S100A1

Gene Summary

Gene:S100A1; S100 calcium binding protein A1
Aliases: S100, S100A, S100-alpha
Location:1q21.3
Summary:The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in stimulation of Ca2+-induced Ca2+ release, inhibition of microtubule assembly, and inhibition of protein kinase C-mediated phosphorylation. Reduced expression of this protein has been implicated in cardiomyopathies. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein S100-A1
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: S100A1 (cancer-related)

Bai Y, Li LD, Li J, Lu X
Prognostic values of S100 family members in ovarian cancer patients.
BMC Cancer. 2018; 18(1):1256 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Exhibiting high consistence in sequence and structure, S100 family members are interchangeable in function and they show a wide spectrum of biological processes, including proliferation, apoptosis, migration, inflammation and differentiation and the like. While the prognostic value of each individual S100 in ovarian cancer is still elusive. In current study, we investigated the prognostic value of S100 family members in the ovarian cancer.
METHODS: We used the Kaplan Meier plotter (KM plotter) database, in which updated gene expression data and survival information are from 1657 ovarian cancer patients, to assess the relevance of individual S100 family mRNA expression to overall survival in various ovarian cancer subtypes and different clinicopathological features.
RESULTS: It was found that high expression of S100A2 (HR = 1.18, 95%CI: 1.04-1.34, P = 0.012), S100A7A (HR = 1.3, 95%CI: 1.04-1.63, P = 0.02),S100A10 (HR = 1.2, 95%CI: 1.05-1.38, P = 0.0087),and S100A16 (HR = 1.23, 95%CI: 1-1.51, P = 0.052) were significantly correlated with worse OS in all ovarian cancer patients, while the expression of S100A1 (HR = 0.87, 95%CI: 0.77-0.99, P = 0.039), S100A3 (HR = 0.83, 95%CI: 0.71-0.96, P = 0.0011), S100A5 (HR = 0.84, 95%CI: 0.73-0.97, P = 0.017), S100A6 (HR = 0.84, 95%CI: 0.72-0.98, P = 0.024), S100A13 (HR = 0.85, 95%CI:0.75-0.97, P = 0.014) and S100G (HR = 0.86, 95%CI: 0.74-0.99, P = 0.041) were associated with better prognosis. Furthermore, we assessed the prognostic value of S100 expression in different subtypes and the clinicopathological features, including pathological grades, clinical stages and TP53 mutation status, of ovarian cancer patients.
CONCLUSION: Comprehensive understanding of the S100 family members may have guiding significance for the diagnosis and outcome of ovarian cancer patients.

Xiong TF, Pan FQ, Li D
Expression and clinical significance of S100 family genes in patients with melanoma.
Melanoma Res. 2019; 29(1):23-29 [PubMed] Free Access to Full Article Related Publications
Genes in the S100 family are abnormally expressed in a variety of tumor cells and are associated with clinical pathology, but their prognostic value in melanoma patients has not yet been fully elucidated. In this study, we extracted and profiled S100 family mRNA expression data and corresponding clinical data from the Gene Expression Omnibus database to analyze how expression of these genes correlates with clinical pathology. Compared with normal skin, S100A1, S100A13, and S100B were expressed at significantly higher levels in melanoma samples. S100A2, S100A7, S100A8, S100A9, S100A10, S100A11, and S100P were all highly expressed in primary melanoma samples but were expressed at low levels in metastatic melanoma, and all of these genes were strongly correlated with each other (P<0.001). We found the expression of these S100 family genes to be significantly correlated with both lymphatic and distant melanoma metastasis, as well as with American Joint Committee on Cancer grade but not with Clark's grade, age, or sex. This suggests that expression of these genes may be related to the degree of tumor invasion. Although further validation through basic and clinical trials is needed, our results suggest that the S100 family genes have the potential to play an important role in the diagnosis of melanoma. S100 expression may be related to tumor invasion and may facilitate the early diagnosis of melanoma, allowing for a more accurate prognosis. Targeted S100 therapies are also potentially viable strategies in the context of melanoma.

Guo Q, Wang J, Cao Z, et al.
Interaction of S100A1 with LATS1 promotes cell growth through regulation of the Hippo pathway in hepatocellular carcinoma.
Int J Oncol. 2018; 53(2):592-602 [PubMed] Free Access to Full Article Related Publications
Despite advances in surgery and chemotherapy, the prognosis of patients with hepatocellular carcinoma (HCC) remains poor. In the present study, the role of S100A1 in the progression of HCC was investigated. Immunohistochemical staining was used to measure the expression of S100A1 in HCC tissues. S100A1 was knocked down by siRNA. A battery of experiments was used to evaluate the biology functions of S100A1. It was found that S100A1 was upregulated in HCC tissues, and its upregulation was associated with a large tumor size, low differentiation and shorter survival time. The biological experiments demonstrated that S100A1 functions as an oncogene in HCC. It was also found that S100A1 knockdown enhanced the inhibitory effects of cisplatin on HCC cells. The results showed that the downregulation of S100A1 induced the phosphorylation of yes‑associated protein (YAP), and treatment with CHX demonstrated that the downregulation of S100A1 accelerated YAP protein degradation. The downregulation of S100A1 did not alter the expression of mammalian sterile 20‑like kinase (MST)1/2 or phosphorylated MST1/2, but upregulated the phosphorylation of large tumor suppressor kinase 1 (LATS1). It was further confirmed that S100A1 interacted with LATS1. LATS1 depletion significantly reduced the effects of S100A1 on cell growth rate and apoptosis, and there was a positive correlation between phosphorylated LATS1 and S100A1 in clinical samples, indicating that LATS1 was responsible for the S100A1-induced changes in cancer cell growth and Hippo signaling. In conclusion, the results of the present study indicated that S100A1 functions as an oncogene and may be a biomarker for the prognosis of patients with HCC. S100A1 exerted its oncogenic function by interacting with LATS1 and activating YAP. S100A1 may serve as a target for novel therapies in HCC.

