Mesothelin (MSLN) represents an attractive molecule for targeted cancer therapies. To identify tumors that might benefit from such therapies, tissue microarrays including 15,050 tumors from 122 different tumor types and 76 healthy organs were analyzed for MSLN expression by immunohistochemistry. Sixty-six (54%) tumor types showed at least occasional weak staining, including 50 (41%) tumor types with at least one strongly positive sample. Highest prevalence of MSLN positivity had ovarian carcinomas (serous 97%, clear cell 83%, endometrioid 77%, mucinous 71%, carcinosarcoma 65%), pancreatic adenocarcinoma (ductal 75%, ampullary 81%), endometrial carcinomas (clear cell 71%, serous 57%, carcinosarcoma 50%, endometrioid 45%), malignant mesothelioma (69%), and adenocarcinoma of the lung (55%). MSLN was rare in cancers of the breast (7% of 1138), kidney (7% of 807), thyroid gland (1% of 638), soft tissues (0.3% of 931), and prostate (0 of 481). High expression was linked to advanced pathological tumor (pT) stage (p < 0.0001) and metastasis (p < 0.0001) in 1619 colorectal adenocarcinomas, but unrelated to parameters of malignancy in 1072 breast-, 386 ovarian-, 174 lung-, 757 kidney-, 171 endometrial-, 373 gastric-, and 925 bladder carcinomas. In summary, numerous important cancer types with high-level MSLN expression might benefit from future anti-MSLN therapies, but MSLN’s prognostic relevance appears to be limited.

Background/Objectives: Carcinoembryonic antigen (CEA) is a cell-surface glycoprotein serving as a drug target, diagnostic marker, and serum marker for cancer monitoring. However, prevalence data on CEA expression in cancer tissues vary considerably. This study was designed to determine CEA expression in normal and neoplastic tissues. Methods: A tissue microarray containing 13,725 samples from 120 different tumor types, as well as 76 different normal tissue types, was analyzed by immunohistochemistry (IHC). Results: CEA was detectable in 65 (54.2%) of 120 tumor categories, including 49 (40.8%) tumor types with at least one strongly positive case. CEA positivity was most common in colorectal adenomas (100%) and carcinomas (98.7%), other gastrointestinal adenocarcinomas (61.1–80.3%), medullary carcinomas of the thyroid (96.3%), pulmonary adenocarcinoma (73.7%), mucinous carcinomas of the ovary (79.8%) and the breast (43.2%), small-cell carcinomas of the lung (64.3%), and urinary bladder (38.9%). CEA overexpression was linked to high tumor grade and invasive growth (p < 0.0001 each) in urinary bladder cancer, and estrogen and HER2 receptor positivity (p ≤ 0.0158) in invasive breast cancer of no special type. In colorectal adenocarcinomas, reduced CEA expression was associated with mismatch repair deficiency (p < 0.0001). Conclusions: The comprehensive list of CEA-positive human tumor types demonstrates that CEA is expressed in a broad range of epithelial neoplasms, many of which might benefit from CEA serum monitoring and anti-CEA therapies.

Angiotensin-converting enzyme 2 (ACE2) is a regulator in the renin-angiotensin system. ACE2 expression was analysed immunohistochemically in 15,306 samples from 119 tumour types and in 608 samples of 76 normal tissue types. In normal tissue, ACE2 was most abundant in testis and corpus luteum, kidney, small intestine and capillaries of selected organs. At least an occasional weak ACE2 positivity of tumour cells was seen in 83 of 119 (70%) tumour types. ACE2 tumour cell positivity was particularly frequent in papillary (94%) and clear cell (86%) renal cell carcinoma, colorectal adenocarcinoma (81%), mucinous ovarian cancer (61%), cholangiocarcinoma (58%), hepatocellular carcinoma (56%), and in adenocarcinomas of the stomach (47%), pancreas (42%), and the lung (35%). ACE2-positive capillaries were found in 409/12,644 (3%) of analysable tumours, most frequently in tumours with endocrine/neuroendocrine activity. Presence of ACE2-positive capillaries was linked to low stage in papillary thyroid cancer and low grade in neuroendocrine neoplasms. In conclusion, ACE2 expression can occur both in tumour cells and tumour-associated capillaries in a broad variety of different tumour types at highly variable frequencies.

