Annexin A3 expression is prevalent but highly variable in human cancer: A tissue microarray study involving 5,914 cancers from 105 tumor entities

Annexin A3 (ANXA3) is a member of the annexin family of calcium-dependent phospholipid-binding proteins which plays a major role in various membrane-related processes, including membrane organization, repair, vesicle trafficking, and regulation of ion channels. Its diverse functions extend across various cellular processes such as apoptosis, cell growth, inflammation, and differentiation. Altered ANXA3 expression has been found in several cancer types. To better comprehend the role of ANXA3 in cancer, ANXA3 expression was analyzed by immunohistochemistry (IHC) on tissue microarrays (TMAs) containing 5,914 samples from 105 different tumor types. ANXA3 staining was seen in 3,490 (72.3%) of the 4,824 analyzable tumors, and was considered weak in 18.2%, moderate in 10.2%, and strong in 44.0% of cases. Of 105 tumor categories, 87 (82.9%) showed ANXA3 expression in at least one case, 69 (65.7%) showed ANXA3 staining in at least 50% of cases, and 78 (74.3%) included at least one case with strong ANXA3 positivity. Among tumors with at least 10 evaluable samples, the highest rates of tumors with strong ANXA3 positivity were observed in ampullary (100.0%) and ductal adenocarcinoma of the pancreas (90.9%), adenocarcinoma of the cervix uteri (95.7%),gastrointestinal stromal tumor (GIST; 90.4%), colorectal adenocarcinoma (90.0%), gastric adenocarcinoma of the intestinal (88.7%) and diffuse (81.6%), basal cell carcinoma of the skin (88.2%), gallbladder adenocarcinoma (88.2%),esophageal adenocarcinoma (87.8%), prostatic adenocarcinoma (83.8%), endometroid (82.5%), serous (78.9%) and mucinous (72.7%) carcinoma of the ovary, papillary renal cell carcinoma (63.2%), cholangiocarcinoma (77.8%), endometroid (76.3%) and serous (50.0%) endometrial carcinoma, squamous cell carcinomas from different organs of origin (up to 61.9%), testicular seminoma (53.8%), carcinosarcoma of the ovary (53.3%), lobular (52.3%), mucinous (40.0%) and tubular (38.9%) carcinoma of the breast, clear cell carcinoma of the ovary (42.1%), muscle-invasive urothelial carcinoma (41.4%), carcinosarcoma of the uterus (40.0%), Brenner tumor (39.3%), invasive breast carcinoma of no special type (NST; 36.1%), urothelial carcinoma of the kidney pelvis (29.8%) and yolk sac tumors of the testis (27.3%). In breast cancer NST, low ANXA3 expression was linked to aggressive tumor phenotype. Strong ANXA3 staining was seen in 100.0% of Gleason 3+3, 87.3% of Gleason 4+4, and in 65.8% of Gleason 5+5 carcinomas of the prostate (p<0.0001). In breast cancer NST, low ANXA3 expression was linked to high grade of malignancy (p<0.0001). In summary, the data from this study provide a catalogue of ANXA3 expression in human cancer, demonstrate that ANXA3 levels are highly variable in most tumor entities, and show that ANXA3 immunostaining is associated with prognostic tumor features in at least some tumor types.