Special AT-rich Sequence-binding Protein 2 Expression Research Articles

SATB2 is an Emergent Biomarker of Anaplastic Thyroid Carcinoma: A Series with Comprehensive Biomarker and Molecular Studies.

Anaplastic thyroid carcinoma (ATC) is a rare and aggressive thyroid malignancy typically comprised of undifferentiated tumor cells with various histologic morphologies, which makes the diagnosis challenging. These tumors commonly show loss of thyroglobulin and TTF1 with preservation of cytokeratin (67%) and Paired Box Gene 8 (PAX8) (55%) expression. Identification of a sensitive immunohistochemical stain to aid in the diagnosis of ATC would be beneficial. Immunohistochemistry (IHC) against special AT-rich sequence-binding protein 2 (SATB2) protein is a sensitive and specific marker expressed in colorectal adenocarcinoma and bone or soft tissue tumors with osteoblastic differentiation. However, SATB2 is also expressed in other sarcomatous/undifferentiated neoplasms lacking osteoblastic differentiation. Using quantitative reverse transcription PCR (RT-qPCR) we showed that there is variable expression of SATB2 mRNA expression in ATCs. To evaluate the role of SATB2 protein expression in ATC, we performed PAX8, SATB2, pancytokeratin (AE1/AE3 & CAM5.2), claudin-4 and TTF1 immunostaining on 23 cases. ATCs showed retained expression of PAX8 in 65% (15/23); SATB2 was detected in 74% (17/23); pancytokeratin was expressed in 65% (15/23); claudin-4 was expressed in 35% (8/23) and TTF1 showed expression in 13% (3/23) of cases. Furthermore, 83% (5/6) of ATCs which lacked SATB2 expression, retained PAX8 expression, while 88% (7/8) of the tumors without PAX8 expression were positive for SATB2. Differentiated follicular cell-derived thyroid cancers (n = 30), differentiated high grade thyroid carcinoma (n = 3), and poorly differentiated thyroid carcinoma (n = 8) were negative for SATB2 immunoreactivity. Next-generation selected cases detected the commonly identified oncogenic variants including those in BRAF, RAS, TP53, and TERT promoter. Overall, we hereby demonstrate that SATB2 IHC may be used to support the diagnosis of ATC.

GATA4 is diagnostically useful for distinguishing primary ovarian mucinous carcinomas from metastatic colorectal adenocarcinomas to the ovary.

Determining the primary origin of an ovarian mucin-producing carcinoma can be challenging at times because some metastases of primary colorectal origin may exhibit gross, microscopic, and/or immunohistochemical features that overlap with those of primary ovarian mucinous carcinomas (OMCs). We hypothesized that GATA binding protein 4 (GATA4) might be a novel, useful marker for differentiating primary OMCs from metastatic colorectal adenocarcinomas to the ovary. For comparison with the usefulness of other markers (special AT-rich sequence-binding protein 2 (SATB2) and caudal type homeobox 2 (CDX2)), we elucidated the expression profiles of GATA4 in OMCs, colorectal non-mucinous adenocarcinomas (CNMACs), and colorectal mucinous adenocarcinomas (CMACs) using immunohistochemistry. We confirmed GATA4 expression (H-score ≥50 points) in 93%, SATB2 in 0%, and CDX2 in 64% of 14 OMCs. GATA4 was expressed in 13%, SATB2 in 90%, and CDX2 in 93% of 30 CNMACs. GATA4 was expressed in 20%, SATB2 in 73%, and CDX2 in 100% of 30 CMACs. The expression of GATA4 in a mucus-producing ovarian tumor strongly supports it being a primary OMC rather than a metastatic colorectal carcinoma: GATA4 expression indicates OMC and SATB2 expression indicates colorectal adenocarcinoma. However, three cases of colorectal adenocarcinoma were GATA4-positive and SATB2-negative, so the GATA4/SATB2 marker combination is not absolute for determining the primary site. Further research for more markers is necessary to find the ideal combination.

Increased GS-II lectin binding and SATB2 downregulation are biological features for sessile serrated lesions and microvesicular hyperplastic polyps.

Sessile serrated lesions (SSLs) and microvesicular hyperplastic polyps (MVHPs) are colorectal lesions displaying gastric differentiation. Griffonia simplicifolia-II (GS-II) is a lectin specific to terminal α/βGlcNAc residues. Here, we assessed GS-II binding and performed immunostaining for HIK1083 (specific to terminal αGlcNAc residues), MUC5AC, MUC6, and special AT-rich sequence binding protein 2 (SATB2) in SSLs, MVHPs, and tubular adenomas (TAs). We observed MUC5AC positivity in 28 of 30 SSLs, but in only three of 23 TAs. Moreover, 24 of 30 SSLs were MUC6-positive, while none of the 23 TAs were MUC6-positive. None of the 30 SSLs or 23 TAs showed HIK1083 positivity. All 30 SSLs and 26 MVHPs were GS-II-positive, while only seven of 23 were in TAs. GS-II staining was mainly distributed in the Golgi region, but SSLs and MVHPs showed goblet cell distribution, in 20 of 30 and 19 of 26 cases, respectively. All SSLs, MVHPs, and TAs were SATB2-positive, but 21 of 30 SSLs and 12 of 26 MVHPs showed decreased staining intensity relative to adjacent mucosa, a decrease seen in only two of 23 in TAs. These results indicate overall that increased terminal βGlcNAc and decreased SATB2 expression are characteristics of SSLs and MVHPs.

