Causes of early-onset gastric cancer occurring around 40s identified!
Increased research on diagnosis and therapy of early-onset gastric cancer anticipated.
▲ Professor Sang-Won Lee (left) and Ph.D. student Dong-Gi Mun (right)
Professor Sang-Won Lee’s research team of the Center for Proteogenome Research at Korea University has identified the causes of early-onset gastric cancer through a proteogenomic study conducted with early-onset gastric cancer patients.
* Early-onset gastric cancer: Gastric cancer occurring in patients in their 40s or younger.
* Proteogenomics: Comprehensive analytical research on the extensive genome and proteome using patients’ disease tissue samples.
Professor Sang-Won Lee’s research team of the Center for Proteogenome Research at Korea University, supported by the Korea Post-Genome Project of the Ministry of Science and ICT (MSIT), published the research result in Cancer Cell (IF=22.84), the top academic journal in the field of cancer research, in the online edition of January 14 (morning, January 15, KST).
* Title of Article: Proteogenomic Characterization of Human Early-Onset Gastric Cancer
* Author Information: Daehee Hwang (Professor in the Department of New Biology, DGIST), Sang-Won Lee (Professor in the Department of Chemistry, Korea University), Sanghyuk Lee (Department of Life Science, Ewha Womans University), Eunok Paek (Department of Computer Science and Engineering, Hanyang University), Hark Kyun Kim (National Cancer Center), Eun Gyeong Yang (Biomedical Research Institute, Korea Institute of Science and Technology) (The aforementioned are corresponding authors with equal contribution.), Dong-Gi Mun (Ph.D. student in the Department of Chemistry, Korea University), Jinhyuk Bhin (Ph.D. in the Department of New Biology, DGIST), Sangok Kim (Ph.D. student in the Department of Life Science, Ewha Womans University), Hyunwoo Kim (Ph.D. in the Department of Computer Science and Engineering, Hanyang University), Jae Hun Jung (Ph.D. student in the Department of Applied Chemistry, Kyung Hee University), and others.
Gastric cancer, a common cancer worldwide, is a fatal disease responsible for over 700,000 deaths a year and its mortality rate is the third highest for cancers after lung cancer and liver cancer. Gastric cancer rarely occurs before the 30s, and its onset is usually between the 40s and 70s as its incidence rate increases with the age. Early-onset gastric cancer refers to gastric cancer of which the onset is around the 40s.
In Korea, the proportion of early-onset gastric cancer patients is about 15% of all gastric cancer patients, a figure higher than that of other countries. Early-onset gastric cancer is caused more by genetic factors than environmental factors. The risk of onset is higher in those who have a family history, and higher in women than in men. Early-onset gastric cancer occurring in young populations is often of the diffuse type, which is difficult to treat since it is diagnosed late, progresses rapidly, and is highly metastatic. The causes of early-onset gastric cancer had not been previously identified.
* The diffuse type refers to a type of gastric cancer where the cancer tissues are diffused under the gastric mucosa, rather than existing as a cancerous mass. Therefore, this diffuse type gives no signs, is thus difficult to diagnose by endoscopy, and has a high mortality rate.
Through joint research with many Korean basic science researchers and gastric cancer clinical researchers, the research group performed a proteomic analysis of the cancer tissues and surrounding normal tissues obtained from 80 early-onset gastric cancer patients over 5 years using a method known as next generation sequencing (NGS). As a result, the research group was able to identify the mutated genes correlated with the onset of early-onset gastric cancer (CDH1, ARID1A, RHOA) from about 7,000 somatic mutated genes, and showed that these genes are involved in the signaling pathways significantly related to the onset of early-onset gastric cancer. In addition, the genetic analysis of the tissues from the 80 gastric cancer patients showed that the gastric cancer is divided into four subtypes, each exhibiting different therapeutic responses. The research group found that the four gastric cancer subtypes each have different cell signaling pathways, and this discovery enables more precisely targeted searches for the causes of gastric cancer.