Raffat MA, Hadi NI, Hosein M, et al.
S100 proteins in oral squamous cell carcinoma.
Clin Chim Acta. 2018; 480:143-149 [PubMed] Related Publications
BACKGROUND: Controversy exists in the literature regarding the differential expression of S100 protein members and their functional correlations in oral squamous cell carcinoma (OSCC). The aim of the present study was to systematically review the expression of S100 protein family members among OSCC and healthy controls and to evaluate whether S100 protein members serve as diagnostic marker in OSCC.
METHODS: Indexed databases were searched up to and including October 2017. Case-control/cross-sectional studies in human diagnosed clinically and/or histologically with OSCC and evaluated the expression of S100 protein family among OSCC and healthy controls were included.
RESULTS: A total of 11 studies were included. Four studies were of good quality, 5 were of moderate and 2 were of poor quality. Five studies evaluated S100A2, A7 and A12 and showed overexpression of these protein levels in OSCC patients when compared to healthy controls. Three studies reported down-regulation of S100A1, A3, A6, A11, A13, A14, A16 and S100Z in OSCC patients as compared to healthy controls. Two studies reported overexpression of S100A9 and one study each reported overexpression of S100A4, A8, A10, and S100P in OSCCs as compared to healthy controls respectively.
CONCLUSION: It remains debatable whether up-regulation or down-regulation of specific S100 protein members serves as a diagnostic marker in OSCC. With the findings of the present systematic review, the threshold for diagnostic levels of S100 proteins cannot be proposed. In addition, S100A7 protein could act as a potential OSCC marker. However, further case-control studies with larger sample size are required to obtain strong conclusion in this regard.

Chen G, Sun W, Hua X, et al.
Long non-coding RNA FOXD2-AS1 aggravates nasopharyngeal carcinoma carcinogenesis by modulating miR-363-5p/S100A1 pathway.
Gene. 2018; 645:76-84 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) have been wildly verified to modulate multiple tumorigenesis, especially nasopharyngeal carcinoma (NPC). In present study, we aim to investigate the role of lncRNA FOXD2-AS1 in the NPC carcinogenesis. It was indicated that FOXD2-AS1 was markedly increased in NPC tissues and cells in comparison to their corresponding controls. Moreover, the aberrant overexpression of FOXD2-AS1 indicated the poor prognosis of NPC patients. Silence of FOXD2-AS1 was able to repress NPC cell growth in vitro while overexpression of FOXD2-AS1 inversed this process. Moreover, in vivo tumor xenografts were established using CNE-1/SUNE-1 cells to investigate the function of FOXD2-AS1 in NSCLC tumorigenesis. Rescue assay was performed to further confirm that FOXD2-AS1 contributed to NPC progression by regulating miR-363-5p/S100A1 signal pathway. Taken together, our study discovered the oncogenic role of FOXD2-AS1 in clinical specimens and cellular experiments, showing the potential FOXD2-AS1/miR-363-5p/S100A1 pathway. This results and findings provide a novel insight for NPC tumorigenesis.

Wu L, Zhou X, Xiao Z, et al.
Functional expression, characterization, and application of human S100B.
Oncol Rep. 2017; 38(4):2309-2316 [PubMed] Related Publications
The EF-hand calcium-binding protein S100B presents a wide range of biological activities and functions. This binding protein is involved in various human diseases, including cancer, brain trauma and ischemia, neuro-degenerative disease (Alzheimer's disease), and psychiatric disorders. In this study, we prepared human S100B protein and its monoclonal antibodies. Human S100B protein was expressed in Escherichia coli, successfully purified by diethylaminoethyl cellulose anion-exchange chromatography, and then identified by western blot analysis. Monoclonal antibodies (mAbs) were produced by the standard hybridoma method and validated by enzyme-linked immunosorbent assay and western blot analysis. The prepared human S100B protein and its mAbs demonstrated potential biological activities. The KD of one mAb is approximately 4.72x10-8 mol/l, and its cross reactivity is low with human S100A4, mouse S100A4, and human S100A1. Recombinant Soluble S100B can promote the migration and invasion of HeLa cells. The expression of S100B protein in tumor tissues can be detected effectively by using the prepared monoclonal antibodies. Increasing concentration of the anti-human S100B mAbs showed a reduced expression of the S100B protein. Subsequently, the expression of p53 increased significantly (P<0.05) in A375 cells. A significant increase in apoptosis in A375 cells was observed with increasing S100B mAb concentration. Results showed that our prepared S100B mAbs were suitable for detecting S100B expression in human tissues, furnishing promising tools for further functional investigation and clinical applications.

Tian T, Li X, Hua Z, et al.
S100A1 promotes cell proliferation and migration and is associated with lymph node metastasis in ovarian cancer.
Discov Med. 2017; 23(127):235-245 [PubMed] Related Publications
S100A1 is a calcium-binding protein belonging to the family of S100 proteins, and is highly expressed in ovarian cancer. However, its role in ovarian cancer has not yet been fully elucidated. In this study, we examined S100A1 expression in ovarian cancer tissues and normal tissue controls and analyzed the correlation between S100A1 expression and clinicopathological parameters. We found that S100A1 expression was significantly upregulated in ovarian cancer tissues compared with fallopian and normal ovarian epithelium tissues and was significantly associated with lymph node metastasis and International Federation of Gynecology and Obstetrics (FIGO) stages and tumor grades. We then investigated the biological functions of S100A1 in ovarian cancer by cell proliferation, fluorescence-activated cell sorting (FACS), and migration and invasion assays. The results indicated that S100A1 enhanced the ovarian cancer cell proliferation and migration. Together, our findings demonstrated that S100A1 plays an important role in the malignancy of ovarian cancer, and serves as a useful marker for the detection of ovarian malignancy.

