Prevalence and Significance of AGR2 Expression in Human Cancer

Abstract

Backround: Anterior gradient 2 (AGR2) is a resident endoplasmic reticulum (ER) protein with a vital role in embryonal development, mucus maturation, tissue regeneration, and wound healing.

Methods: To determine the prevalence and clinical significance of AGR2 expression in cancer, a tissue microarray containing 14,966 tumors from 134 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry (IHC).

Results: AGR2 positivity was found in 103 of 134 tumor categories, and 83 tumor categories contained at least one strongly positive case. AGR2 expression was most frequently seen in tumors of the female genital tract, particularly adenocarcinomas (up to 100%), various breast cancer subtypes (57.1%-100%), urothelial carcinoma (74.6%-100%), adenocarcinomas of the upper and lower gastrointestinal tract (93.6%-99.6%), and pancreaticobiliary cancers (65.2%-98.2%). AGR2 positivity was slightly less common in squamous cell carcinomas (46.4%-77.3%) and mainly absent in mesenchymal and lymphoid tumors. While AGR2 expression was only weak or absent in the normal thyroid, it was moderate to strong in 46.0% of adenomas, 52.8% of follicular carcinomas, and 81.8% of papillary carcinomas of the thyroid. High AGR2 expression was strongly linked to poor ISUP (p < 0.0001), Fuhrman (p < 0.0001), and Thoenes (p < 0.0001) grades as well as advanced pT stage (p = 0.0035) in clear cell renal cell carcinoma (ccRCC). Low AGR2 expression was associated with high BRE grade in breast cancer (p = 0.0049), nodal metastasis (p = 0.0275) and RAS mutation (p = 0.0136) in colorectal cancer, nodal metastasis (p = 0.0482) in endometrioid endometrial carcinoma, high grade in noninvasive urothelial carcinoma (p = 0.0003), and invasive tumor growth in urothelial carcinoma (p < 0.0001).

Conclusions: It is concluded that AGR2 expression occurs in a broad range of different tumor entities and that AGR2 assessment may serve as a diagnostic aid for the distinction of thyroidal neoplasms and as a prognostic marker in various cancer types.

FIGURE 1

AGR2 immunostaining of normal tissues. The panels show a strong cytoplasmic AGR2 immunostaining of all epithelial cells of the stomach except parietal cells (a), as well as of all epithelial cells of the duodenal mucosa (b), the colorectal mucosa (c), the endocervical epithelium (d), the endometrium of the pregnant uterus (e), the cauda epididymis (f), and the seminal vesicle (g). Most epithelial cells of a prostate sample are also AGR2 positive (h).

FIGURE 2

AGR2 immunostaining in cancer. AGR2 staining was cytoplasmic. The panels show a strong AGR2 positivity in cancer cells of adenocarcinoma of colon (a), gastric adenocarcinoma (b), adenocarcinoma of the pancreas (c), urothelial carcinoma (d), follicular thyroid carcinoma (e) and clear cell renal cell carcinoma (f), AGR2 immunostaining is absent in mesothelioma (g), and seminoma (h).

FIGURE 3

Ranking order of AGR2‐positive immunostaining in different human tumors. Orange dots show the percentage of strongly stained samples, whereas blue dots show the percentage of positive samples of any intensity.

FIGURE 4

AGR2 protein expression in cancer (own findings vs. literature data). Graphical representation of AGR2 data from this study (X) compared to the previous literature. The colors of the dots represent the number of tumors analyzed in these studies: Red: n ≤ 20, yellow: n = 21 to 100, green: n > 100. For raw data and references, see Table S1.