Professor Sang-Won Lee, who participated in the research, explained its significance: “With the incidence rate of early-onset gastric cancer increasing in Korea, especially in the female population, this study identified the precise genetic causes of early-onset gastric cancer and is expected to trigger active research into the development of precise diagnoses and improved gastric cancer therapy.”
1. Cancer Cell
ㅇ An internationally authoritative academic journal in the field of cancer research
※ Impact factor: 22.84
ㅇ A convergence technology integrating genome-proteome information technology. Proteogenomics is a multi-omics technology for discovering and identifying biomolecular signatures significant to diseases by systematically integrating genomic and proteomic information.
3. Early-onset gastric cancer
ㅇ Gastric cancer occurring in young populations in their 40s or younger. Early-onset gastric cancer accounts for 15% of the gastric cancers in Korea. The incidence rate is particularly high in young women. The incidence rate of early-onset gastric cancer is also increasing in the US. Early-onset gastric cancer is life threatening because it is typically of the diffuse type with extensively diffused small-sized cancer masses and thus difficult to discover and highly metastatic.
4. Cancer subtypes
ㅇCancers are divided into subtypes according to the characteristics of their cancer cells, namely their microscopic morphology, the specific substances contained within them, or the specific changes found in their DNA. Given the additional results available from proteogenomics, cancers can now be divided into more precise subtypes by integrating the changes found in specific genomes and specific proteomes.
5. RNA and mRNA
ㅇ RNA: Genetic molecules existing in the cell nucleus and cytoplasm and involved in protein synthesis.
ㅇ mRNA: A specific type of RNA that transfers the genetic information from DNA to ribosomes where proteins are synthesized.
6. Proteome: The entire set of proteins existing in cells.
ㅇ Studies of the genome, transcriptome, proteome, metabolome, epigenome, and lipidome in our cells are respectively called “-omics,“ and the studies combining at least two “-omics“ are called “multi-omics.“
8. Biomolecular signature
ㅇ The collection of gene and protein attributes, such as DNA/RNA mutations, protein sequence mutations, protein expression and the modifications, that allow molecular measurement of disease states.
9. Diffuse type and intestinal type
ㅇ About half of the gastric cancers found in Korean patients are classified microscopically as the diffuse type in which the cancer cells, rather than being clustered together, are extensively diffused. By contrast, the cancer cells of the intestinal type are clustered together and the cancer tissues can be identified microscopically.
■Gene mutations related to the disease were identified in the genome of the early-onset gastric cancer patients.
Figure 1. Proteogenomic analysis of nonsynonymous somatic mutation
A) Significant mutated genes found in the early-onset gastric cancer patients (CDH1, TP53, BANP, MUC5B, RHOA, ARID1A).
B) CDH1, ARID1A, and RHOA showing a high correlation with phosphorylation.
■The correlation of the proteogenome related to early-onset gastric cancer with cancer onset was analyzed.
Figure 2. Quantitative analysis of mRNA-proteome correlation
A) The analysis of the correlation between mRNA and proteome showed a 34.3% correlation.
B) The analysis of the functions of the genes having a low correlation and a high correlation showed that the genes are involved in different signaling pathways.
■The analysis of the proteogenome of the 80 early-onset gastric cancer patients showed that the gastric cancer is divided into four subtypes.
Figure 3. Subtypes of early-onset gastric cancer identified by proteogenomic analysis
■The genomic analysis of the four subtypes of early-onset gastric cancer identified distinct signaling pathways.
Figure 4. Major signaling pathways of the four identified subtypes
A) Analysis of the representative signaling pathways of the four subtypes. The signaling pathways provide information essential to the definition of the molecular levels of early-onset gastric cancer.
B) The representative immune response signaling pathway of subtype 2.
C) The representative cell migration signaling pathway of subtype 4.