Kryvenko ON
Categorizing renal oncocytic neoplasms on core needle biopsy: a morphologic and immunophenotypic study of 144 cases with clinical follow-up. Alderman MA, Daignault S, Wolf JS Jr, Palapattu GS, Weizer AZ, Hafez KS, Kunju LP, Wu AJ. Hum Pathol.September 2016;55:1-10.
Urol Oncol. 2017; 35(6):452-453 [PubMed] Related Publications
There is limited literature on renal oncocytic neoplasms diagnosed on core biopsy. All renal oncocytic neoplasm core biopsies from 2006 to 2013 were, retrospectively, reviewed. Morphologic features and an immunohistochemical panel of CK7, c-KIT, and S100A1 were assessed. Concordance with resection diagnosis, statistical analysis including a random forest classification, and follow-up were recorded. The postimmunohistochemical diagnoses of 144 renal oncocytic core biopsies were favor oncocytoma (67%), favor renal cell carcinoma (RCC) (12%), and cannot exclude RCC (21%). Diagnosis was revised following immunohistochemistry in 7% of cases. The most common features for oncocytoma (excluding dense granular cytoplasm) were nested architecture, edematous stroma, binucleation and tubular architecture; the most common features for favor RCC were sheet-like architecture, nuclear pleomorphism, papillary architecture, and prominent cell borders. High nuclear grade, necrosis, extensive papillary architecture, raisinoid nuclei, and frequent mitoses were not seen in oncocytomas. Comparing the pathologist and random forest classification, the overall out-of-bag estimate of classification error dropped from 23% to 13% when favor RCC and cannot exclude RCC was combined into 1 category. Resection was performed in 19% (28 cases) with a 94% concordance (100% of favor RCC biopsies and 90% of cannot exclude RCC biopsies confirmed as RCC; 83% of favor oncocytomas confirmed); ablation in 23%; and surveillance in 46%. Follow-up was available in 92% (median follow-up, 33 months) with no adverse outcomes. Renal oncocytic neoplasms comprise a significant subset (16%) of all core biopsies, and the majority (78%) can be classified as favor oncocytoma or favor RCC.

Palo S, Biligi DS
Differential diagnostic significance of HBME-1, CK19 and S100 in various thyroid lesions.
Malays J Pathol. 2017; 39(1):55-67 [PubMed] Related Publications
OBJECTIVE: Due several overlapping histomorphological features and pitfalls in thyroid pathology, there is need to establish a panel of immunomarkers that would aid in proper diagnosis. This study was carried out to investigate the ability of HBME-1, CK19, and S100 in differentiating between hyperplastic, benign and malignant thyroid lesions.
MATERIALS AND METHODS: Immunohistochemical analysis of 60 thyroidectomy specimens (10 hyperplastic nodules, 14 follicular adenomas and 36 malignant thyroid neoplasms) was carried out. The extent and intensity of HBME-1, CK19, and S100 immunoreactivity was assessed in each case.
RESULTS: HBME-1 positivity was noted in 86.1% of malignant cases while the majority of the benign lesions were negative. Diffuse strong CK19 positivity was documented in 27/31 papillary carcinoma whereas all cases of follicular carcinoma and medullary carcinoma were negative. Most of the hyperplastic nodules and follicular adenomas were also CK19 negative, although focal weak staining was noted in a few cases. S100 was positive only in medullary carcinoma. HBME-1 was most sensitive (86.1%) and specific (87.5%) in distinguishing between benign and malignant thyroid lesions. The diagnostic accuracy was further increased when HBME-1 was used simultaneously with CK19/S100/CK19+S100. The sequential use of HBME-1 and CK19 also proved beneficial in discriminating between the various follicular-patterned thyroid lesions.
CONCLUSION: HBME-1 immunolabeling suggests malignancy, whereas strong diffuse CK19 positivity substantiates papillary differentiation. The utilization of these markers (alone or in combination) along with histomorphological evaluation is helpful in the differential diagnosis. S100 has minimal utility in this regard.

Hatoum D, Yagoub D, Ahadi A, et al.
Annexin/S100A Protein Family Regulation through p14ARF-p53 Activation: A Role in Cell Survival and Predicting Treatment Outcomes in Breast Cancer.
PLoS One. 2017; 12(1):e0169925 [PubMed] Free Access to Full Article Related Publications
The annexin family and S100A associated proteins are important regulators of diverse calcium-dependent cellular processes including cell division, growth regulation and apoptosis. Dysfunction of individual annexin and S100A proteins is associated with cancer progression, metastasis and cancer drug resistance. This manuscript describes the novel finding of differential regulation of the annexin and S100A family of proteins by activation of p53 in breast cancer cells. Additionally, the observed differential regulation is found to be beneficial to the survival of breast cancer cells and to influence treatment efficacy. We have used unbiased, quantitative proteomics to determine the proteomic changes occurring post p14ARF-p53 activation in estrogen receptor (ER) breast cancer cells. In this report we identified differential regulation of the annexin/S100A family, through unique peptide recognition at the N-terminal regions, demonstrating p14ARF-p53 is a central orchestrator of the annexin/S100A family of calcium regulators in favor of pro-survival functions in the breast cancer cell. This regulation was found to be cell-type specific. Retrospective human breast cancer studies have demonstrated that tumors with functional wild type p53 (p53wt) respond poorly to some chemotherapy agents compared to tumors with a non-functional p53. Given that modulation of calcium signaling has been demonstrated to change sensitivity of chemotherapeutic agents to apoptotic signals, in principle, we explored the paradigm of how p53 modulation of calcium regulators in ER+ breast cancer patients impacts and influences therapeutic outcomes.

Zhang S, Wang Z, Liu W, et al.
Distinct prognostic values of S100 mRNA expression in breast cancer.
Sci Rep. 2017; 7:39786 [PubMed] Free Access to Full Article Related Publications
S100 family genes encode low molecular weight, acidic-Ca

Moy AP, Duncan LM, Kraft S
Lymphatic invasion and angiotropism in primary cutaneous melanoma.
Lab Invest. 2017; 97(2):118-129 [PubMed] Related Publications
Access of melanoma cells to the cutaneous vasculature either via lymphatic invasion or angiotropism is a proposed mechanism for metastasis. Lymphatic invasion is believed to be a mechanism by which melanoma cells can disseminate to regional lymph nodes and to distant sites and may be predictive of adverse outcomes. Although it can be detected on hematoxylin- and eosin-stained sections, sensitivity is markedly improved by immunohistochemistry for lymphatic endothelial cells. Multiple studies have reported a significant association between the presence of lymphatic invasion and sentinel lymph node metastasis and survival. More recently, extravascular migratory metastasis has been suggested as another means by which melanoma cells can spread. Angiotropism, the histopathologic correlate of extravascular migratory metastasis, has also been associated with melanoma metastasis and disease recurrence. Although lymphatic invasion and angiotropism are not currently part of routine melanoma reporting, the detection of these attributes using ancillary immunohistochemical stains may be useful in therapeutic planning for patients with melanoma.

