Gene Summary

Gene:ANO1; anoctamin 1, calcium activated chloride channel
Aliases: DOG1, TAOS2, ORAOV2, TMEM16A
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: ANO1 (cancer-related)

Kataoka TR, Yamashita N, Furuhata A, et al.
An inflammatory myofibroblastic tumor exhibiting immunoreactivity to KIT: a case report focusing on a diagnostic pitfall.
World J Surg Oncol. 2014; 12:186 [PubMed] Free Access to Full Article Related Publications
Inflammatory myofibroblastic tumors (IMTs) and gastrointestinal stromal tumors (GISTs) are both spindle cell tumors, and occur rarely in the wall of the urinary bladder. In general, immunostaining allows differentiation of IMTs and GISTs. Most IMTs are positive for anaplastic lymphoma kinase (ALK) and negative for KIT, whereas most GISTs are ALK-negative and KIT-positive. Here, we describe a case of a spindle cell tumor in the wall of the urinary bladder. The spindle cells were positive for both ALK and KIT, and it was thus difficult to determine whether the tumor was an IMT or a GIST. We eventually diagnosed an IMT, because ALK gene rearrangement was confirmed by fluorescent in-situ hybridization. Cytoplasmic staining for KIT and the absence of other GIST markers, including DOG1 and platelet-derived growth factor α, indicated that the tumor was not a GIST. Therefore, IMTs should be included in the differential diagnosis of spindle cell tumors, even those that are KIT-positive.

Choi EJ, Yun JA, Jabeen S, et al.
Prognostic significance of TMEM16A, PPFIA1, and FADD expression in invasive ductal carcinoma of the breast.
World J Surg Oncol. 2014; 12:137 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: 11q13 region is a frequently amplified locus in human malignancies. Among the genes located in this region, FADD is one of the alleged driving genes. Because amplification is not generally confined to a single gene and amplified genes may not show increased expression, we need to evaluate clinical significance of changes occurring in 11q13 region to understand their roles in carcinogenesis. Therefore, we screened expressions of FADD and closely located genes (PPFIA1 and TMEM16A) and evaluated the expressions to find clinical significance in invasive ductal carcinoma of the breast.
METHODS: Ninety-eight cases of invasive ductal carcinoma of the breast were collected. Using archival tissues resected from the cases, we built a tissue microarray and used it in immunohistochemistry. We evaluated the association of FADD, PPFIA1, and TMEM16A expression scores with clinicopathological parameters, including disease-free survival.
RESULTS: FADD expression was associated with T stage (P=0.046). The combined score of FADD, PPFIA1, and TMEM16A gene expressions was associated with perineural invasion (P=0.022). Although individual gene expressions of TMEM16A, FADD, and PPFIA1 failed to show significant association with disease-free survival, combined gene expression scores did show association with disease-free survival (P=0.034).
CONCLUSIONS: FADD, TMEM16A, and PPFIA1 gene expressions as a whole were associated with disease-free survival in breast cancer.

Qu Z, Yao W, Yao R, et al.
The Ca(2+) -activated Cl(-) channel, ANO1 (TMEM16A), is a double-edged sword in cell proliferation and tumorigenesis.
Cancer Med. 2014; 3(3):453-61 [PubMed] Free Access to Full Article Related Publications
Since anoctamin 1 ANO1 (TMEM16A) was found to be a molecular component of Ca(2+) -activated Cl(-) channels, its role in tumorigenesis has gained attention at a fast pace. ANO1 overexpression frequently occurs in the cancer tissues along with 11q13 chromosome amplification. Poor prognosis of many types of cancers has been closely correlated with ANO1 gene amplification and protein overexpression. ANO1 is now considered an excellent biomarker for certain cancers. Recent research suggests that it is the channel function of ANO1 that is involved in the tumorigenesis. However, how the overexpression of the functional ANO1 causes malignant transformation of tissues via signaling pathways, for example, MAPK remains to be investigated. Clarification of the reasons in future will avail to make ANO1 as a target for cancer treatment.

