The panoramic picture of pepsinogen gene family with pan-cancer

Our plain-English summary of The panoramic picture of pepsinogen gene family with pan-cancer, by S. Shen, H. Li, J. Liu, et al (Cancer Medicine, 2020).

The study

• Authors: S. Shen, H. Li, J. Liu, L. Sun, Y. Yuan
• Journal: Cancer Medicine
• Published: 2020;9(23):9064-9080
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: It is well known that pepsinogen (PGs), as an important precursor of pepsin performing digestive function, has a good correlation with the occurrence and development of gastric cancer and it is also known that ectopic PGs expression is related to the prognosis of some cancers. However, the panoramic picture of pepsinogen gene family in human cancer is not clear. This study focused on elucidating the expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their potential role in human cancer.

Method: Based on the next generation sequence data from TCGA, Oncomine, and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically by R language, including the expression, mutation, and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration, and prognostic potential in different cancers.

Results: PGs expression profiles appear different in 33 tumors. The transcriptional expression of PGs was detected in 16 of all 33 tumors. PGC was highly expressed in cholangiocarcinoma, colon adenocarcinoma, rectum adenocarcinoma, uterine corpus endometrial carcinoma, bladder urothelial carcinoma and breast cancer, while decreased in stomach adenocarcinoma, kidney renal clear cell carcinoma, prostate adenocarcinoma, lung squamous cell carcinoma, and esophageal carcinoma. PGA3, PGA4, and PGA5 were expressed in most normal tissues, but decreased in cancer tissues. PGs expression was significantly related to the activation or inhibition of many signal transduction pathways, in which PGC and PGA5 are more likely to be associated with cancer-related pathways. PGC participated in 33 regulatory network pathways in pan-cancer, mainly distributed in stomach adenocarcinoma, esophageal carcinoma, and lung squamous cell carcinoma, respectively. PGC and PGA3 expression were significantly correlated with immune cell infiltration. The results of survival analysis showed that different PGs expression play significantly different prognostic roles in different cancers. PGC was correlated with poor survival in brain lower grade glioma, skin cutaneous melanoma, and higher survival in kidney renal clear cell carcinoma, acute myeloid leukemia, mesothelioma, and uveal melanoma. PGA4 was only associated with higher survival in kidney renal clear cell carcinoma. Genetic variation analysis showed that PGC gene often mutated in uterine corpus endometrial carcinoma and stomach adenocarcinoma had extensive copy number amplification in various tumor types. PGC expression was upregulated with the increase of copy number in cholangiocarcinoma, esophageal carcinoma, and kidney renal papillary cell carcinoma, while in stomach adenocarcinoma, PGC was upregulated regardless of whether the copy number was increased or decreased.

Conclusions: PGs was expressed unevenly in a variety of cancer tissues and was related to many carcinogenic pathways and involved in the immune regulation. PGC participated in 33 regulatory pathways in human cancer. Different PGs expression play significantly different prognostic roles in different cancers. The variation of copy number of PGC gene could affect the PGC expression. These findings suggested that PGs, especially PGC have characteristic of broad-spectrum expression in multiple cancers rather than being confined to the gastric mucosa, which may made PGs be useful biomarkers for prediction/diagnosis/prognosis and effective targets for treatment in human cancer.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

In plain English

This was a computer-based analysis of publicly available genetic data. It was not about asbestos: the article does not mention asbestos or any fiber. The authors looked at four pepsinogen genes (PGC, PGA3, PGA4 and PGA5), best known for stomach digestion, in 33 tumor types from The Cancer Genome Atlas, including mesothelioma. They also used Oncomine, the Protein Atlas and data on 431 cancer cell lines. They reported that gene activity differed between tumor types and between tumors and normal tissue. It was linked to many cancer-related signaling pathways and to immune cells in tumors. The survival analysis linked PGC to mesothelioma survival, but the article contradicts itself on the direction. The results section says poorer survival; the abstract and discussion say higher. A survival figure lists 86 mesothelioma patients and appears to give PGC a value of 1.57 there, matching the results section; no confidence interval is readable. The authors concluded that pepsinogen genes, especially PGC, are expressed in many cancers beyond the stomach and may be useful markers and treatment targets. They said some findings need further verification.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Bioinformatics analysis of existing public databases (pan-cancer analysis of gene expression, mutation and copy number data)
• Who was studied: Tumor data for 33 cancer types in The Cancer Genome Atlas (TCGA), including mesothelioma. Also 431 cancer cell lines from six cancer types (CCLE) and Protein Atlas data on 21 cancers. Places and dates are not stated.
• Exposure: Not an exposure study. It examined the activity, mutation and copy number of the pepsinogen genes PGC, PGA3, PGA4 and PGA5. No asbestos, fibers, products or jobs are mentioned.
• Main results:
  • Pepsinogen gene messenger RNA (gene activity) was detected in 16 of the 33 tumor types.
  • At the protein level (Protein Atlas data on 21 cancers), PGA3, PGA4 and PGA5 protein was not detected in any cancer tissue.
  • Across cancers, pepsinogen gene activity was significantly related to the activation or inhibition of many cancer-related pathways. PGC was linked to 33 regulatory pathways (p less than 0.05, R greater than 0.24), mainly in stomach adenocarcinoma, esophageal carcinoma and lung squamous cell carcinoma.
  • PGC and PGA3 activity was significantly correlated with immune cell infiltration in tumors.
  • The results section states that in mesothelioma, PGC was associated with poorer survival. It gives the same direction for kidney renal clear cell carcinoma, acute myeloid leukemia and uveal melanoma.
  • The discussion states the opposite: that in mesothelioma, PGC was correlated with higher survival. It gives the same direction for kidney renal clear cell carcinoma, acute myeloid leukemia and uveal melanoma.
  • Figure 9 shows survival results by cancer type, including mesothelioma (MESO). Its PGC forest plot lists 86 mesothelioma patients. Read by position in the scanned text, the heat map appears to give PGC a value of 1.57 in mesothelioma, which matches the results section's poorer-survival statement. The mesothelioma confidence interval cannot be read.
  • The overall average mutation rate of the pepsinogen genes was 0% to 5.3%. PGC mutations occurred most often in uterine corpus endometrial carcinoma and stomach adenocarcinoma.
  • PGC activity rose with increased copy number in cholangiocarcinoma, esophageal carcinoma and kidney renal papillary cell carcinoma. Mutations did not affect pepsinogen gene activity in any cancer.
• The authors' conclusion: The authors concluded that pepsinogen genes, especially PGC, are expressed in many cancers rather than only in the stomach lining. They suggested this may make them useful biomarkers for prediction, diagnosis or prognosis, and possible treatment targets.
• Limitations the authors state:
  • The authors said their finding that mutations do not affect gene activity conflicts with earlier work in their lab and needs further verification.
  • The authors noted that cancer prognosis is affected by many factors, including the local tissue environment.

Topics

Medical terms in this study, explained in our Lexicon: Stomach Cancer, Prognosis, Adenocarcinoma, Carcinoma, Squamous Cell Carcinoma, Mesothelioma, Carcinogenic, Biomarker.

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