Eccher A, Boschiero L, Delahunt B, et al.
De Novo Renal Neoplasia After Kidney Transplantation According to New 2016 WHO Classification of Renal Tumors.
Ann Transplant. 2016; 21:745-754 [PubMed] Related Publications
BACKGROUND De novo renal neoplasia developing after kidney transplantation at Verona Kidney Transplant Center were reviewed according to new 2016 WHO Renal Tumor Classification. MATERIAL AND METHODS Primary renal tumors developed in native or transplanted kidneys de novo following renal transplantation were retrieved and histologically reviewed by three expert uropathologists. Immunoexpression of the diagnostic antigens CD13, CD10, CK7, CK34bE12, AMACR, CAIX, AE1/AE3, CK14, GATA-3, HMB-45, cathepsin-k, S100A1, and parvalbumin was assessed. Predictive antigens ph-mTOR and ph-p70S6k were also tested. RESULTS Two thousands and sixteen kidney transplantations have been carried out from 1968-2015. Follow-up was available per 1,646 patients (mean 8.4 years). We observed 16 cases of de novo renal neoplasia arising in patients 16 to 286 months post-transplantation. Nine clear cell, two papillary RCCs and a single case of the new WHO entity denominated "acquired cystic disease-associated RCC" were identified in native kidneys. Another new WHO tumor entity called "clear cell papillary RCC" was diagnosed and a new variant of papillary RCC with diffuse clear cytoplasm was also identified. The majority of tumors were low stage and low grade according to the new ISUP grading system. Seven patients were additionally treated with mTOR inhibitors. Post-cancer follow-up ranged from 62 to 281 months. One patient showed a recurrence (a lung metastases) and died. Of the remaining patients, three died of non-cancer-related causes. CONCLUSIONS The application of the new WHO 2016 classification has importance as it identifies new (18% of tumors) morphotypes that are likely to behave in a less aggressive fashion.

Máca J, Burša F, Ševčík P, et al.
Alarmins and Clinical Outcomes After Major Abdominal Surgery-A Prospective Study.
J Invest Surg. 2017; 30(3):152-161 [PubMed] Related Publications
PURPOSE: Tissue injury causing immune response is an integral part of surgical procedure. Evaluation of the degree of surgical trauma could help to improve postoperative management and determine the clinical outcomes.
MATERIALS AND METHODS: We analyzed serum levels of alarmins, including S100A5, S100A6, S100A8, S100A9, S100A11, and S100A12; high-mobility group box 1; and heat-shock protein 70, after elective major abdominal surgery (n = 82). Blood samples were collected for three consecutive days after surgery. The goals were to evaluate the relationships among the serum levels of alarmins and selected surgical characteristics and to test potential of alarmins to predict the clinical outcomes.
RESULTS: Significant, positive correlations were found for high-mobility group box 1 with the length of surgery, blood loss, and intraoperative fluid intake for all three days of blood sampling. The protein S100A8 serum levels showed positive correlations with intensive care unit length of stay, 28-day and in-hospital mortality. The protein S100A12 serum levels had significant, positive correlations with intensive care unit length of stay, 28-day mortality, and in-hospital mortality. We did not find significant differences in alarmin levels between cancer and noncancer subjects.
CONCLUSION: The high-mobility group box 1 serum levels reflect the degree of surgical injury, whereas proteins S100A8 and S100A12 might be considered good predictors of major abdominal surgery morbidity and mortality.

Alderman MA, Daignault S, Wolf JS, et al.
Categorizing renal oncocytic neoplasms on core needle biopsy: a morphologic and immunophenotypic study of 144 cases with clinical follow-up.
Hum Pathol. 2016; 55:1-10 [PubMed] Related Publications
There is limited literature on renal oncocytic neoplasms diagnosed on core biopsy. All renal oncocytic neoplasm core biopsies from 2006 to 2013 were retrospectively reviewed. Morphologic features and an immunohistochemical panel of CK7, c-KIT, and S100A1 were assessed. Concordance with resection diagnosis, statistical analysis including a random forest classification, and follow-up were recorded. The post-immunohistochemical diagnoses of 144 renal oncocytic core biopsies were favor oncocytoma (67%), favor renal cell carcinoma (RCC) (12%), and cannot exclude RCC (21%). Diagnosis was revised following immunohistochemistry in 7% of cases. The most common features for oncocytoma (excluding dense granular cytoplasm) were nested architecture, edematous stroma, binucleation and tubular architecture; the most common features for favor RCC were sheet-like architecture, nuclear pleomorphism, papillary architecture, and prominent cell borders. High nuclear grade, necrosis, extensive papillary architecture, raisinoid nuclei, and frequent mitoses were not seen in oncocytomas. Comparing the pathologist and random forest classification, the overall out-of-bag estimate of classification error dropped from 23% to 13% when favor RCC and cannot exclude RCC were combined into 1 category. Resection was performed in 19% (28 cases) with a 94% concordance (100% of favor RCC biopsies and 90% of cannot exclude RCC biopsies confirmed as RCC; 83% of favor oncocytomas confirmed); ablation in 23%; and surveillance in 46%. Follow-up was available in 92% (median follow-up, 33months) with no adverse outcomes. Renal oncocytic neoplasms comprise a significant subset (16%) of all core biopsies, and the majority (78%) can be classified as favor oncocytoma or favor RCC.