SATB2 as a Marker of the Proximal Nephron: Expression in Nephrogenic Adenoma and Correlation With Other Renal Tubular Markers.

Nephrogenic adenoma (NA) is an infrequent reactive urothelial lesion. The expression of immunohistochemical renal tubular markers has been reported in NA, although a proximal or distal nephron phenotype has not been established. Special AT-rich sequence-binding protein 2 (SATB2) is a marker of a colorectal origin of adenocarcinomas, occasionally reported in renal samples. We have analyzed SATB2 expression in NA, with correlation with other tubular markers, as well as in the normal kidney. Fifty cases of NA were immunostained with PAX8, SATB2, proximal nephron markers [CD10, renal cell carcinoma (RCC) marker, alpha-methylacyl-CoA racemase (AMACR), and CD15], and distal markers (Ksp cadherin, cytokeratin 7, E-cadherin (E-cad), and cytokeratin 19). Ten normal kidney sections were stained with a double method combining SATB2 plus CD10, RCC marker, AMACR, Ksp cadherin, cytokeratin 7, or E-cad. All NA were immunoreactive for PAX8 and 57% for SATB2. Every case was positive for proximal and distal nephron markers: 100% for cytokeratins 7 and 19, 84.1% E-cad +, 81.6% AMACR +, 68.9% Ksp cadherin +, 63% CD15 +, 53.3% CD10 +, and 28.6 % RCC +. In the normal kidney, SATB2 was detected in the straight part of the proximal tubules and the thin descending loops of Henle. NA shows a multiphenotypic pattern with coexpression of both proximal and distal nephron markers, and constant expression of PAX8, cytokeratins 7 and 19. SATB2 is often positive in NA, which should be kept in mind to avoid a possible misdiagnosis of intestinal adenocarcinoma. SATB2 is a marker of the normal proximal nephron.

Immunohistochemical Expression Profile of SATB2 in Colorectal Adenocarcinoma and Association with Clinicopathological Parameters

Introduction: Colorectal carcinoma is the third most common cancer worldwide. Several clinicopathological parameters act as prognostic factors in colorectal carcinoma, but only a few are helpful in predicting the treatment outcome. Therefore, there is a need for better prognostic markers which also aids in assessing treatment benefits in colorectal carcinoma patients. Special AT Rich Sequence Binding Protein 2 (SATB2) is a highly specific marker for colorectal tissue. Decreased expression of SATB2 is also associated with poor prognosis in colorectal carcinoma. Aim: To analyse the histomorphology, immunohistochemical expression profile of SATB2 and association with clinicopathological parameters in colorectal adenocarcinoma. Materials and Methods: The cross-sectional study included 84 cases of colorectal carcinoma received in the Department of Pathology, SRM Medical College Hospital and Research Centre, Kattankulathur, Chennai, Tamil Nadu, India, in the period between April 2021 to September 2022. Both biopsy and resected specimens were included in the study. Relevant clinical data was collected. Histological diagnosis, grading and staging of the tumour was done using Haematoxylin and Eosin (H&E) slides as described and tabulated. Immunohistochemistry (IHC) for SATB2 and was done and expression profile compared with the clinicopathological parameters to assess prognostic significance. Data was analysed using software-Statistical Package for Social Sciences (SPSS, version 23.0). Results: Out of the 84 cases, 42 were biopsy and 42 resected specimens. Mean age of the patients in the study was 57.9 years. Patients were predominantly males (n=51, 60.7%) with a male:female ratio of 1.54:1. Of the 84 cases, 40.5% (n=34) had tumour located in the rectum. Majority of the cases were moderately differentiated adenocarcinoma (n=48, 57.1%). Predominantly, stage III tumours (n=33, 39.3%) were noted. Out of the tumours showing decreased expression of SATB2, 55% (n=22) were left-sided tumours, metastasis was seen in 60% (n=24 cases), 37.5% of cases (n=9) showed lymphovascular invasion, and 55% (n=22) had a stage III tumour. Conclusion: The present study results indicate that a decrease in SATB2 expression is associated with presence of lymphovascular invasion, perineural invasion, regional and distant metastasis and a higher pathological stage which signifies poor prognosis in colorectal carcinoma. These aid the physician for risk stratification of patients and enable personalised treatment choices including adjuvant chemotherapy in high-risk groups.

