Expression of Annexin A4 in Cancer: A Tissue Microarray Study Involving More than 17,600 Cancers from 148 Tumor Entities

Our plain-English summary of Expression of Annexin A4 in Cancer: A Tissue Microarray Study Involving More than 17,600 Cancers from 148 Tumor Entities, by C. Völkel, N. Malas, F. Gehrisch, et al (Cancers, 2026).

The study

• Authors: C. Völkel, N. Malas, F. Gehrisch, A. Menz, F. Lutz, V. Chirico, F. Viehweger, D. Dum, R. Schlichter, A. Hinsch, C. Fraune, C. Bernreuther, S. Büyücek, M. Kluth, C. Hube-Magg, G. Makrypidi-Fraune, N. Schraps, K. Möller, A.M. Luebke, P. Lebok, G. Sauter, M. Lennartz, T.S. Clauditz, A.H. Marx, R. Simon, E. Burandt, N. Gorbokon, M.C. Tsourlakis, S. Minner, T. Krech, M. Freytag, V. Reiswich, S. Steurer
• Journal: Cancers
• Published: 2026;18(19)
• Read it: PubMed · Publisher · Free full text

Abstract

Background/Objectives: Annexin A4 (ANXA4) is one of twelve members of the annexin superfamily that bind membrane phospholipids in a calcium-dependent manner, and which are involved in several processes related to the membrane. Methods: To learn more about the role of ANXA4 in cancer, the ANXA4 expression was analyzed by immunohistochemistry (IHC) on tissue microarrays (TMAs) containing 17,654 tumors and precursor lesions from 148 tumor types. Results: ANXA4 immunostaining was found in 10,858 (83.4%) of 13,017 analyzable tumors, and was considered weak in 10.1%, moderate in 16.6%, and strong in 61.8% of cases. Of 148 tumor categories, 144 showed ANXA4 staining in at least one case and 133 included at least one case with strong staining. Among tumor entities with at least 10 evaluable samples, strong ANXA4 staining in >50.0% of cases was seen in 56 of 120 entities, while absence of staining in >50.0% of cases was seen in 13. Clinically important tumor entities where ANXA4 staining was always positive (>99.5%) included gallbladder adenocarcinoma, cholangiocarcinoma, pancreatic/ampullary, various subtypes of salivary gland tumors, papillary renal cell carcinoma, urothelial carcinoma, squamous and basal cell carcinoma of the skin, and epithelioid mesothelioma. A reduced ANXA4 expression was linked to features of cancer aggressiveness in breast cancer, clear cell renal cell carcinoma, urothelial carcinoma, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, colorectal adenocarcinoma, and follicular thyroid carcinoma. Conclusions: It is concluded that ANXA4 is abundantly expressed in human malignancies and that a reduced expression may be linked to unfavorable disease characteristics in many important tumor entities.

In plain English

This laboratory study measured how often cancers contain the protein Annexin A4 (ANXA4). It did not study asbestos or any other exposure. The authors stained tissue microarrays (slides holding small tissue spots from many patients) containing 17,654 tumors and precursor lesions from 148 tumor types, taken from pathology archives in Hamburg, Osnabrueck and Fuerth, Germany. Of these, 13,017 samples could be interpreted. ANXA4 staining was found in 10,858 (83.4%) of the 13,017. None of 28 analyzable epithelioid mesotheliomas was negative, and 89.3% stained strongly. Of 23 analyzable biphasic mesotheliomas, 4.3% were negative and 69.6% stained strongly. In some other cancers, reduced ANXA4 staining was statistically associated with features of more aggressive disease, for example more advanced tumor stage in invasive breast carcinoma of no special type (p less than 0.0001). The article's analysis of aggressive features did not include mesothelioma. The authors concluded that ANXA4 is abundantly expressed in most human malignancies and that reduced expression may be associated with unfavorable disease characteristics in many tumor types. They said their findings should be regarded as hypothesis-generating.

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: Laboratory study using immunohistochemistry (antibody staining) on tissue microarrays of archived tumor and normal tissue samples
• Who was studied: 17,654 tumors and precursor lesions from 148 tumor types and subtypes, from the pathology archives of University Hospital Hamburg, Clinical Center Osnabrueck and Academic Hospital Fuerth, Germany. 13,017 (73.7%) were interpretable. These included 32 epithelioid mesotheliomas (28 analyzable) and 25 biphasic mesotheliomas (23 analyzable). A separate normal-tissue array held 76 normal tissue types, with 8 donors each. No study dates are given.
• Exposure: No asbestos or other exposure was studied. The study measured staining for the protein ANXA4 in tumor tissue.
• Main results:
  • Across all tumor types, ANXA4 staining was found in 10,858 (83.4%) of the 13,017 interpretable tumor samples.
  • Of the interpretable tumor samples, 1310 (10.1%) showed weak, 1510 (11.6%) moderate, and 8038 (61.8%) strong staining.
  • Epithelioid mesothelioma: 32 cases on the array, 28 analyzable. 0.0% were negative, 3.6% weak, 7.1% moderate, and 89.3% strong.
  • Biphasic mesothelioma: 25 cases on the array, 23 analyzable. 4.3% were negative, 8.7% weak, 17.4% moderate, and 69.6% strong.
  • In invasive breast carcinoma of no special type, reduced ANXA4 expression and/or loss of staining was associated with advanced tumor stage (p less than 0.0001), high grade (p = 0.0018) and nodal metastasis (p = 0.0247).
  • In clear cell renal cell carcinoma, reduced expression was associated with high ISUP grade (p = 0.0026), Fuhrman grade (p = 0.0006) and Thoenes grade (p = 0.0135).
  • Reduced expression was also associated with advanced tumor stage in pancreatic ductal adenocarcinoma (p = 0.0017) and with high grade in hepatocellular carcinoma (p = 0.0247).
  • ANXA4 expression was unrelated to tumor features in papillary renal cell carcinoma, gastric adenocarcinoma, endometrioid endometrial carcinoma, ovarian serous high-grade carcinoma, papillary thyroid carcinoma and testicular seminoma.
• The authors' conclusion: The authors concluded that ANXA4 is abundantly expressed in most human malignancies, and that reduced expression may be associated with unfavorable disease characteristics in many important tumor entities.
• Limitations the authors state:
  • Because there were no functional, survival, or interventional data, the authors said their findings should be regarded as hypothesis-generating.
  • The authors said results for tumor types with few analyzable tumors should be interpreted with caution.

Topics

Medical terms in this study, explained in our Lexicon: Immunohistochemistry, Adenocarcinoma, Carcinoma, Epithelioid, Mesothelioma.

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