Ng KL, Morais C, Bernard A, et al.
A systematic review and meta-analysis of immunohistochemical biomarkers that differentiate chromophobe renal cell carcinoma from renal oncocytoma.
J Clin Pathol. 2016; 69(8):661-71 [PubMed] Related Publications
BACKGROUND: Numerous immunohistochemical (IHC) biomarkers have been employed to aid in the difficult differentiation between chromophobe renal cell carcinoma (chRCC) and renal oncocytoma (RO). A systematic review and meta-analysis of the published literature was carried out to summarise and analyse the evidence for discriminatory IHC biomarkers to differentiate the two entities.
METHODS: PubMed database was used to identify relevant literature. Primary end point was comparison of positive immunostaining of the biomarkers in chRCC and RO, with extracted data used to calculate OR and 95% CI and statistical I(2) test of heterogeneity for multiple studies.
RESULTS: One hundred and nine manuscripts were available for review. Data extracted were subjected to quantitative meta-analysis. Ten most effective biomarkers (OR of chRCC/RO and CI) are: amylase α1A (n=129, OR=0.001, 95% CI 0.0001 to 0.019); Wnt-5a (n=38, OR=0.0076, 95% CI 0.0004 to 0.015); FXYD2 (n=57, OR=130, 95% CI 14.2 to 1192.3); ankyrin-repeated protein with a proline-rich region (ARPP) (n=25, OR=0.0054, 95% CI 0.0002 to 0.12); cluster of differentiation 63 (CD63) (n=62, diffuse (chRCC) vs apical/polar (RO) stain pattern); transforming growth factor β 1 (TGFβ1) (n=34, membranous (chRCC) vs cytoplasmic (RO)); cytokeratin 7 (CK7) (11 studies, n=448, pooled OR=44.22, 95% CI 22.52 to 86.64, I(2)=15%); S100A1 (4 studies, n=124, pooled OR=0.01, 95% CI 0 to 0.03, I(2)=0%); caveolin-1 (2 studies, n=102, pooled OR=32.95, 95% CI 3.67 to 296.1, I(2)=70%) and claudin-7 (3 studies, n=89, pooled OR=24.7, 95% CI 6.28 to 97.1, I(2)=0%).
CONCLUSIONS: We recommend a panel of IHC biomarkers of amylase α1A, Wnt-5a, FXYD2, ARPP, CD63, TGFβ1, CK7, S100A1, caveolin-1 and claudin-7 to aid in the differentiation of chRCC and RO.

Zhang W, Wang K, Yu W, et al.
[Diagnostic utility of S100A1, GLUT-1 and Caveolin-1 in renal tumors with oncocytic features: a comparative study].
Zhonghua Bing Li Xue Za Zhi. 2015; 44(11):767-71 [PubMed] Related Publications
OBJECTIVE: To study the immunohistochemical expression of S100A1, GLUT-1 and Cavolin-1 and its diagnostic significance in renal tumors with oncocytic features.
METHODS: Tissue microarray and immunohistochemical staining for S100A1, GLUT-1 and Cavolin-1 were carried out in 59 cases of renal tumors with oncocytic features, including 19 cases of renal oncocytoma, 15 cases of clear cell renal cell carcinoma (CCRCC) with eosinophilic cells, 11 cases of eosinophilic variant of chromophobe renal cell carcinoma, 7 cases of oncocytic papillary renal cell carcinoma and 7 cases of epithelioid angiomyolipoma.
RESULTS: S100A1 was expressed in renal oncocytoma, with a positive propotion of 16/19 (including 14 cases showing widespread and strong positivity). On the other hand, the rate of expression of S100A1 was 2/11 in eosinophilic variant of chromophobe renal cell carcinoma, 10/15 in CCRCC with eosinophilic cells, 3/7 in oncocytic papillary renal cell carcinoma and 6/7 in epithelioid angiomyolipoma (P>0.05). The difference of S100A1 expression between renal oncocytoma and eosinophilic variant of chromophobe renal cell carcinoma was statistically significant. GLUT-1 was located in cell membrane, with a positive rate of 13/15 in CCRCC with eosinophilic cells, 7/19 in renal oncocytoma, 4/7 (weak) in oncocytic papillary renal cell carcinoma, 1/11 in eosinophilic variant of chromophobe renal cell carcinoma and 0/7 in epithelioid angiomyolipoma. The rate of expression of Cav-1 was 6/15 in CCRCC with eosinophilic cells, 2/7 in oncocytic papillary renal cell carcinoma, 5/7 in epithelioid angiomyolipoma, 2/11 (weak) in eosinophilic variant of chromophobe renal cell carcinoma and 0/19 in renal oncocytoma. S100A1 showed high sensitivity and 50% specificity in the diagnosis of renal oncocytoma. GLUT-1 and Cav-1 showed high specificity and sensitivity in the diagnosis of CCRCC and epithelioid angiomyolipoma.
CONCLUSIONS: S100A1 is widely expressed in various oncocytic renal neoplasms and helpful in differential diagnosis of renal oncocytoma from eosinophilic variant of chromophobe renal cell carcinoma, but not from other 3 oncocytic renal tumors. Overexpression of GLUT-1 can be used in distinction between CCRCC and renal oncocytoma. Cav-1 is widely expressed in CCRCC and epithelioid angiomyolipoma but not in renal oncocytoma. Cav-1 expression thus rules out renal oncocytoma.

Eryilmaz U, Demirci B, Aksun S, et al.
S100A1 as a Potential Diagnostic Biomarker for Assessing Cardiotoxicity and Implications for the Chemotherapy of Certain Cancers.
PLoS One. 2015; 10(12):e0145418 [PubMed] Free Access to Full Article Related Publications
This study examined the value of blood marker S100A1 in detecting cardiotoxicity induced by chemotherapy agents; trastuzumab and lapatinib, in normal rat heart. The rats were divided into three groups: control (n = 8, no treatment), T (n = 8, one time ip treatment with 10 mg/kg trastuzumab) and L (n = 8, oral treatment with 100 mg/kg/day lapatinib for 7 days). The activities of oxidative stress parameters Malondialdehyde (MDA), Superoxide dismutase (SOD), Catalase (CAT) and Glutathione (GSH) were measured from the extracted cardiac tissues. The levels of troponinI and S100A1 expressions were measured from blood samples. All biomarkers responded to the treatments as they exhibited alterations from their normative values, validating the chemically induced cardiotoxicity. S100A1 expression attenuated significantly (75%), which made the sensitive detection of cardiotoxicity feasible. Assessment of cardiotoxicity with S100A1 may be a valuable alternative in clinical oncology of cancers in some organs such as breast and prostate, as they do not overexpress it to compete against.

