A group of scientists in China combined their classic “wet lab” skills with bioinformatic power to understand how a protein involved in blood coagulation plays a key role in the development of stomach adenocarcinoma.
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With an estimated survival rate of 35.7% five years post diagnosis, gastric cancer is the third most common cause of cancer death globally (Smyth et al. 2020; NIH 2023). Although the American Cancer Society highlights that it has become less common over the past years, stomach adenocarcinoma (STAD) accounts for 1.5% of new cancer diagnosis in the United States (ACS 2024). People over the age of 60, especially men, are more at risk of developing STAD; other risk factors include regular alcohol or tobacco consumption, poor diet and infection with Helicobacter pylori bacteria (ACS 2021). Dr. Xingwei Wu knew that high levels of expression of F2R, a protein know to regulate processes involved with the formation of blood cloths, are associated with many types of cancer (Wu et al. 2024). But not much was known about the relationship of F2R and STAD. Thus, Dr. Wu and his team embarked on an exciting adventure to understand what the role of F2R in the development of STAD is, and whether it has any value in predicting the outcome of the disease, also known as prognosis.
To understand how the expression of F2R can help predict the prognosis of STAD, the researchers looked at how genes are expressed and regulated in patients diagnosed with STAD compared to healthy counterparts. Data from the genome of 375 patients was obtained from a previously existing database and analyzed with multiple bioinformatic tools to understand whether there is a particular set of genes that is expressed differently in STAD patients. The logic behind this is that a change in normal gene expression could be a determining factor in the prognosis of the disease. Thus, Wu et al. used a statistical analysis software to perform gene ontology (GO) and the gene set enrichment analysis (GSEA), two different ways to cluster genes by level of expression (GSEA) and by the functionality of what they code for (GO). These two methods revealed that F2R is involved in regulating the expression of genes involved it the immune system, specifically the immune response needed to combat STAD. The researchers also conducted experiments in cells coming from human STAD tumors and healthy gastric cells. Wu and his team performed qPCR; a technique that helps visualize the differences in amounts of expression of a gene. The qPCR experiments revealed that F2R is over-expressed in STAD-positive tissues. Moreover, a follow up experiment where they compared tissues from STAD patients with positive and negative prognosis showed that high F2R expression can be used as a marker for patients with poor prognosis. Thus, when someone is newly diagnosed with the disease, a qPCR of tumor tissues can give the care team a better panorama of the type of treatment the patient will need. The authors proposed over expression F2R as an effective sign of STAD, specifying that this is correlated with a poor prognosis because of how it mis-regulates the immune response in charge of combating STAD.
This study opens the door to new treatment possibilities for STAD. As Wu and his collaborators discuss in their piece, immunotherapy and chemotherapy approaches should be further explored. The use of F2R as a marker for bad prognosis in STAD is an exciting new resource for physicians to plan more tailored treatment, depending on the levels of F2R the patient has. Still, this study has a relatively small sample size, especially for the cell experiments: the authors mention how they got samples from 30 patients paired with a healthy counterpart. Moreover, all the samples were collected in a hospital in China, thus we can infer most of the patients, if not all, were of Asian descent. The small number of samples from a not diverse background could potentially skew the results, and not be representative of the entirety of the biological variation that humans have. It would be interesting to conduct the same experiments in samples from different ancestries, so that a more holistic conclusion could be reached. Understanding the mechanisms by which cancer develops is of outmost importance for society, because of how deathly the disease is. This is one of the initial steps towards reaching a more effective treatment for cancers with such high mortality as STAD has.
References:
ACS, 2021 What Are the Risk Factors for Stomach Cancer?
ACS, 2024 Stomach (Gastric) Cancer Key Statistics
NIH, 2023 Cancer of the Stomach – Cancer Stat Facts. SEER.
Smyth E. C., M. Nilsson, H. I. Grabsch, N. C. van Grieken, and F. Lordick, 2020 Gastric cancer. The Lancet 396: 635–648. https://doi.org/10.1016/S0140-6736(20)31288-5
Wu X., S. Wang, C. Wang, C. Wu, and Z. Zhao, 2024 Bioinformatics analysis identifies coagulation factor II receptor as a potential biomarker in stomach adenocarcinoma. Sci Rep 14: 2468. https://doi.org/10.1038/s41598-024-52397-6
© Copyright 2022 Department of Biology, Davidson College, Davidson, NC 28036
This is a really cool study and it looks like a classic example of how RNA-seq data can be used in a multitude of ways. In this study, they found a gene to be implicated in STAD which is super helpful and illuminating in the field of cancer genomics. I also really like that you mentioned the lack of diversity in the study as further investigation into other patients with STAD can uncover other gene variants that might be associated with STAD.
This was an interesting read and was easy to understand! The possibility of silencing F2R expression via targeted therapy is fascinating, especially since it tends to be associated with poorer health outcomes. I also wonder how accessible qPCR is in oncology or pathology labs. I looked up F2R expression patterns and interestingly, lymphatic and bone marrow tissue have the highest mRNA expression. This is probably a biochemical question, but I would be interested to know how targeted therapies could silence the gene only in tissues where it is overexpressed. Also, is H. pylori-associated cancer associated with F2R upregulation?
Thanks for sharing your insights about this article. Before reading this article, I had limited knowledge of STAD but your insight gave me a valuable perspective. It was interesting to see how they exploited GO term analysis (a technique we talked about in class) to group genes involved in the immune response of F2R to STAD. I also appreciated how you mentioned that such studies shed light on possible therapeutic techniques and I agree on the need to collect more samples from different backgrounds.