Diagnostic accuracy of SATB2 in identifying primary and metastatic colorectal carcinoma: a comparative immunohistochemical study.

Special AT-rich sequence-binding protein 2 (SATB2) is a new marker that could identify the colonic origin, but whether its expression is preserved in metastatic colorectal carcinomas (CRCs) remains unclear. This study was designed to investigate SATB2 validity in the identification of CRC either alone or in combination with caudal-type homeobox 2 (CDX2) and/or cytokeratin 20 (CK20). Moreover, we examined the concordance of SATB2 expression in primary CRC and paired metastatic specimen. Immunohistochemical expression of SATB2, CDX2 and CK20 was evaluated in primary CRC, 50 paired metastatic CRC and 80 non-CRC specimens. This study demonstrated that the ideal SATB2 cut-off value for recognising colonic from non-colonic origin was 10%. SATB2 was more sensitive and specific than CK20. However, it was more specific but less sensitive than CDX2. Analysing the combined markers expression, SATB2 and CDX2 combination revealed better sensitivity, specificity and larger area under curve compared to SATB2 alone, CDX2 alone and combined CDX2 and CK20. Moreover, SATB2 was able to retain its expression at the metastatic sites. SATB2 was totally concordant between primary CRC and their paired metastatic sites (concordance rate = 100%) with perfect level of agreement. SATB2 could be considered as an accurate diagnostic marker of primary and metastatic CRC. SATB2 and CDX2 is the best combination serving the highest sensitivity and specificity in detection of CRC.

Loss of SATB2 expression correlates with cytokeratin 7 and PD-L1 tumor cell positivity and aggressiveness in colorectal cancer

Colorectal carcinoma (CRC) is a disease that causes significant morbidity and mortality worldwide. To improve treatment, new biomarkers are needed to allow better patient risk stratification in terms of prognosis. This study aimed to clarify the prognostic significance of colonic-specific transcription factor special AT-rich sequence-binding protein 2 (SATB2), cytoskeletal protein cytokeratin 7 (CK7), and immune checkpoint molecule programmed death-ligand 1 (PD-L1). We analyzed a cohort of 285 patients with surgically treated CRC for quantitative associations among the three markers and five traditional prognostic indicators (i.e., tumor stage, histological grade, variant morphology, laterality, and mismatch-repair/MMR status). The results showed that loss of SATB2 expression had significant negative prognostic implications relative to overall survival (OS) and cancer-specific survival (CSS), significantly shortened 5 years OS and CSS and 10 years CSS in patients with CRC expressing CK7, and borderline insignificantly shortened OS in patients with PD-L1 + CRC. PD-L1 showed a significant negative impact in cases with strong expression (membranous staining in 50–100% of tumor cells). Loss of SATB2 was associated with CK7 expression, advanced tumor stage, mucinous or signet ring cell morphology, high grade, right-sided localization but was borderline insignificant relative to PD-L1 expression. CK7 expression was associated with high grade and SATB2 loss. Additionally, a separate analysis of 248 neoadjuvant therapy-naïve cases was performed with mostly similar results. The loss of SATB2 and CK7 expression were significant negative predictors in the multivariate analysis adjusted for associated parameters and patient age. In summary, loss of SATB2 expression and gain of CK7 and strong PD-L1 expression characterize an aggressive phenotype of CRC.

SATB2 Expression in Human Tumors: A Tissue Microarray Study on More Than 15 000 Tumors.

Special AT-rich sequence-binding protein 2 (SATB2) induces local chromatin loops to facilitate transcription. SATB2 immunostaining is commonly used as a marker for colorectal adenocarcinoma and osteosarcoma. To extend our knowledge on the diagnostic value of SATB2 analysis in a comprehensive set of human tumors. Tissue microarrays with 15 012 samples from 120 tumor types and 608 samples of 76 different normal tissues were analyzed. SATB2 positivity was found in 89 of 120 different tumor types (74%), including 59 of 120 (49%) with at least 1 moderately positive tumor and 38 of 120 tumor types (32%) with at least 1 strongly positive tumor. Expression was frequent in adenomas (44/42-47/44; 94%-96% positive), adenocarcinomas (1747 of 2023; 86%), and various subtypes of neuroendocrine neoplasms (3/7-12/12; 43%-100%) of the colorectum and appendix, Merkel cell carcinoma (25 of 34, 74%), osteosarcomas (15 of 25; 60%), and papillary renal cell carcinoma (RCC) (121 of 235; 52%). Associations to clinicopathologic tumor features were assessed in colorectal and kidney cancers. In colorectal cancer, weak SATB2 expression was linked to high pT (P < .001), nodal metastasis (P < .001), right-sided tumor location (P < .001), microsatellite instability (P < .001), and BRAF mutations (P = .02). In papillary RCC, low SATB2 expression was associated with high pT (P = .02), distant metastasis (P = .04), and reduced tumor-specific survival (P = .04). In clear cell RCC, low SATB2 expression was linked to high pT (P < .001), high Union for International Cancer Control stage (P < .001), high Thoenes grade (P = .02), and reduced recurrence-free survival (P = .02). Strong SATB2 expression argues for a colorectal origin within adenocarcinomas and neuroendocrine neoplasms. Weak SATB2 expression reflects progression and poor prognosis in colorectal and kidney cancer.

