Background: The complete loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression, often due to homozygous 9p21 deletion, creates a druggable vulnerability in cancer cells. Methods: A total of 769 primary pancreatic ductal adenocarcinomas were analyzed on tissue microarrays with MTAP immunohistochemistry (IHC) and 9p21 fluorescence in situ hybridization (FISH). Intratumoral heterogeneity was assessed on a “heterogeneity” TMA containing up to nine samples from different areas of 236 primary tumor and nodal metastases, and whole sections of all tumor blocks from 19 cancers. Results: MTAP expression loss was found in 181 (37.9%) of 478 interpretable primary tumors and was unrelated to pT, pN, grade, and tumor size. MTAP expression loss was homogenous in 37.6% and heterogeneous in 1.1% of the 181 tumors, with at least three evaluable samples on the heterogeneity TMA. On whole sections, 1 of 19 tumors showed heterogeneous MTAP loss. The correlation between IHC and FISH was nearly perfect, with 98.8% of MTAP-deficient samples showing a 9p21 deletion. Conclusions: MTAP expression loss is frequent, caused by homozygous deletion, and mostly homogeneous in pancreatic ductal adenocarcinomas. Considering also their aggressive clinical behavior, pancreatic adenocarcinomas may represent an ideal cancer type for studying new drugs targeting MTAP-deficient cancer cells in clinical trials.

Occludin is a key component of tight junctions. Reduced occludin expression has been linked to cancer progression in individual tumor types, but a comprehensive and standardized analysis across human tumor types is lacking. To study the prevalence and clinical relevance of occludin expression in cancer, a tissue microarray containing 16,870 samples from 148 different tumor types and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Occludin immunostaining was observed in 10,746 (76.6%) of 14,017 analyzable tumors, including 18.9% with weak, 16.2% with moderate, and 41.6% with strong staining intensity. Occludin positivity was found in 134 of 148 tumor categories and was most frequent in adenocarcinomas (37.5-100%) and neuroendocrine neoplasms (67.9-100%), less common in squamous cell carcinomas (23.8-93%) and in malignant mesotheliomas (up to 48.1%), and rare in Non-Hodgkin’s lymphomas (1-2%) and most mesenchymal tumors. Reduced occludin staining was linked to adverse tumor features in several tumor types, including colorectal adenocarcinoma (advanced pT stage, p < 0.0001; L1 status, p = 0.0384; absence of microsatellite instability, p < 0.0001), pancreatic adenocarcinoma (advanced pT stage, p = 0.005), clear cell renal cell carcinoma (high ISUP grade, p < 0.0001; advanced pT stage, p < 0.0001; high UICC stage, p < 0.0001; distant metastasis, p = 0.0422; shortened overall or recurrence-free survival, p ≤ 0.0116), papillary renal cell carcinoma (high pT stage, p < 0.0001; high UICC stage, p = 0.0228; distant metastasis, p = 0.0338; shortened recurrence-free survival, p = 0.006), and serous high-grade ovarian cancer (advanced pT stage, p = 0.0133). Occludin staining was unrelated to parameters of tumor aggressiveness in breast, gastric, endometrial, and thyroidal cancer. Our data demonstrate significant levels of occludin expression in many different tumor entities and identify reduced occludin expression as a potentially useful prognostic feature in several tumor entities.

Background: The glucocorticoid receptor (GR) is a nuclear receptor protein for cortisol and other glucocorticoids and regulates the transcription of thousands of genes involved in metabolism, development, stress and inflammatory response. In prostate cancer, GR may confer resistance to anti-androgen receptor therapies by bypassing AR blockade. However, only few data are available on the prognostic role of GR expression in prostate cancer. Methods: To estimate the prognostic value of GR, a tissue microarray containing 17,747 prostate cancers with associated follow-up and molecular data was analyzed by immunohistochemistry. Results: All patients had undergone radical prostatectomy. GR immunostaining was found in 10,832 (89.1%) of 12,125 interpretable tumors, including 48.5% with weak, 29.8% with moderate and 11% with strong staining intensity. Increased GR staining was strongly linked to adverse feature of the disease, including high tumor stage (pT), high classical and quantitative Gleason grade, presence of nodal metastases (pN+), a positive surgical margin (R1) status, and early biochemical recurrence ( p < 0.0001 each). A multivariate analysis showed that the prognostic value of strong GR staining was independent of pT, Gleason grade, pN and R status. High level GR staining was significantly linked to TMPRSS2:ERG fusion ( p < 0.0001) and high androgen receptor expression ( p < 0.0001 each). A combined analysis of the impact of GR and AR on patient prognosis identified the best prognosis for AR ^neg /GR ^neg cancers while AR ^pos /GR ^pos cancers showed the worst prognosis ( p < 0.0001). Moreover, high GR expression was a strong predictor of poor prognosis in AR low, AR intermediate and AR high cancers ( p < 0.0001 each). Conclusion: High level expression of GR is strongly linked to prostate cancer aggressiveness in uni- and multivariate analysis. GR immunohistochemistry – alone or in combination with other markers – holds great potential to identify patients with a high risk for tumor progression.

Background/Objectives: The double-strand break repair protein MRE11 forms the core of the MRE11/RAD50/NBS1 (MRN) complex. Cancers with reduced MRE11 expression have been suggested to be more sensitive to radio-chemotherapy and may be subject to synthetic lethality. The aim of this study was to assess the prevalence of MRE11 deficiency and the potential role and clinical significance of elevated and/or reduced MRE11 expression in human cancer. Methods: A tissue microarray containing 14,966 samples from 134 different tumor entities was analyzed for MRE11 by immunohistochemistry. Results: In normal tissues, strong nuclear MRE11 staining occurred in almost all cell types. In cancers, nuclear MRE11 staining was strong in 11,797 (91.0%), moderate in 1018 (7.9%), weak in 86 (0.7%), and completely absent (MRE11 deficiency) in 55 (0.4%) of 12,956 informative tumor samples. Only six tumor entities had more than one MRE11-deficient cases including hepatocellular carcinoma (9 of 193), intestinal type gastric adenocarcinoma (4 of 208), endometrioid endometrial carcinoma (5 of 268), pulmonary adenocarcinoma (2 of 165), colorectal adenocarcinoma (CRC, 16 of 2183), and clear cell renal cell carcinoma (ccRCC, 7 of 1011). Reduced MRE11 staining was associated with mismatch repair deficiency (dMMR) in CRC and in gastric adenocarcinoma (p < 0.0001 each), advanced pT stage (p = 0.0003) and L1 status (p = 0.0019) in testicular seminoma, high grade (p < 0.05), advanced pT (p < 0.0001), and high UICC stage (p = 0.0014) in ccRCC, advanced pT stage in high-grade serous ovarian carcinoma (p = 0.0396), and nodal metastases in papillary thyroid cancer (p = 0.0332). Conclusions: MRE11 is highly expressed in most cancers. Reduced MRE11 expression is associated with aggressive phenotype in multiple cancer types. The potential to exploit MRE11 deficiency as a target for synthetic lethality deserves to be further explored.

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: 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.