Conner JR, Hirsch MS, Jo VY
HNF1β and S100A1 are useful biomarkers for distinguishing renal oncocytoma and chromophobe renal cell carcinoma in FNA and core needle biopsies.
Cancer Cytopathol. 2015; 123(5):298-305 [PubMed] Related Publications
BACKGROUND: Morphologic overlap between renal oncocytoma (RO) and chromophobe renal cell carcinoma (ChRCC) can pose diagnostic challenges, especially in biopsy samples in which tumor quantity may be limited, architectural features are not well represented, and gross examination is not possible. It has been demonstrated that immunohistochemistry (IHC) for HNF1α, HNF1β, and S100A1 are differentially expressed in RO and ChRCC in resection specimens. We evaluated the utility of these markers in FNA and core biopsies of RO and ChRCC.
METHODS: IHC for HNF1α, HNF1β, and S100A1 were performed on 61 RO specimens (36 FNA biopsies and 25 core biopsies) and on 14 ChRCC specimens (10 FNA biopsies and 4 core biopsies), and results were scored semiquantitatively for staining intensity (0-3: negative, weak, moderate, strong) and staining extent (0-4: 0%, 1-25%, 26-50%, 51-75%, 76-100%).
RESULTS: Forty-four (44) of 60 (73%) RO displayed moderate-to-strong nuclear reactivity for HNF1β compared to 3 of 14 (21%) ChRCC (P < .001). Staining was present in >50% of tumor cells in 34 of 60 (57%) RO and in 2 of 14 (14%) ChRCC (P = .004). S100A1 was moderately-to-strongly positive in 45 of 56 (80%) RO and in 1 of 13 (8%) ChRCC (P < .001), with 39 of 56 (70%) and 2 of 13 (15%) cases, respectively showing positivity in >50% of tumor cells (P< .001). No ChRCCs were positive for both markers. There was no statistically significant difference in intensity or extent of HNF1α staining between RO and ChRCC.
CONCLUSIONS: HNF1β and S100A1 positivity was observed in a significantly greater proportion of RO than ChRCC. IHC for both markers can thus aid in the differential diagnosis. Accurate distinction is of increasing importance as tumor-ablative procedures and active surveillance become more widely adopted.

Iribe Y, Kuroda N, Nagashima Y, et al.
Immunohistochemical characterization of renal tumors in patients with Birt-Hogg-Dubé syndrome.
Pathol Int. 2015; 65(3):126-32 [PubMed] Related Publications
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder associated with a germline mutation of folliculin (FLCN). The affected families are at a high risk for developing multiple renal cell carcinomas (RCC). Little is known about the immunostaining patterns of mutant FLCN-associated RCCs. We investigated 32 RCCs obtained from 17 BHD patients. The studied tumors included chromophobe RCCs (n = 15), hybrid oncocytic/chromophobe tumors (HOCT) (n = 14) and clear cell RCCs (n = 3). Almost all chromophobe RCCs and HOCTs revealed positive staining for S100A1, Ksp-cadherin and CD82. They stained either focally or diffusely for CK7, and were negative for CA-IX. All clear cell RCCs were positively stained for CA-IX and negative for CK7. These data confirmed that mutant FLCN-associated oncocytic and clear cell RCCs exhibited generally similar immunostaining patterns compared to their sporadic counterparts. Frequent positive staining for S100A1, Ksp-cadherin and CD82 in chromophobe RCCs and HOCTs indicated that these two types were relatively similar rather than distinctively different in their patterns of immunoreactivity. Characteristic peri-nuclear halos and polygonal cells with clear cytoplasm, which often misleads pathologists into the diagnosis of clear cell RCC, should be carefully examined using an immunohistochemical panel including CA-IX, Ksp-cadherin, CD82 and CK7.

Tsuchiya M, Yamaguchi F, Shimamoto S, et al.
Oxidized S100A4 inhibits the activation of protein phosphatase 5 through S100A1 in MKN‑45 gastric carcinoma cells.
Int J Mol Med. 2014; 34(6):1713-9 [PubMed] Related Publications
S100 proteins bind to numerous target proteins, as well as other S100 proteins and activate signaling cascades. S100 proteins can be modified by various post-translational modifications, such as phosphorylation, methylation and acetylation. In addition, oxidation is important for modulating their activities. Previous studies have shown that S100A1 interacts with S100A4 in vitro and in vivo. Due to this potential cross‑talk among the S100 proteins, the aim of the present study was to examine whether S100A4 modulates the activity of S100A1. S100A4 was readily oxidized and formed disulfide-linked dimers and oligomers. Although non-oxidized S100A4 bound to protein phosphatase 5 (PP5), the Cu-oxidized S100A4 failed to bind PP5. Instead, the Cu-oxidized S100A4 directly interacted with S100A1 and prevented PP5 activation. Hydrogen peroxide induced S100A4 oxidation in MKN-45 gastric adenocarcinoma cells and decreased S100A1‑PP5 interaction, resulted in the inhibition of PP5 activation by S100A1. These data indicate that oxidized S100A4 regulates PP5 activity in a unique manner under oxidative stress conditions.

Tyszkiewicz T, Jarzab M, Szymczyk C, et al.
Epidermal differentiation complex (locus 1q21) gene expression in head and neck cancer and normal mucosa.
Folia Histochem Cytobiol. 2014; 52(2):79-89 [PubMed] Related Publications
Epidermal differentiation complex (EDC) comprises a number of genes associated with human skin diseases including psoriasis, atopic dermatitis and hyperkeratosis. These genes have also been linked to numerous cancers, among them skin, gastric, colorectal, lung, ovarian and renal carcinomas. The involvement of EDC components encoding S100 proteins, small proline-rich proteins (SPRRs) and other genes in the tumorigenesis of head and neck squamous cell cancer (HNSCC) has been previously suggested. The aim of the study was to systematically analyze the expression of EDC components on the transcript level in HNSCC. Tissue specimens from 93 patients with HNC of oral cavity and 87 samples from adjacent or distant grossly normal oral mucosawere analyzed. 48 samples (24 tumor and 24 corresponding surrounding tissue) were hybridized to Affymetrix GeneChip Human 1.0 ST Arrays. For validation by quantitative real-time PCR (QPCR) the total RNA from all180 samples collected in the study was analyzed with Real-Time PCR system and fluorescent amplicon specific-probes. Additional set of samples from 14 patients with laryngeal carcinoma previously obtained by HG-U133 Plus 2.0 microarray was also included in the analyses. The expression of analyzed EDC genes was heterogeneous. Two transcripts (S100A1 and S100A4) were significantly down-regulated in oral cancer when compared to normal mucosa (0.69 and 0.36-fold change, respectively), showing an opposite pattern of expression to the remaining S100 genes. Significant up-regulation in tumors was found for S100A11, S100A7, LCE3D, S100A3 and S100A2 genes. The increased expression of S100A7 was subsequently validated by QPCR, confirming significant differences. The remaining EDC genes, including all encoding SPRR molecules, did not show any differences between oral cancer and normal mucosa. The observed differences were also assessed in the independent set of laryngeal cancer samples, confirming the role of S100A3 and LCE3D transcripts in HNC. In HNC of oral cavity only one family of EDC genes (S100 proteins) showed significant cancer-related differences. A number of other transcripts which showed altered expression in HNC require further validation.