Association Between Loss of SATB2 Expression in Inflammatory Bowel Disease Indefinite for Dysplasia and a Diagnosis of Definitive Dysplasia on Follow-up.

Special AT-rich sequence-binding protein 2 (SATB2) is a sensitive and specific biomarker for sporadic colonic adenocarcinomas. Previous studies have found that SATB2 is lost in some adenocarcinomas and dysplasias associated with inflammatory bowel disease (IBD). In establishing these findings, the prior studies did not examine cases of IBD interpreted as indefinite for dysplasia. We examined SATB2 expression in this diagnostic category to determine if any potential loss is associated with a diagnosis of definitive dysplasia on follow-up. To investigate this possibility, we collected 87 biopsies of IBD indefinite for dysplasia from 62 patients and stained them with SATB2. Among patients' indefinite for dysplasia, we found SATB2 loss in 6/62 (9.7%). Among those with follow-up (n=51), we observed 5/6 (83%) with a future dysplasia in those with SATB2 loss compared with 10/45 (22%) in those with SATB2 retention, absolute difference 61.1% (95% confidence interval=28.9%-93.3%). We conclude that loss of SATB2 on biopsies otherwise interpreted as IBD indefinite for dysplasia may mark a population at high risk for showing definitive dysplasia on future biopsies.

Impact of Neoadjuvant Chemotherapy on SATB2 Expression in Colorectal Carcinomas: SATB2 Positivity is Preserved in Most Cases, but Down-Expressed in Effective Cases of Chemotherapy.

Special AT-rich sequence-binding protein 2 (SATB2) is a novel, diagnostically useful, and highly sensitive immunohistochemical marker for both primary and metastatic colorectal or appendiceal tumors. In the present study, we aimed to assess the impact of neoadjuvant chemotherapy on SATB2 expression in primary colorectal carcinomas and their corresponding liver metastases. Forty-four patients with colorectal carcinomas who received neoadjuvant chemotherapy were included. SATB2 expression in specimens of biopsy, resected primary colorectal carcinomas, and resected metastatic foci were examined by immunohistochemistry and compared to caudal-type homeobox transcription factor 2 (CDX2). Using a modified H-score, expressions were scored semiquantitatively for both staining intensity and tumor cell proportion with nuclear staining. SATB2 was positive in 43/44 cases (98%) in biopsy specimens, 42/44 cases (96%) in resected colorectal carcinomas with neoadjuvant chemotherapy, and 9/9 cases (100%) with liver metastases. However, these expressions were variably decreased, and the H-score was lower in resected colorectal carcinomas (158 ± 69) than in biopsy specimens (174 ± 60) (p < 0.01). The proportion of SATB2-positive area of colorectal carcinoma was 93% in metastatic foci, while the CDX2-positive area was 78%. When categorized by histopathological tumor regression, the most effective tumors of chemotherapy showed the lowest H-score in resected colorectal carcinomas among the three groups (p < 0.01). SATB2 is a useful marker for both primary colorectal carcinoma and corresponding liver metastases, even with neoadjuvant chemotherapy. However, caution should be exercised when performing needle biopsy for metastatic foci with neoadjuvant therapy because expressions could be decreased, especially in chemotherapy-effective cases, and show immunohistochemically negative results.

Loss of SATB2 Occurs More Frequently Than CDX2 Loss in Colorectal Carcinoma and Identifies Particularly Aggressive Cancers in High-Risk Subgroups

