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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. [ABSTRACT FROM AUTHOR]

Androgen receptor (AR) is a transcription factor expressed in various normal tissues and is a therapeutic target for prostate and possibly other cancers. A TMA containing 18,234 samples from 141 different tumor types/subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. AR positivity was found in 116 tumor types including 66 tumor types (46.8%) with ≥1 strongly positive tumor. Moderate/strong AR positivity was detected in testicular sex cord-stromal tumors (93.3–100%) and neoplasms of the prostate (79.3–98.7%), breast (25.0–75.5%), other gynecological tumors (0.9–100%), kidney (5.0–44.1%), and urinary bladder (5.4–24.2%). Low AR staining was associated with advanced tumor stage (pTa versus pT2-4; p < 0.0001) in urothelial carcinoma; advanced pT (p < 0.0001), high tumor grade (p < 0.0001), nodal metastasis (p < 0.0001), and reduced survival (p = 0.0024) in invasive breast carcinoma; high pT (p < 0.0001) and grade (p < 0.0001) in clear cell renal cell carcinoma (RCC); and high pT (p = 0.0055) as well as high grade (p < 0.05) in papillary RCC. AR staining was unrelated to histopathological/clinical features in 157 endometrial carcinomas and in 221 ovarian carcinomas. Our data suggest a limited role of AR immunohistochemistry for tumor distinction and a prognostic role in breast and clear cell RCC and highlight tumor entities that might benefit from AR-targeted therapy. [ABSTRACT FROM AUTHOR]

Survivin is an inhibitor of apoptosis. Aberrant survivin expression occurs in malignant tumors and has often been linked to unfavorable patient outcome. Here we analyzed 12 432 prostate cancers by immunohistochemistry. Survivin immunostaining was regularly expressed at high levels in normal prostate epithelium but expression was often reduced in prostate cancers. Among 9492 evaluable prostate cancers, 9% expressed survivin strongly, 19% moderately, 28% weakly, and 44% lacked it. Loss of cytoplasmic survivin was seen in advanced tumor stage, higher Gleason score, preoperative PSA levels, and Ki‐67 labeling index, and associated with earlier PSA recurrence (P <.0001). Survivin loss was significantly more common in cancers carrying TMPRSS2:ERG fusions (61% survivin negative) than in ERG wild‐type cancers (32% survivin negative; P <.0001). Multivariate analysis revealed that reduced cytoplasmic survivin expression predicted poor prognosis independent from Gleason score, pT, pN, and serum PSA level. This was valid for ERG‐positive and ERG‐negative cancers. Survivin expression loss even retained its prognostic impact in 1020 PTEN deleted cancers, a group that is already characterized by dismal patient prognosis. In conclusion, reduced survivin expression is associated with more aggressive tumors and inferior prognosis in prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Centromere protein F (CENPF) is a key component of the kinetochore complex and plays a crucial role in chromosome segregation and cell cycle progression. Recent work suggests that CENPF upregulation is linked to aggressive tumor features in a variety of malignancies including prostate cancer. Materials and methods: Using a highly annotated tissue microarray, we analyzed CENPF protein expression from a cohort of 8,298 prostatectomized patients by immunohistochemistry to study its effect on prostate-specific antigen recurrence-free survival. Results: CENPF overexpression was found in 53% of cancers, and was linked to higher Gleason grade, advanced pathological tumor stage, accelerated cell proliferation, and lymph node metastasis (p<0.0001, each). A comparison with other key molecular features accessible through the microarray revealed strong associations between CENPF overexpression and presence of erythroblast transformation-specific (ETS)-related gene (ERG) fusion as well as phosphatase and tensin homolog deletion (p<0.0001, each). CENPF overexpression was linked to early biochemical recurrence. A subset analysis revealed that this was driven by the ERG-negative subset (p<0.0001). This was independent of established preoperative and postoperative prognostic parameters in multivariate analyses. Conclusion: The results of our study identify CENPF overexpression as an important mechanism and a potential biomarker for prostate cancer aggressiveness. [ABSTRACT FROM AUTHOR]