Yordanov A, Ivanov I, Popovska S, et al.
[Evaluation of the expression of S100A1 protein in serous, mucinous and endometroid ovarian carcinoma].
Akush Ginekol (Sofiia). 2013; 52(5):22-6 [PubMed] Related Publications
According to literature approximately 60% from all ovarian malignances express epithelial phenotype. According to their histomorphological characteristics, epithelial ovarian tumors are divided into eight groups. In some particular cases, separate histological types are hard to distinguish one from another. Recent studies show the presence of beneficial effect of adjuvant radiotherapy on most of the early ovarian carcinomas (all, except serous carcinomas). In renal cell carcinomas SI00A 1 is used to distinguish between different subtypes of the malignancy. Forty cases of ovarian carcinomas were analyzed in a retrospective study. Immunohistochemical evaluation of the S100A1 protein expression was carried out on representative archival formalin -fixed -paraffin-embedded tissue materials. Positivity for S100A1 was observed in 31 (77.50%) of the studied cases. Twenty-seven out of thirty-two (84.38%) cases of serous ovarian carcinoma were found to express S100A1. S100A1 expression was observed in one out of the two mucinous and three out of the six endometroid ovarian carcinomas. Immunopositivity was nuclear, cytoplasmic or nuclear and cytoplasmic in serous carcinomas, nuclear in the one positive mucinous carcinoma and sytoplasmic in the three imunopositive endometroid ovarian carcinomas. The S100A1 immunohistochemical marker is not likely to be useful in clinical practice to distinguish between different histological subtypes of ovarian cancer. The large percentage of S100A1 positivity in serous ovarian carcinomas needs a better understanding.

López JI, Schiavo-Lena M, Corominas-Cishek A, et al.
Nephrogenic adenoma of the urinary tract: clinical, histological, and immunohistochemical characteristics.
Virchows Arch. 2013; 463(6):819-25 [PubMed] Related Publications
Nephrogenic adenoma is a benign condition of the urinary tract resulting from the displacement and seeding of renal tubular cells from the renal pelvis to the urethra. A retrospective series of 134 cases collected from four hospitals in three different countries was analyzed in this study. Recorded clinical data included age and sex, topography, urological antecedents, coexistent lesions, and follow-up. Cytonuclear and architectural features were reviewed, and PAX-8, p63, PSMA, S100A1, CEA, EMA, CD117, cannabinoid receptor CB1, AMACR, E-cadherin, and CD10 antibodies were included in an immunohistochemical panel. Males predominated (105 M/29 F) with an average age of 66 years (range, 14-96). Urothelial carcinoma was the most frequent clinical antecedent (43.2 %) and also the most common coexisting lesion (14 %). Tubular architecture was the most frequent pattern detected (40 %) although most cases showed a mixed pattern (45.5 %). Deep infiltrative growth into the muscularis propria occurred in two cases. EMA and PAX-8 were expressed in 100 % of nephrogenic adenomas, while E-cadherin reactivity was observed in 66.6 % of cases, cannabinoid receptor CB1 in 25 %, CD10 in 13.6 %, CD117 in 4.1 %, and AMACR in 2.7 %. For the rest of the antigens, no reactivity was found. The average time lapse between the pathological antecedent and the discovery of a nephrogenic adenoma was 32 months. We conclude that nephrogenic adenoma displays a broad spectrum of histological features that may mimic malignancy. In our experience, CB1 immunostaining adds a further argument in favor of a renal origin of this lesion. The combination of PAX-8+, p63-, and EMA + distinguishes nephrogenic adenoma from urothelial and prostate carcinoma, its most frequent malignant look-alikes.

Lyle M, Long GV
Diagnosis and treatment of KIT-mutant metastatic melanoma.
J Clin Oncol. 2013; 31(26):3176-81 [PubMed] Related Publications
A 52-year-old man has unresectable locally recurrent melanoma of the left foot (Fig 1) and pulmonary metastases. Nine months before this presentation, he underwent a wide local excision and sentinel node biopsy for an acral melanoma on his left heel. Pathology disclosed Breslow thickness of 4.8 mm, Clark level IV, and tumor ulceration with a mitotic rate of 37 mitoses/mm(2). Both sentinel nodes in the left groin were positive for melanoma cells, which expressed S100, HMB45, and melan A. At subsequent left inguinal dissection, seven more nodes showed no additional nodal metastases. Within 3 months of his original surgery, the patient developed a local recurrence in the foot, and over the subsequent 6 months, he underwent serial local excisions and topical diphencyprone treatment. A recent staging scan showed at least 20 foci of in-transit disease in the left lower leg and foot, as well as a solitary lung metastasis (12 mm). His Eastern Cooperative Oncology Group performance status is 1, with no significant comorbidities. High-resolution melt followed by sequencing of an in-transit metastasis showed there is no BRAF exon 15 mutation. However, Sanger sequencing of KIT exons 9, 11, 13, and 17, performed as screening for a clinical trial enrolling patients with metastatic acral and mucosal melanomas, showed an exon 13 K642E mutation.

