrectomy and lymphadenectomy without a need for chemotherapy or radiation. Stage I tumors penetrate to the second or third layers of the stomach (IA) or to the second layer and nearby lymph nodes (IB). Stage IA is treated by surgery and Stage IB may in addition to surgery, be treated with chemotherapy (5-fluorouracil) and radiation therapy. In Stage II, the tumor penetrates to the second layer of the stomach and involve more distant lymph nodes. Patients with stage II receive the same treatment as for Stage I tumors, sometimes with the addition of neoadjuvant chemotherapy. Stage III is characterized by penetration to the third layer and metastases in more distant lymph nodes and is treated in the same way as stage. Stage IV involved spread to adjacent tissues or metastasis to distant organs. A cure is very rarely possible at this stage and treatment to prolong life or reduce symptoms may be implemented, including laser treatment, chemotherapy, surgery, and/or stents to keep the digestive tract open.

There are four major histologic types of stomach cancers: tubular, papillary, mucinous and poorly cohesive carcinoma (including signet-ring cell carcinomas). Tubular and papillary adenocarcinomas are the most common histological type of early stomach cancer. The tubular type is composed of irregular glands that form fused or branched tubules and papillary carcinoma are characterized by epithelial projections. Mucinous adenocarcinoma accounts for 10% of gastric cancers and typically shows extracellular pools of mucin. Signet-ring cell carcinomas consist of mucin containing cells. In immunohistochemical assays 50% of stomach cancers express cytokeratin 7 and 75% are positive for cytokeratin 20. Stomach cancer is discriminated from metastatic colorectal cancer by showing SATB2 negative immunohistochemical results.

Relevant links and publications

Uhlen M et al., A pathology atlas of the human cancer transcriptome. Science. (2017)
PubMed: 28818916 DOI: 10.1126/science.aan2507

Cancer Genome Atlas Research Network et al., The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. (2013)
PubMed: 24071849 DOI: 10.1038/ng.2764

Uhlén M et al., Tissue-based map of the human proteome. Science (2015)
PubMed: 25613900 DOI: 10.1126/science.1260419

Gremel G et al., The human gastrointestinal tract-specific transcriptome and proteome as defined by RNA sequencing and antibody-based profiling. J Gastroenterol. (2015)
PubMed: 24789573 DOI: 10.1007/s00535-014-0958-7

Histology dictionary - Stomach cancer