Background: Breast cancer anti-estrogen resistance 1 (BCAR1/p130cas) is a hub for diverse oncogenic signaling cascades and promotes tumor development and progression.Methods: To understand the effect of BCAR1 in prostate cancer, we analyzed its expression on more than 11,000 prostate cancer samples. BCAR1 expression levels were compared with clinical characteristics, PSA recurrence, molecular subtype defined by ERG status and 3p, 5q, 6q and PTEN deletion.Results: BCAR1 staining was barely detectable in normal prostate glands but seen in 77.6% of 9472 interpretable cancers, including strong expression in 38.5%, moderate in 23.2% and weak in 15.9% of cases. BCAR1 up regulation was associated with positive ERG status (p < 0.0001), high Gleason score (p < 0.0001), advanced pathological tumor stage (p = 0.0082), lower preoperative PSA level (p < 0.0001), increased cell proliferation (p < 0.0001), early PSA recurrence (p = 0.0008), and predicted prognosis independently from clinico-pathological parameters available at the time of the initial biopsy. However, subset analyses revealed that the prognostic impact of BCAR1 expression was limited to ERG-negative cancer. That BCAR1 up regulation was linked to almost all analyzed deletions (p < 0.0001 each for PTEN, 5q, 6q deletion) may suggest a functional link to genomic instability.Conclusion: The results of our study identify BCAR1 as a prognostic biomarker with potential clinical value for risk stratification of ERG-negative prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Animal model experiments have suggested a role of the DNA repair protein ERCC1 (Excision Repair Cross-Complementation Group 1) in prostate cancer progression.Methods: To better understand the impact of ERCC1 protein expression in human prostate cancer, a preexisting tissue microarray (TMA) containing more than 12,000 prostate cancer specimens was analyzed by immunohistochemistry and data were compared with tumor phenotype, PSA recurrence and several of the most common genomic alterations (TMPRSS2:ERG fusions: deletions of PTEN, 6q, 5q, 3p).Results: ERCC1 staining was seen in 64.7% of 10,436 interpretable tissues and was considered weak in 37.1%, moderate in 22.6% and strong in 5% of tumors. High-level ERCC1 staining was linked to advanced pT stage, high Gleason grade, positive lymph nodes, high pre-operative serum PSA, and positive surgical margin status (p < 0.0001 each). High ERCC1 expression was strongly associated with an elevated risk of PSA recurrence (p < 0.0001). This was independent of established prognostic features. A subgroup analysis of cancers defined by comparable quantitative Gleason grades revealed that the prognostic impact was mostly driven by low-grade tumors with a Gleason 3 + 3 or 3 + 4 (Gleason 4: ≤5%). High ERCC1 expression was strongly associated with the presence of genomic alterations and expression levels increased with the number of deletions present in the tumor. These latter data suggest a functional relationship of ERCC1 expression with genomic instability.Conclusion: The results of our study demonstrate that expression of ERCC1 - a potential surrogate for genomic instability - is an independent prognostic marker in prostate cancer with particular importance in low-grade tumors. [ABSTRACT FROM AUTHOR]

Mitochondria are relevant for cancer initiation and progression. Antibodies against mitochondrially encoded cytochrome c oxidase II (MTCO2), targeting a mitochondria specific epitope, can be used to quantitate the mitochondria content of tumor cells. The present study evaluated the impact of the cellular mitochondrial content on the prognosis of patients with breast cancer using immunohistochemical analysis on 2,197 arrayed breast cancer specimens. Results were compared with histological tumor parameters, patient overall survival, tumor cell proliferation using Ki67 labeling index (Ki67LI) and various other molecular features. Tumor cells exhibited stronger MTCO2 expression than normal breast epithelial cells. MTCO2 immunostaining was largely absent in normal breast epithelium, but was observed in 71.9% of 1,797 analyzable cancer specimens, including 34.6% tumors with weak expression, 22.3% with moderate expression and 15.0% with strong expression. High MTCO2 expression was significantly associated with advanced tumor stage, high Bloom-Richardson-Elston/Nottingham (BRE) grade, nodal metastasis and shorter overall survival (P<0.0001 each). In multivariate analysis, MTCO2 expression did not provide prognostic information independent of BRE grade, pathological tumor and pathological lymph node status. Additionally, significant associations were observed for high MTCO2 expression and various molecular features, including high Ki67LI, amplifications of HER2, MYC, CCND1 and MDM2, deletions of PTEN, 8p21 and 9p, low estrogen receptor expression (P<0.0001 each) and progesterone receptor expression (P<0.0001). The present study demonstrated that high MTCO2 expression was strongly associated with a poor prognosis and unfavorable phenotypical and molecular tumor features in patients with breast cancer. This suggests that the mitochondrial content may have a pivotal role in breast cancer progression. [ABSTRACT FROM AUTHOR]

