Expression of annexin A4 in cancer: A tissue microarray study involving 6,058 cancers from 105 tumor entities

Annexin A4 (ANXA4) is a member of the annexin family of calcium-dependent phospholipid-binding proteins. In line with its capability to bind to phospholipid membranes, it has roles in processes related to membrane dynamics such as membrane trafficking, vesicle aggregation, membrane organization, and ion channel regulation. ANXA4 dysregulation can contribute to abnormal cell migration, proliferation, and resistance to apoptosis. ANXA4 overexpression has been described in several cancer types and has been linked to tumor aggressiveness and treatment resistance. Due to its differential expression in tumors versus normal tissues, ANXA4 is being investigated as a diagnostic biomarker. To learn more on the role of ANXA4 in cancer, ANXA4 expression was analyzed by immunohistochemistry (IHC) on tissue microarrays (TMAs) containing 6,058 samples from 105 different tumor types. ANXA4 staining was seen in 3,649 (75.4%) of the 4,839 analyzable tumors, and was considered weak in 11.3%, moderate in 17.5%, and strong in 46.6% of cases. Of 105 tumor categories, 100 (95.2%) showed ANXA4 expression in at least one case, 92 (87.6%) showed ANXA4 staining in more than 50% of cases, and 90 (85.7%) included at least one case with strong ANXA4 positivity. Highest rates of strong ANXA4 positivity occurred in adenocarcinoma of the ampulla Vateri (100%) and ductal adenocarcinoma of the pancreas (96.0%), gallbladder adenocarcinoma (100%), gastric adenocarcinoma (93.0-99.1%), clear cell (97.7%), papillary (97.4%) and chromophobe (94.9%) renal cell carcinoma (RCC), Brenner tumor (96.4%), colorectal adenocarcinoma (95.0%), clear cell carcinoma of the ovary (94.7%), adenocarcinoma of the esophagus (94.7%), oncocytoma od the kidney (94.6%), hepatocellular carcinoma (91.8%), mucinous carcinoma of the ovary (90.9%), cholangiocarcinoma of the liver (88.6%), adenocarcinoma of the cervix uteri (87.0%), endometrioid endometrial carcinoma (76.1%), endometrioid carcinoma of the ovary (66.7%), and in urothelial carcinoma of the kidney pelvis (66.7%). The 1,219 evaluable breast cancers of no specific type (NST) represented the largest subset of tumors from one entity. In these tumors, ANXA4 staining was negative in 642 (52.7%), weak in 84 (6.9%), moderate in 169 (13.9%), and strong in 324 (26.6%) cases. A comparison with tumor phenotype revealed that low ANXA4 expression was linked to advanced pT-stage (p<0.0001), high grade of malignancy (p=0.0018), and nodal metastasis (p=0.0247). In summary, our data provide a comprehensive overview on ANXA4 expression in cancer. They demonstrate, that ANXA4 is often expressed at high levels in a broad range of different tumor entities. At least in breast cancer NST, a low level of ANXA4 expression is a feature of high cancer aggressiveness.