Simple SummaryThe immunohistochemical analysis of Special AT-rich sequence-binding protein 2 (SATB2) is increasingly being used to detect colorectal differentiation. Our study aimed to investigate SATB2 expression levels and the prognostic relevance of SATB2 loss in colorectal carcinoma (CRC), especially in comparison with CDX2, the standard marker of colorectal differentiation. We tested SATB2 expression in 1039 CRCs and identified SATB2 as a strong prognosticator in the overall cohort as well as in specific subcohorts, including high-risk subgroups. Compared to CDX2, SATB2 showed a higher prognostic power but was lost at a much higher frequency, generally rendering SATB2 as the less sensitive marker for colorectal differentiation compared to CDX2.Background: Special AT-rich sequence-binding protein 2 (SATB2) has emerged as an alternative immunohistochemical marker to CDX2 for colorectal differentiation. However, the distribution and prognostic relevance of SATB2 expression in colorectal carcinoma (CRC) have to be further elucidated. Methods: SATB2 expression was analysed in 1039 CRCs and correlated with clinicopathological and morphological factors, CDX2 expression as well as survival parameters within the overall cohort and in clinicopathological subgroups. Results: SATB2 loss was a strong prognosticator in univariate analyses of the overall cohort (p < 0.001 for all survival comparisons) and in numerous subcohorts including high-risk scenarios (UICC stage III/high tumour budding). SATB2 retained its prognostic relevance in multivariate analyses of these high-risk scenarios (e.g., UICC stage III: DSS: p = 0.007, HR: 1.95), but not in the overall cohort (DSS: p = 0.1, HR: 1.25). SATB2 loss was more frequent than CDX2 loss (22.2% vs. 10.2%, p < 0.001) and of higher prognostic relevance with only moderate overlap between SATB2/CDX2 expression groups. Conclusions: SATB2 loss is able to identify especially aggressive CRCs in high-risk subgroups. While SATB2 is the prognostically superior immunohistochemical parameter compared to CDX2 in univariate analyses, it appears to be the less sensitive marker for colorectal differentiation as it is lost more frequently.

SATB2 expression in human tumors: A tissue microarray study on more than 15,000 tumors

Abstract Introduction/Objective Introduction: Special AT-rich sequence-binding protein 2 (SATB2) binds to DNA in specific nuclear matrix attachment regions and facilitates chromatin remodeling. SATB2 immunostaining is commonly used as a marker for colorectal adenocarcinoma and osteosarcoma. Methods/Case Report Methods: To comprehensively evaluate SATB2 expression in normal and tumor tissues, a tissue microarray containing 15,012 samples from 120 different tumor types and subtypes and 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry. Results (if a Case Study enter NA) Result: SATB2 positivity was found in 89 different tumor types including 59 with at least one moderately positive and 38 tumor types with at least one strongly positive tumor. Most frequent and strongest expression were found in adenomas (94-96%), adenocarcinomas (86%) and various subtypes of neuroendocrine neoplasms (43-100%) of the colorectum and appendix, Merkel cell carcinoma (74%), osteosarcomas (60%), and papillary renal cell carcinoma (RCC) (52%). In colorectal cancer, weak SATB2 expression was linked to high pT (p&amp;lt;0.0001), nodal metastasis (p&amp;lt;0.0001), right-sided tumor location (p&amp;lt;0.0001), microsatellite instability (p=0.0004), and BRAF mutations (p&amp;lt;0.0224). In papillary RCC, low SATB2 was associated with high pT (p=0.0197), distant metastasis (p=0.042), and reduced tumor specific survival (p=0.0395). In clear cell RCC, low SATB2 was linked to high pT (p&amp;lt;0.0001), high UICC stage (p&amp;lt;0.0001), high Thoenes grade (p=0.0178), and reduced recurrence free survival (p=0.0216). Conclusion SATB2 expression can occur in many different tumor entities. Strong SATB2 expression argues for a colorectal tumor origin within adenocarcinomas and neuroendocrine neoplasms. Weak SATB2 expression reflects cancer progression and poor prognosis in colorectal and kidney cancer.

Expression of SATB2 in Acute Myeloid Leukemia and Its Prognostic Significance

Background: Human special AT-rich sequence-binding protein-2 (SATB2) is a novel DNA binding protein, which is involved in regulating gene expression. Recent studies conducted to evaluate the clinical significance of SATB2 in multiple malignant carcinomas, and have yielded controversial results. The purpose of this study is to investigate the expression status of SATB2 and its prognostic significance in AML patients.Methods: Total RNA was extracted from bone marrow or plasma of 87 patients with AML and 21 health volunteers. The expression of SATB2 was examined by Realtime quantitative PCR. The relationship of SATB2 expression and other clinicopathological charactors and its prognosis significance were statistically analyzed.Results: The relative expression of SATB2 was significantly up-regulated in AML patients (median value 0.061, range: 0.007-0.328) in comparison to those of healthy volunteers (median value 0.033, range: 0.008-0.077; P < 0.001) , and SATB2 expression level was much lower in patients who had achieved CR (median value 0.005, range: 0.001-0.006;P < 0.001) compared with newly diagnosed AML patients(median value 0.010, range: 0.002-0.027;P < 0.001).Furthermore, the expression of SATB2 was markedly associated with gender(P =0.043), WBC count(P =0.001), platelet count (P =0.025), BM blast count (P = 0.007) and Complete Remission (P < 0.001). Patients with higher SATB2 expression had a relatively poor overall survival(OS) (P = 0.009) and short disease-free survival(DFS) (P < 0.001). Moreover, SATB2 expression was an independent prognostic factors for both OS (P = 0.001) and DFS (P = 0.006).Conclusions: SATB2 was significantly up-regulated in AML patients in comparison to healthy donors. Patients who had achieved CR usually had a lower level of SATB 2 expression compared with newly diagnosed AML patients. The over-expression of SATB2 is associated with poor prognosis in AML patients, and was an independent prognostic factor for both OS and DFS. DisclosuresNo relevant conflicts of interest to declare.