Plantier F
[Granular cell tumour or Abrikissoff's tumour].
Ann Dermatol Venereol. 2013; 140(5):399-402 [PubMed] Related Publications

Quinones W, Ziober A, Yao Y, Bing Z
Immunohistochemical markers for the differential diagnosis of nephrogenic adenomas.
Ann Diagn Pathol. 2013; 17(1):41-4 [PubMed] Related Publications
Nephrogenic adenoma (NA) is a rare benign lesion commonly occurring in the urinary bladder that poses challenges to devising a diagnosis. In this study, 21 cases of NAs were studied by performing immunohistochemistry for PAX8, p63, CK903, PSA, S100A1, BerEP4, and CEA on routine tissue sections. PAX8 showed diffuse moderate to strong (2+ and 3+) nuclear staining in all of NAs (n = 6 and 15, respectively) and negative in the normal urothelium (n = 15). Nuclear staining for p63 was not seen in any case of NAs examined (n = 19) and was diffuse and strong (3+) in the normal urothelium (n = 14). High-molecular-weight keratin CK903 showed weak (1+) diffuse staining in all of the NAs examined (n = 19) and diffuse and moderate to strong positivity in the normal urothelium (n = 16). PSA staining was negative in both of the NAs (n = 21) and normal urothelium (n = 16). S100A1 showed strong (3+) diffuse staining in 19 of 20 of the NAs examined (n = 19) and diffuse weak (1+) (n = 14) to moderate (n = 3) staining in the normal urothelium. BerEP4 showed focal to diffuse, mild to moderate (1+ and 2+) cytoplasmic staining in all of NAs (n = 2 and 19) and negative in the normal urothelium (n = 19). CEA staining was negative in both of the NAs (n = 21) and normal urothelium (n = 17). A panel composed of PAX8, p63, PSA, S100A1, and CEA appears to be sensitive and specific in differentiating NA from its mimics of urothelial and prostatic origins.

Rizzardi AE, Johnson AT, Vogel RI, et al.
Quantitative comparison of immunohistochemical staining measured by digital image analysis versus pathologist visual scoring.
Diagn Pathol. 2012; 7:42 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Immunohistochemical (IHC) assays performed on formalin-fixed paraffin-embedded (FFPE) tissue sections traditionally have been semi-quantified by pathologist visual scoring of staining. IHC is useful for validating biomarkers discovered through genomics methods as large clinical repositories of FFPE specimens support the construction of tissue microarrays (TMAs) for high throughput studies. Due to the ubiquitous availability of IHC techniques in clinical laboratories, validated IHC biomarkers may be translated readily into clinical use. However, the method of pathologist semi-quantification is costly, inherently subjective, and produces ordinal rather than continuous variable data. Computer-aided analysis of digitized whole slide images may overcome these limitations. Using TMAs representing 215 ovarian serous carcinoma specimens stained for S100A1, we assessed the degree to which data obtained using computer-aided methods correlated with data obtained by pathologist visual scoring. To evaluate computer-aided image classification, IHC staining within pathologist annotated and software-classified areas of carcinoma were compared for each case. Two metrics for IHC staining were used: the percentage of carcinoma with S100A1 staining (%Pos), and the product of the staining intensity (optical density [OD] of staining) multiplied by the percentage of carcinoma with S100A1 staining (OD*%Pos). A comparison of the IHC staining data obtained from manual annotations and software-derived annotations showed strong agreement, indicating that software efficiently classifies carcinomatous areas within IHC slide images. Comparisons of IHC intensity data derived using pixel analysis software versus pathologist visual scoring demonstrated high Spearman correlations of 0.88 for %Pos (p < 0.0001) and 0.90 for OD*%Pos (p < 0.0001). This study demonstrated that computer-aided methods to classify image areas of interest (e.g., carcinomatous areas of tissue specimens) and quantify IHC staining intensity within those areas can produce highly similar data to visual evaluation by a pathologist.
VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1649068103671302.

Cmoch A, Groves P, Palczewska M, Pikuła S
S100A proteins in propagation of a calcium signal in norm and pathology.
Postepy Biochem. 2012; 58(4):429-36 [PubMed] Related Publications
Calcium ions are essential factors controlling the balance between cell survival, growth, differentiation and metabolism. Ca2+ acts as a global second messenger involved in the regulation of all aspects of cell function. Fluctuations in the intra- and extracellular Ca2+ concentration [Ca2+] in response to different environmental stimuli drive most cellular functions. Therefore, sustenance of calcium homeostasis requires perfect organization in time and space that is achieved by calcium binding proteins (CaBPs). These proteins are involved in sensing and transforming calcium signals to downstream cellular responses. Growing number of evidence suggests than many human disorders, including cancer progression, are related to deregulation of cellular calcium homeostasis and defects in CaBPs functions. In this review we will focus on the roles of S100A proteins in intracellular and extracellular calcium signalling and homeostasis. The S100A subfamily is among the most distinctive of EF-hand CaBPs and are found exclusively in vertebrates. They are believed to have evolved to enable activation of specific biochemical pathways in parallel to the activity of Ca2+ sensors such as calmodulin and/or annexins. The importance of S100 proteins is underscored by their deregulated expression in neurodegenerative and inflammatory disorders, myopathies and cancer. In addition, S100 proteins serve as diagnostic markers in the clinic and are under constant investigation. Their roles and the roles of the S100A protein partners in normal and pathology will be also discussed.

Balluff B, Rauser S, Meding S, et al.
MALDI imaging identifies prognostic seven-protein signature of novel tissue markers in intestinal-type gastric cancer.
Am J Pathol. 2011; 179(6):2720-9 [PubMed] Free Access to Full Article Related Publications
Proteomics-based approaches allow us to investigate the biology of cancer beyond genomic initiatives. We used histology-based matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry to identify proteins that predict disease outcome in gastric cancer after surgical resection. A total of 181 intestinal-type primary resected gastric cancer tissues from two independent patient cohorts were analyzed. Protein profiles of the discovery cohort (n = 63) were directly obtained from tumor tissue sections by MALDI imaging. A seven-protein signature was associated with an unfavorable overall survival independent of major clinical covariates. The prognostic significance of three individual proteins identified (CRIP1, HNP-1, and S100-A6) was validated immunohistochemically on tissue microarrays of an independent validation cohort (n = 118). Whereas HNP-1 and S100-A6 were found to further subdivide early-stage (Union Internationale Contre le Cancer [UICC]-I) and late-stage (UICC II and III) cancer patients into different prognostic groups, CRIP1, a protein previously unknown in gastric cancer, was confirmed as a novel and independent prognostic factor for all patients in the validation cohort. The protein pattern described here serves as a new independent indicator of patient survival complementing the previously known clinical parameters in terms of prognostic relevance. These results show that this tissue-based proteomic approach may provide clinically relevant information that might be beneficial in improving risk stratification for gastric cancer patients.

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