GATA2 is a pioneering transcription factor governing androgen receptor expression and signaling in prostate cells. To understand the prognostic potential of GATA2 assessment in prostate cancer, we analyzed nuclear GATA2 expression on an annotated tissue microarray with 12,427 prostate cancer samples. Normal prostate glands were negative to weakly positive. GATA2 staining was found in almost all prostate cancers (95%). Strong GATA2 staining was linked to advanced tumor stage, high classical and quantitative Gleason grade (p < 0.0001 each), positive nodal stage (p = 0.0116), and early biochemical recurrence (p < 0.0001). GATA2 was linked to ERG -fusion-type cancers, with strong GATA2 staining in 29% of ERG-negative and 53% of ERG-positive cancers (p < 0.0001). Separate calculations in 3854 cancers with and 4768 cancers without TMPRSS2:ERG fusion revealed that these associations with tumor phenotype and patient outcome were largely driven by the subset of ERG-negative tumors. GATA2 expression was further linked to androgen receptor expression: Only 8% of androgen receptor-negative, but 56% of strongly androgen receptor expressing cancers had strong GATA2 expression (p < 0.0001). In conclusion, the results of our study demonstrate that increasing GATA2 levels are linked to prostate cancer progression and aggressiveness. The prognostic value of GATA2 is remarkable in ERG-negative cancers. However, the upregulation of GATA2 in ERG-positive cancers makes it unsuitable as a prognostic marker in this patient subset. [ABSTRACT FROM AUTHOR]

Background Nodal metastasis (N1) is a strong prognostic parameter in prostate cancer; however, lymph node evaluation is always incomplete. Objective To study the prognostic value of lymphatic invasion (L1) and whether it might complement or even replace lymph node analysis in clinical practice. Design, setting, and participants Retrospective analysis of pathological and clinical data from 14 528 consecutive patients. Intervention Radical prostatectomy. Outcome measurements and statistical analysis The impact of L1 and N1 on patient prognosis was measured with time to biochemical recurrence as the primary endpoint. Results and limitations Nodal metastases were found in 1602 (12%) of 13 070 patients with lymph node dissection. L1 was seen in 2027 of 14 528 patients (14%) for whom lymphatic vessels had been visualized by immunohistochemistry. N1 and L1 continuously increased with unfavorable Gleason grade, advanced pT stage, and preoperative prostate-specific antigen (PSA) values ( p < 0.0001 each). N1 was found in 4.3% of 12 501 L0 and in 41% of 2027 L1 carcinomas ( p < 0.0001). L1 was seen in 11% of 9868 N0 and in 61% of 1360 N1 carcinomas ( p < 0.0001). Both N1 and L1 were linked to PSA recurrence ( p < 0.0001 each). This was also true for 17 patients with isolated tumor cells (ie, <200 unequivocal cancer cells without invasive growth) and 193 metastases ≤1 mm. Combined analysis of N and L status showed that L1 had no prognostic effect in N1 patients but L1 was strikingly linked to PSA recurrence in N0 patients. N0L1 patients showed a similar outcome as N1 patients. Conclusions Analysis of lymphatic invasion provides comparable prognostic information than lymph node analysis. Even minimal involvement of the lymphatic system has pivotal prognostic impact in prostate cancer. Thus, a thorough search for lymphatic involvement helps to identify more patients with an increased risk for disease recurrence. Patient summary Already minimal amounts of tumor cells inside the lymph nodes or intraprostatic lymphatic vessels have a severe impact on patient prognosis. [ABSTRACT FROM AUTHOR]

Background Gleason grading is the strongest prognostic parameter in prostate cancer. Gleason grading is categorized as Gleason ≤6, 3 + 4, 4 + 3, 8, and 9–10, but there is variability within these subgroups. For example, Gleason 4 components may range from 5–45% in a Gleason 3 + 4 = 7 cancer. Objective To assess the clinical relevance of the fractions of Gleason patterns. Design, setting, and participants Prostatectomy specimens from 12 823 consecutive patients and of 2971 matched preoperative biopsies for which clinical data with an annual follow-up between 2005 and 2014 were available from the Martini-Klinik database. Outcome measurements and statistical analysis To evaluate the utility of quantitative grading, the fraction of Gleason 3, 4, and 5 patterns seen in biopsies and prostatectomies were recorded. Gleason grade fractions were compared with prostatectomy findings and prostate-specific antigen recurrence. Results and limitations Our data suggest a striking utility of quantitative Gleason grading. In prostatectomy specimens, there was a continuous increase of the risk of prostate-specific antigen recurrence with increasing percentage of Gleason 4 fractions with remarkably small differences in outcome at clinically important thresholds (0% vs 5%; 40% vs 60% Gleason 4), distinguishing traditionally established prognostic groups. Also, in biopsies, the quantitative Gleason scoring identified various intermediate risk groups with respect to Gleason findings in corresponding prostatectomies. Quantitative grading may also reduce the clinical impact of interobserver variability because borderline findings such as tumors with 5%, 40%, or 60% Gleason 4 fractions and very small Gleason 5 fractions (with pivotal impact on the Gleason score) are disclaimed. Conclusions Quantitative Gleason pattern data should routinely be provided in addition to Gleason score categories, both in biopsies and in prostatectomy specimens. Patient summary Gleason score is the most important prognostic parameter in prostate cancer, but prone to interobserver variation. The results of our study show that morphological aspects that define the Gleason grade in prostate cancer represent a continuum. Quantitation of Gleason patterns provides clinically relevant information beyond the traditional Gleason grading categories ≤3 + 3, 3 + 4, 4 + 3, 8, 9–10. Quantitative Gleason scoring can help to minimize variations between different pathologists and substantially aid in optimized therapy decision-making. [ABSTRACT FROM AUTHOR]