SATB2 Expression in Uterine Sarcoma: A Multicenter Retrospective Study.

Uterine sarcomas represent a clinical challenge because of their difficult diagnosis and the poor prognosis of certain subtypes. The aim of this study was to evaluate the expression of the special AT-rich sequence-binding protein 2 (SATB2) in endometrial stromal sarcoma (ESS) and other types of uterine sarcoma by immunohistochemistry. We studied the expression of SATB2 on 71 full tissue sections of endometrial stromal nodule, low-grade ESS, uterine leiomyomas and leiomyosarcoma, undifferentiated uterine sarcoma, adenosarcoma, and carcinosarcoma samples. Nuclear SATB2 expression was then evaluated in an extended sample set using a tissue microarray, including 78 additional uterine tumor samples. Overall, with a cut-off of ≥10% of tumor cell staining as positive, the nuclear SATB2 score was negative in all endometrial stromal nodule samples (n=10) and positive in 83% of low-grade ESS samples (n=29/35), 40% of undifferentiated uterine sarcoma (n=4/10), 13% of leiomyosarcoma (n=2/16), 14% of adenosarcoma (n=3/22), and 8% carcinosarcoma (n=2/25) samples. Furthermore, in ESS patients, direct comparison of nuclear SATB2 scores with clinicopathologic parameters and other reported biomarkers such as progesterone receptor and estrogen receptor showed that nuclear SATB2 was associated with PR expression and a decreased risk of disease-specific death (odds ratio=0.06, 95% confidence interval=0.04-0.81, P=0.04). Our data suggest that SATB2 could be a marker with relative sensitivity (83%) for distinguishing between endometrial stromal nodule and ESS with potential prognostic value.

Wrong place, wrong time: Runt-related transcription factor 2/SATB2 pathway in bone development and carcinogenesis.

Upregulation or aberrant expression of genes such as special AT-rich sequence-binding protein 2 (SATB2) is necessary for normal cell differentiation and tissue development and is often associated with carcinogenesis and metastatic progression. SATB2 is a critical transcription factor for biological development of various specialized cell lineages, such as osteoblasts and neurons. The dysregulation of SATB2 expression has recently been associated with various types of cancer, while the mechanisms and pathways by which it mediates tumorigenesis are not well elucidated. Runt-related transcription factor 2 (RUNX2) is a master regulator for osteogenesis, and it shares common pathways with SATB2 to regulate bone development. Interestingly, these two transcription factors co-occur in several epithelial and mesenchymal cancers and are linked by multiple cancer-related proteins and microRNAs. This review examines the interactions between RUNX2 and SATB2 in a network necessary for normal bone development and the circumstances in which the expression of RUNX2 and SATB2 in the wrong place and time leads to carcinogenesis.

Small Bowel Adenocarcinomas Featuring Special AT-Rich Sequence-Binding Protein 2 (SATB2) Expression and a Colorectal Cancer-Like Immunophenotype: A Potential Diagnostic Pitfall.