Introduction: Myxovirus resistance protein 1 (MX1) contributes to resistance against viral infections, including to influenza, and has recently been implicated in cancer. Methods: A tissue microarray with 17,909 samples from 145 tumor types/subtypes and 608 samples from 76 normal tissue types was analyzed by immunohistochemistry (IHC) to assess MX1 expression. Results: MX1 positivity was found in tumor cells of 5956 of 14,512 analyzable samples, and 131 of 145 entities included at least one positive case. High positivity rates occurred in squamous cell carcinomas (up to 88%), neuroendocrine neoplasms (up to 85%), germ cell neoplasms (up to 77%), salivary gland tumors (up to 75%), mesothelioma (up to 74%), endometrial and ovarian carcinomas (up to 73%), cervical adenocarcinoma (73%), pancreatic ductal adenocarcinoma (65%), and urothelial carcinoma (up to 62%). MX1 expression correlated with PD-L1 positivity and CD8+ lymphocyte density (p < 0.0001 each). High MX1 expression was linked to grade progression in breast cancer (p < 0.0001), microsatellite instability in colorectal adenocarcinoma (p = 0.0003), high grade (p = 0.0431) and advanced pT stage (p = 0.0269) in hepatocellular carcinoma, distant metastasis in clear cell renal cell carcinoma (ccRCC, p = 0.0164), and nodal metastasis in papillary RCC (pRCC; p = 0.0326). Low MX1 expression was linked to stage progression in muscle-invasive urothelial carcinoma (p = 0.0372) and colorectal adenocarcinoma (p = 0.0002), papillary (p = 0.013) and follicular (p = 0.0221) thyroid cancer, and nodal metastasis in serous high-grade ovarian carcinoma (p = 0.0355). MX1 expression was unrelated to phenotype in endometrioid endometrial and ovarian carcinoma. Conclusions: MX1 expression in tumors is strongly linked to CD8+ lymphocyte density and PD-L1 expression, suggesting an association with an immune-inflamed, type I interferon-related tumor microenvironment.

Background/Objectives: Aberrant expression of high-mobility group protein B1 (HMGB1) has been linked to cancer development and progression. Methods: To better comprehend the role of HMGB1 expression in cancer, a tissue microarray containing 14,966 samples from 134 different tumor entities and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results: Strong HMGB1 staining occurred in almost all normal cell types and in most cancers. Of 11,808 evaluable cancers, only 7.8% showed complete absence of HMGB1 staining (HMGB1 deficiency) while 9.9% showed 1+, 25.0% showed 2+, and 57.2% showed 3+ HMGB1 positivity. Absence of HMGB1 staining mostly occurred in pheochromocytoma (90.0%), seminoma (72.4%), gastrointestinal stromal tumor (28.6%), adrenal cortical carcinoma (25.0%), and Hodgkin’s lymphoma (25.0%). Low HMGB1 staining was linked to poor histologic grade (p < 0.0001), advanced pT stage (p < 0.0001), high UICC stage (p < 0.0001), and distant metastasis (p = 0.0413) in clear cell renal cell carcinoma, invasive tumor growth in urothelial carcinoma (pTa vs. pT2–4, p < 0.0001), mismatch repair deficiency (p = 0.0167) in colorectal cancers, and advanced pT stage in invasive breast carcinoma of no special type (p = 0.0038). Strong HMGB1 staining was linked to nodal metastases in high-grade serous ovarian carcinomas (p = 0.0213) and colorectal adenocarcinomas (p = 0.0137), as well as to poor histological grade in squamous cell carcinomas (p = 0.0010). Conclusions: HMGB1 deficiency and reduced HMGB1 expression occur in a broad range of different tumor entities. Low rather than strong HMGB1 staining is often linked to an aggressive tumor phenotype. Whether HMGB1 deficiency renders cells susceptible to specific drugs remains to be determined.