Liu J, Liu Y, Ren Y, et al.
Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor-κB signaling pathway.
Mol Med Rep. 2014; 9(3):1068-74 [PubMed] Related Publications
Ion channels have been suggested to be important in the development and progression of tumors, however, chloride channels have rarely been analyzed in tumorigenesis. More recently, transmembrane protein with unknown function 16A (TMEM16A), hypothesized to be a candidate calcium‑activated Cl‑ channel, has been found to be overexpressed in a number of tumor types. Although several studies have implicated the overexpression of TMEM16A in certain tumor types, the exact role of TMEM16A in gliomas and the underlying mechanisms in tumorigenesis, remain poorly understood. In the present study, the role of TMEM16A in gliomas and the potential underlying mechanisms were analyzed. TMEM16A was highly abundant in various grades of gliomas and cultured glioma cells. Knockdown of TMEM16A suppressed cell proliferation, migration and invasion. Furthermore, nuclear factor‑κB (NF‑κB) was activated by overexpression of TMEM16A. In addition, TMEM16A regulated the expression of NF‑κB‑mediated genes, including cyclin D1, cyclin E and c‑myc, involved in cell proliferation, and matrix metalloproteinases (MMPs)‑2 and MMP‑9, which are associated with the migration and invasion of glioma cells. Collectively, results of the present study provide evidence for the involvement of TMEM16A in gliomas and the potential mechanism through which TMEM16A promotes glioma formation.

Corless CL
Gastrointestinal stromal tumors: what do we know now?
Mod Pathol. 2014; 27 Suppl 1:S1-16 [PubMed] Related Publications
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

Wada T, Tanabe S, Ishido K, et al.
DOG1 is useful for diagnosis of KIT-negative gastrointestinal stromal tumor of stomach.
World J Gastroenterol. 2013; 19(47):9133-6 [PubMed] Free Access to Full Article Related Publications
Approximately 80%-95% of gastrointestinal stromal tumors (GISTs) show positive staining for KIT, while the other 5%-20% show negative staining. If the tumor is negative for KIT, but is positive for CD34, a histological diagnosis is possible. However, if the tumor is negative for KIT, CD34, S-100, and SMA, a definitive diagnosis is often challenging. Recently, Discovered on GIST-1 (DOG1) has received considerable attention as a useful molecule for the diagnosis of GIST. DOG1, a membrane channel protein, is known to be overexpressed in GIST. Because the sensitivity and specificity of DOG1 are higher than those of KIT, positive staining for DOG1 has been reported, even in KIT-negative GISTs. KIT-negative GISTs most commonly arise in the stomach and are mainly characterized by epithelioid features histologically. We describe our experience with a rare case of a KIT-negative GIST of the stomach that was diagnosed by positive immunohistochemical staining for DOG1 in a patient who presented with severe anemia. Our findings suggest that immunohistochemical staining for DOG1, in addition to gene analysis, is useful for the diagnosis of KIT-negative tumors that are suspected to be GISTs.

Xue L, Qiu T, Song Y, et al.
Long segmental hyperplasia of interstitial cells of Cajal with giant diverticulum formation.
Int J Clin Exp Pathol. 2013; 6(12):2989-96 [PubMed] Free Access to Full Article Related Publications
Sporadic gastrointestinal stromal tumors (GISTs) usually form a well-circumscribed mass. In contrast, diffuse interstitial cell of Cajal (ICC) hyperplasia along the Auerbach plexus without a discrete mass may occur in patients with germline mutations in the NF1, c-KIT or PDGFRA genes. However, sporadic, diffuse ICC hyperplasia without c-KIT or PDGFRA mutations has not been reported. We describe herein one such case, forming a giant diverticulum. A 63-year-old woman with no features of Neurofibromatosis 1 (NF1) presented with increasing abdominal pain for more than 30 years. A large, diverticulum-like mass in the ileum was resected. Microscopically, a diffuse proliferation of bland spindle cells was seen extending for 12 cm, replacing the muscularis propria and lined by intact mucosa. The spindle cells were CD117+/CD34+/DOG1+/SMA+/Desmin-/S100-. Mutation analyses did not reveal any mutations in c-KIT or PDGFRA. The lesion had two silent mutations in the NF1 gene. It is rare of the diffuse form of sporadic ICC hyperplasia showing diffuse longitudinal microscopic growth completely replacing the muscularis propria, mimicking diffuse ICC hyperplasia in hereditary GIST syndromes, but without solid components and no c-KIT or PDGFRA gene mutations. This peculiar form of sporadic ICC hyperplasia may be related to intestinal dysmotility in this ileal segment and giant diverticulum formation.