Simple SummarySince small bowel adenocarcinoma may mimic a colorectal primary neoplasm histologically, it is pivotal to find biomarkers to discriminate these two biologically distinct neoplasms. The aim of our study was to evaluate the expression of special AT-rich sequence-binding protein 2 (SATB2), expressed in the vast majority of colorectal carcinomas, and other gastrointestinal phenotypic markers, such as cytokeratin 7, cytokeratin 20 and caudal type homeobox 2 (CDX2), in 100 small bowel adenocarcinomas. We identified 20 SATB2-positive small bowel adenocarcinomas, including nine sporadic cancers, seven celiac disease-associated cancers and four Crohn’s disease-associated small bowel adenocarcinomas. Six small bowel adenocarcinomas, including two cases associated with celiac disease and four sporadic, displayed a full colorectal carcinoma-like immunoprofile. Unlike SATB2, cytokeratin patterns stratified small bowel adenocarcinoma patient prognosis. The small bowel should be considered as one of the possible sites of origin in cancers of unknown primary, even when the neoplasm shows a colorectal carcinoma-like immunoprofile.Special AT-rich sequence-binding protein 2 (SATB2) is a transcription factor expressed by colonic cryptic epithelium and epithelial neoplasms of the lower gastrointestinal (GI) tract, as well as by small bowel adenocarcinomas (SBAs), though at a lower rate. Nevertheless, up to now, only small SBA series, often including a very limited number of Crohn’s disease-associated SBAs (CrD-SBAs) and celiac disease-associated SBAs (CD-SBA), have been investigated for SATB2 expression. We evaluated the expression of SATB2 and other GI phenotypic markers (cytokeratin (CK) 7 and CK20, caudal type homeobox 2 (CDX2) and alpha-methylacyl-CoA racemase (AMACR)), as well as mismatch repair (MMR) proteins, in 100 SBAs, encompassing 34 CrD-SBAs, 28 CD-SBAs and 38 sporadic cases (Spo-SBAs). Any mutual association and correlation with other clinico-pathologic features, including patient prognosis, were searched. Twenty (20%) SATB2-positive SBAs (4 CrD-SBAs, 7 CD-SBAs and 9 Spo-SBAs) were identified. The prevalence of SATB2 positivity was lower in CrD-SBA (12%) in comparison with both CD-SBAs (25%) and Spo-SBAs (24%). Interestingly, six SBAs (two CD-SBAs and four Spo-SBAs) displayed a full colorectal carcinoma (CRC)-like immunoprofile (CK7−/CK20+/CDX2+/AMACR+/SATB2+); none of them was a CrD-SBA. No association between SATB2 expression and MMR status was observed. Although SATB2-positive SBA patients showed a more favorable outcome in comparison with SATB2-negative ones, the difference did not reach statistical significance. When cancers were stratified according to CK7/CK20 expression patterns, we found that CK7−/CK20- SBAs were enriched with MMR-deficient cases (71%) and patients with CK7−/CK20− or CK7−/CK20+ SBAs had a significantly better survival rate compared to those with CK7+/CK20− or CK7+/CK20+ cancers (p = 0.002). To conclude, we identified a small (6%) subset of SBAs featuring a full CRC-like immunoprofile, representing a potential diagnostic pitfall in attempts to identify the site of origin of neoplasms of unknown primary site. In contrast with data on colorectal carcinoma, SATB2 expression is not associated with MMR status in SBAs. CK patterns influence patient survival, as CK7−/CK20− cancers show better prognosis, a behavior possibly due to the high rate of MMR-deficient SBAs within this subgroup.

Hepatocellular carcinomas can be Special AT-rich sequence-binding protein 2 positive: an important diagnostic pitfall

Special AT-rich sequence-binding protein 2 (SATB2) is a sensitive and specific marker for tumors originating with the colon and appendix. It is now commonly used in surgical pathology, while working up carcinomas of unknown primary. We had anecdotally encountered occasional hepatocellular carcinomas (HCCs) that were SATB2 positive. Immunohistochemical expression of SATB2 in HCChas not yet been examined in detail. In this study, we evaluated SATB2 expression in 46 HCCs. Nineteen (41%) of 46 HCCs were positive for SATB2. SATB2 expression in HCCs was more commonly seen in poorly differentiated tumors (11 of 13 cases, 85%) than well and moderately differentiated tumors (8 of 33 cases, 24%), p value=0.0001. No other statistically significant correlations were observed (p>0.05). There were no other statistically significant correlations between SATB2 expression and age, gender, background liver disease, and cirrhosis (p>0.05). Results of our study show that a significant subset (41%) of HCCs can be SATB2 positive. Awareness of this phenomenon is important as SATB2 expression in a liver tumor does not completely exclude a diagnosis of HCC.

A41 LOSS OF SATB2 EXPRESSION IN COLORECTAL CANCER IS ASSOCIATED WITH DURATION OF INFLAMMATORY BOWEL DISEASE

Abstract Background Patients with inflammatory bowel disease (IBD) are at higher risk for developing colitis-associated colorectal cancer (CAC). Clinical and endoscopic features are used to stratify the risk of CAC, but new biomarkers are necessary to improve this stratification. Recent studies have shown that loss of expression of special AT-rich sequence binding protein 2 (SATB2) is frequent in CAC compared to sporadic colorectal cancer and this SATB2 status is found in pre-cancerous dysplastic lesions as well. However, the relationship of known clinical risk factors for CAC and loss of SATB2 has not been explored. Aims To assess the association of loss of SATB2 expression in CAC with clinical characteristics of IBD. Methods Patients with a known diagnosis of ileocolonic or colonic Crohn’s disease (CD), ulcerative colitis (UC), or IBD unclassified (IBDU) who underwent colectomy between October 2010 and December 2017 for CAC were included. SATB2 expression in neoplastic tissue was evaluated using immunohistochemistry (IHC), where less than 5% of tumor cells showing staining was considered loss of SATB2. Tumor grade, P53 and mismatch repair (MMR) status were assessed as well. Available clinical data such as sex, smoking status, IBD diagnosis (CD, UC or IBDU), age at IBD diagnosis, duration of IBD, extent of colitis and previous medications were collected. We used a generalized linear model to assess the association between these biomarkers and clinical data. Results A total of 58 patients with mean age at CAC diagnosis of 50.3 ±13 years, 27 (46%) females were analyzed. Mean IBD duration was 17.6 ±10 years and 22 (37.9%), 34 (58.6%) and 2 (3.4%) were CD, UC and IBDU, respectively. Thirty-two (55.2%) CACs had loss of SATB2 expression. There was no association between age at CAC diagnosis or grade of the tumor and loss of SATB2. However, longer duration of IBD (21.2 ± 9 years vs 13.7 ± 9 years, p = 0.01) was significantly associated with loss of SATB2. There was no association between SATB2 status and other explored clinical or endoscopic variables. Tumors with P53 mutation were associated with a younger age at diagnosis of CAC (47.2 ±13 vs 55.0 ±12 years, p = 0.03), but no other associations of this marker or MMR with clinical or endoscopic variables of IBD were found. Conclusions Loss of SATB2 expression is significantly associated with IBD duration, a well-known risk factor for CAC. This association with duration of IBD could denote an effect of longer chronic inflammation on SATB2 status. Given the previously reported association of loss of expression of SATB2 with pre-cancerous lesions in IBD patients, this could be a potential biomarker for risk of CAC. Funding Agencies National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

