Pan-Cancer Analysis of PAPPA Gene Reveals Tumor-Specific Prognostic Effects

Our plain-English summary of Pan-Cancer Analysis of PAPPA Gene Reveals Tumor-Specific Prognostic Effects, by S.M. Alfadul, K. Omama, A.Y. Potapova, et al (Biology, 2026).

The study

• Authors: S.M. Alfadul, K. Omama, A.Y. Potapova, P.A. Ivanov-Rostovtsev, M. Fanian, R. Mubarak, H.A. Gasimelseed, M.M. Balla, A.M.A. Bakhiet, K. Berma, M. Alfaki, M.V. Babak
• Journal: Biology
• Published: 2026;15(6)
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that regulates insulin-like growth factor availability via cleavage of IGF-binding proteins, yet its role in cancer remains incompletely understood. Using integrated public datasets, we systematically examined PAPPA expression, prognostic relevance, cellular localization, and stromal associations across multiple tumor types. PAPPA was reduced in several cancers and primarily localized to stromal cells, whereas in cholangiocarcinoma and thyroid carcinoma it was elevated and also detected in malignant cells. High PAPPA expression was associated with poorer overall survival in bladder, cervical, lung squamous, mesothelioma, pancreatic, and gastric cancers, but exhibited a protective effect in lower-grade glioma. In tumors with adverse prognosis, PAPPA strongly correlated with cancer-associated fibroblast (CAF) infiltration and CAF marker genes; however, multivariable Cox analyses indicated that PAPPA generally retained an independent prognostic factor, whereas CAF infiltration was mostly not independently associated with overall survival. Interestingly, in LGG, despite negative PAPPA-CAF correlations, multivariable analysis showed that PAPPA remained protective while CAF infiltration was associated with worse survival. Pathway analyses linked PAPPA-associated genes to proteoglycans in cancer and PI3K-AKT and RAS signaling. Collectively, these findings establish PAPPA as an independent prognostic factor across most cancers, while its expression frequently coincides with high CAF infiltration in select tumor types, highlighting the need for further investigation.

In plain English

This was a computer-based 'pan-cancer' analysis of publicly available tumor data, mainly from The Cancer Genome Atlas (TCGA). It looked at a gene called PAPPA across many cancer types, including mesothelioma. It did not study asbestos or any other exposure, and it does not say which form of mesothelioma (pleural or peritoneal) the data covered. The authors compared PAPPA levels in tumors and normal tissue and related high versus low PAPPA to patients' overall survival. PAPPA was lower than normal in seven cancers and higher in cholangiocarcinoma and thyroid carcinoma. In most tumors it came mainly from surrounding fibroblast (connective tissue) cells rather than cancer cells. High PAPPA was associated with poorer overall survival in six cancers, including mesothelioma, and with better survival in lower-grade glioma. In mesothelioma the hazard ratio was 1.6 in one database and 1.54 after adjusting for tumor purity (p less than 0.001). The authors concluded that PAPPA is an independent prognostic biomarker whose effects vary by tumor type. They stated that their database findings need laboratory validation.

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: Bioinformatic (computer-based) pan-cancer analysis of publicly available gene expression, survival and genetic data; no new samples were collected
• Who was studied: Tumor and normal tissue data from TCGA project cohorts (primary tumors), plus GTEx normal tissue, single-cell data from TISCH2, Human Protein Atlas staining images and eight GEO microarray cohorts. The genetic alteration analysis covered 10,967 samples from 32 TCGA tumor types. Mesothelioma (MESO) was one of the cancer types; the article does not give the number of mesothelioma patients.
• Exposure: No asbestos or other environmental or occupational exposure was studied. The factor analysed was the level of PAPPA gene expression, with patients split into high and low groups, usually at the median.
• Main results:
  • PAPPA expression was lower in tumors than in normal tissue in seven cancers (BRCA, CESC, KICH, KIRC, KIRP, PRAD, UCEC) and higher in two (cholangiocarcinoma, CHOL, and thyroid carcinoma, THCA).
  • In single-cell data, PAPPA was found mainly in fibroblasts, with little or no expression in cancer cells, except in CHOL and THCA.
  • Across databases, high PAPPA expression was consistently linked to poorer overall survival in six cancers: bladder (BLCA), cervical (CESC), lung squamous (LUSC), mesothelioma (MESO), pancreatic (PAAD) and stomach (STAD).
  • In mesothelioma, high PAPPA was associated with shorter overall survival in the GEPIA2 database (HR = 1.6, p less than 0.05).
  • After adjustment for tumor purity, PAPPA remained a significant risk factor in mesothelioma (HR = 1.54, p less than 0.001) and in BLCA, CESC, LUSC and STAD. Pancreatic cancer lost statistical significance after this adjustment.
  • In lower-grade glioma (LGG), high PAPPA was associated with better overall survival (GEPIA2 HR = 0.53, p less than 0.001; HR = 0.55 after purity adjustment).
  • PAPPA expression correlated positively with cancer-associated fibroblast infiltration in mesothelioma (r = 0.32, p less than 0.01), as well as in BLCA (r = 0.36), CESC (r = 0.41) and LUSC (r = 0.53).
  • When cancer-associated fibroblast infiltration was added to the survival model, PAPPA remained an independent prognostic factor in most cancers, while fibroblast infiltration was mostly not significant.
  • Genetic alterations of the PAPPA gene were not associated with differences in overall or disease-free survival.
• The authors' conclusion: The authors concluded that PAPPA is an independent prognostic biomarker whose effects vary by tumor type. In their view, high PAPPA is associated with adverse outcomes in BLCA, CESC, LUSC, MESO, PAAD and STAD, often together with high fibroblast infiltration, and with more favorable outcomes in lower-grade glioma.
• Limitations the authors state:
  • The analyses relied only on public databases, so the findings need laboratory experiments to confirm their biological and functional significance.

Topics

Medical terms in this study, explained in our Lexicon: Carcinoma, Overall Survival, Mesothelioma, Stomach Cancer, Prognosis, Fibroblast.

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