Chan JK
Newly available antibodies with practical applications in surgical pathology.
Int J Surg Pathol. 2013; 21(6):553-72 [PubMed] Related Publications
Selected antibodies that have become available in recent years and have applications in diagnostic pathology are discussed. They include antibodies that are organ-related, provide information on cellular differentiation or histogenetic type, have predictive value in tumors, and highlight infective agents. PAX8 (paired box gene 8) is a marker expressed in the lower female genital tract, thyroid, and kidney and their tumors. Napsin A is expressed in the lung and kidney and is an alternative marker for pulmonary adenocarcinoma. Arginase A is a sensitive and specific marker for liver tumors. ERG (Ets-related gene) is an excellent marker for endothelium and vascular tumors as well as prostatic cancer (about 50% of cases). SOX10 (SRY-related HMG box) is expressed predominantly in melanocytic and Schwann cells and the corresponding tumors. DOG1 (discovered on GIST 1) is an excellent marker for gastrointestinal stromal tumor (GIST) and acinic cell carcinoma. OCT3/4 is a pan-germ cell tumor marker, except yolk sac tumor. SALL4 is positive in various types of germ cell tumors, including yolk sac tumor. MUC4 (mucin-related antigen 4) is a sensitive and specific marker for low-grade fibromyxoid sarcoma. Langerin is a specific marker for Langerhans cells and their tumors. SOX11 is a sensitive marker for mantle cell lymphoma. New generation antibodies against anaplastic lymphoma kinase (ALK) are required to reliably demonstrate ALK gene translocation in pulmonary carcinomas. Lack of expression of succinate dehydrogenase B is seen in paragangliomas of the hereditary form and in the pediatric type of GIST. Antibodies against Trepenoma pallidum can facilitate the diagnosis of syphilis, whereas those against SV40 (simian virus 40) are helpful for diagnosis of BK virus infection and progressive multifocal leukoencephalopathy.

Lee CH, Hoang LN, Yip S, et al.
Frequent expression of KIT in endometrial stromal sarcoma with YWHAE genetic rearrangement.
Mod Pathol. 2014; 27(5):751-7 [PubMed] Related Publications
Endometrial stromal sarcomas with the YWHAE-NUTM2A/B genetic fusion characteristically contain high-grade round to epithelioid cell component that is strongly and diffusely cyclin D1-positive and it may or may not show an associated low-grade fibroblastic/myxoid cell component. They are clinically more aggressive than endometrial stromal sarcomas with the JAZF1-SUZ12 genetic fusion and frequently demonstrate extrauterine extension at initial clinical presentation. In this setting, the tumor may be misdiagnosed as gastrointestinal stromal tumor. This study examines the expression of KIT and ANO1 in 14 YWHAE-NUTM2A/B tumors by immunohistochemistry. Staining localization was determined as membranous and/or cytoplasmic, and the staining intensity was assessed (negative, weak, moderate and strong). Of the 14 tumors, 6 contained only a high-grade round cell component, 2 only a low-grade fibroblastic component and 6 had both components in the slides evaluated. The high-grade round cell component displayed moderate to strong membranous/cytoplasmic KIT staining in all tumors (12 of 12). The low-grade fibroblastic cell component showed only weak cytoplasmic KIT staining in 3 of 8 tumors. In contrast, ANO1 was negative in all 14 neoplasms, irrespective of the component evaluated. Sanger sequencing analysis (exons 9, 11, 13 and 17) and Ampliseq Cancer Panel mutation screen (Ion Torrent) demonstrated no KIT mutations in three KIT-positive YWHAE-NUTM2A/B tumors. This study shows that the high-grade round cell component of YWHAE-NUTM2A/B endometrial stromal sarcoma consistently expresses KIT but lacks KIT hotspot mutations. KIT expression may represent a potential diagnostic pitfall in the evaluation of YWHAE-NUTM2A/B endometrial stromal sarcoma presenting with pelvic/abdominal mass, particularly in situations where its uterine origin is not definitive, and thus a panel of antibodies that includes ANO1 and cyclin D1 is necessary.