SATB2 in neuroendocrine neoplasms: strong expression is restricted to well-differentiated tumours of lower gastrointestinal tract origin and is most frequent in Merkel cell carcinoma among poorly differentiated carcinomas.

Special AT-rich sequence-binding protein 2 (SATB2) is a transcriptional regulator with critical roles in brain, craniofacial and skeletal development. It has emerged as a key marker of lower gastrointestinal (GI) tract columnar epithelial and osteoblastic differentiation. Transcription factor immunohistochemistry is useful in assigning site of origin in well-differentiated neuroendocrine tumours (NETs), and has had a limited role in poorly differentiated neuroendocrine carcinomas (NECs). This study sought to evaluate the role of SATB2 in assigning site of origin in neuroendocrine epithelial neoplasms. Tissue microarrays were constructed from the following: 317 NETs (37 thyroid, 46 lung, 16 stomach, 12 duodenum, 70 pancreas, 106 jejunoileum, 24 appendix, and six rectosigmoid), 44 phaeochromocytomas/paragangliomas, and 79 NECs (29 Merkel cell, 30 lung, and 20 extrapulmonary visceral); nine appendiceal and 19 rectal NETs were examined in whole sections. SATB2 immunohistochemistry was scored for extent (%) and intensity (0-3+), with an H-score being calculated. SATB2 was expressed by 96% of rectosigmoid NETs, 79% of appendiceal NETs, and only 7% of other well-differentiated neoplasms (P<0.0001). Expression in lower GI tract NETs (median H-score of 255) was stronger than in other positive tumours (median H-score of 7) (P<0.0001). Any SATB2 expression was 86% sensitive/93% specific for lower GI tract origin. SATB2 was expressed by 79% of Merkel cell carcinomas (median H-score of 300), 33% of lung NECs (median H-score of 23), and 60% of extrapulmonary visceral NECs (median H-score of 110), with stronger expression in Merkel cell carcinoma (P<0.001). At an H-score cutoff of ≥150, SATB2 was 69% sensitive/90% specific for Merkel cell carcinoma. SATB2 is frequently and strongly expressed by lower GI tract NETs; we have adopted it as our rectal NET marker. Relatively frequent and strong expression in Merkel cell carcinoma may have value in assigning NEC site of origin.

MiR‐34a inhibits the proliferation, migration, and invasion of oral squamous cell carcinoma by directly targeting SATB2

In various kinds of carcinomas, the special AT-rich sequence-binding protein 2 (SATB2) with its atypical expression promotes the metastasis and progression of the tumor, though in the oral squamous cell carcinoma (OSCC) its inherent mechanism and the status of SATB2 remain unclear. The role played by the SATB2 expression in the OSCC cell lines and tissue samples in the target of miR-34a downstream is the intended endeavor of this study. In te OSCCs the miR-34a expression was determined by quantitative real-time polymerase chain reaction (q-PCR), while the SATB2 expression in the cell lines and tissue samples in OSCC was analyzed with the q-PCR and the western blot. Studies in both in vitro and in vivo of the effects of miR-34a on the initiation of OSCC were conducted. As a direct target of the miR-34a the SATB2 was verified with the luciferase reporter assay. In cases where the miR-34a levels were low, the SATB2 in OSCCs seemed to be overexpressed. Besides, both in the in vitro and in vivo a suppression of migration, invasion, and cell growth was caused by miR-34a by down regulating the SATB2 expression. The SATB2 being a direct target of miR-34a was confirmed by the cotransfection of miR-34a mimics specifically the decrease in the expression of luciferase of SATB2-3'UTR-wt reporter. As a whole, our study confirmed the inhibition of miR-34a in the invasion, proliferation, and migration of the OSCCs, playing a potential tumor suppressor role with SATB2 as its downstream target.