Mucin 5AC (MUC5AC) is a secreted gel-forming mucin which is expressed by mucus producing cells of several organs but can also be found in cancer cells of the ovary, pancreas, and gastrointestinal tract. This study aimed to characterize the expression of MUC5AC and its potential prognostic implications in different ovarian cancer subtypes. MUC5AC expression was analyzed by immunohistochemistry on a tissue microarray containing 603 ovarian cancers. MUC5AC was commonly expressed in mucinous (27/36; 75%) and endometrioid (12/39; 31%) carcinomas, whereas malignant mixed Mullerian tumors (2/27; 7%), high-grade serous (20/373; 5%) and clear cell carcinomas (1/28; 4%) were only rarely MUC5AC positive and also showed lower expression levels. MUC5AC positive endometroid carcinomas and high-grade serous carcinomas lacked lymph node metastases (p = 0.0495 and p = 0.0216) suggesting a more favorable prognosis. Deficient mismatch repair (dMMR), associated with a favorable prognosis in different cancer types, was found in 4/39 (10%) MUC5AC positive cancers but in only 5/375 (1%) of MUC5AC negative cancers (p = 0.0052). In subgroup analyses MUC5AC positive endometroid carcinomas more frequently showed dMMR (4/10; 40%) as opposed to MUC5AC negative endometroid carcinomas (3/23; 13%; p = 0.0932). In summary, the results of our study show that MUC5AC expression is associated with mucinous and endometrioid ovarian carcinomas, lack of nodal metastases and dMMR. MUC5AC expressing ovarian cancers should be evaluated for dMMR. [ABSTRACT FROM AUTHOR]

Background: The ongoing approval of adjuvant systemic therapy in high-risk kidney tumor will increase the demand for prognostic assessment in these tumors. 9p21 deletion has been suggested as a possible prognostic feature in clear cell kidney cancer.Material and Methods: To learn more on the prognostic relevance of 9p21 deletions in clear cell and other kidney tumors, 1,809 kidney tumor specimens were analyzed by dual-labeling fluorescence in situ hybridization (FISH) with probes for 9p21 and centromere 9 in a tissue microarray format. Results were compared to histologic tumor type, pT stage, grade, and patient outcome.Results: A total of 1,341 (74%) of tumor samples had interpretable FISH results. 9p21 deletion was found in 4.4% of 894 clear cell, 5.1% of 197 papillary, and 4.2% of 71 chromophobe carcinomas. 9p21 deletions were not found in 112 oncocytomas and in 21 clear cell tubulo-papillary cancers. In clear cell carcinomas, 9p deletions were associated with advanced stage (P = 0.009) and nodal metastasis (P = 0.0067), but not with ISUP grade (P = 0.1039) and distant metastasis (P = 0.4809). Also, in papillary carcinomas, 9p deletions were associated with advanced stage (P = 0.0008) and nodal metastasis (P = 0.0202) but not with ISUP grade (0.0904) and distant metastasis (P = 0.2022). Follow-up data were available for 789 clear cell and 177 papillary cancers. In both tumor entities, 9p21 deletions were associated with shortened overall survival, tumor-specific death, and progression-free survival in univariate analysis (P < 0.02 each). In a multivariate analysis, 9p21 deletion was an independent predictor of early tumor recurrence (P = 0.04).Conclusion: 9p21 deletions, 9p21 deletions identify a small subset of aggressive renal carcinomas. 9p deletion assessment may be clinically useful to identify high-risk renal cell carcinomas. [ABSTRACT FROM AUTHOR]