Deshpande A, Nelson D, Corless CL, et al.
Leiomyoma of the gastrointestinal tract with interstitial cells of Cajal: a mimic of gastrointestinal stromal tumor.
Am J Surg Pathol. 2014; 38(1):72-7 [PubMed] Related Publications
Leiomyomas (LMs) of the gastrointestinal tract arise within the muscularis mucosae (superficial) and muscularis propria (deep). There are isolated reports of KIT-positive cells, presumed interstitial cells of Cajal (ICCs), within gastrointestinal LMs. We have encountered esophageal LMs with a high proportion of KIT-positive and DOG1-positive spindle-shaped cells, an appearance that mimicked gastrointestinal stromal tumor. Our aim was to explore the prevalence of ICCs in LMs of the gastrointestinal tract and the etiopathogenic significance of these cells in this benign neoplasm. We identified 34 esophageal LMs (28 deep, 6 superficial), 8 gastric LMs, and 5 small-bowel LMs (all lesions in muscularis propria). We performed immunohistochemical staining studies for desmin, DOG1, and KIT on these neoplasms. We also evaluated 12 superficial colonic LMs. ICCs were distinguished from mast cells on the basis of morphology (elongated and occasionally branching spindle-shaped cells) and the presence of DOG1 reactivity. Four cases were screened for mutations in PDGFRA exons 12, 14, and 18 and KIT exons 9, 11, 13, and 17. ICCs were identified in all deep esophageal LMs and constituted an average of 20% of the lesional cells; focally, these cells comprised >50% of cells. The density of these cells was significantly higher than the background muscularis propria, and hyperplasia of ICCs was not identified in the adjacent muscle. ICCs were identified in 6 of 8 gastric LMs and 1 of 5 small-bowel LMs and were entirely absent in all superficial esophageal and colonic/rectal LMs. There were no mutations in KIT or PDGFRA. ICCs are universally present in deep esophageal LMs, and thus these neoplasms could be mistaken for gastrointestinal stromal tumors, particularly on biopsy samples, an error associated with adverse clinical consequences. ICCs are also identified in gastric and intestinal LMs, albeit in a smaller proportion of cases. Colonization and hyperplasia by non-neoplastic ICCs likely account for this phenomenon.

Shi ZZ, Shang L, Jiang YY, et al.
Consistent and differential genetic aberrations between esophageal dysplasia and squamous cell carcinoma detected by array comparative genomic hybridization.
Clin Cancer Res. 2013; 19(21):5867-78 [PubMed] Related Publications
PURPOSE: Our aim was to identify frequent genomic aberrations in both esophageal squamous cell carcinoma (ESCC) and esophageal dysplasia and to discover important copy number-driving genes and microRNAs (miRNA) in ESCC.
EXPERIMENTAL DESIGN: We conducted array-based comparative genomic hybridization (array CGH) on 59 ESCC resection samples and 16 dysplasia biopsy samples. Expression of genes at 11q13.3 was analyzed by real-time PCR (RT-PCR) and immunohistochemistry (IHC). Integrated analysis was conducted to identify genes or miRNAs with copy number-expression correlations.
RESULTS: Array CGH identified 11 amplifications and eight homozygous deletions in ESCC. Integrated analysis of array CGH data with matched gene expression microarray data showed that 90 overexpressed genes and 24 underexpressed genes were consistent with DNA copy number changes, including 12 copy number-driving miRNAs. In esophageal dysplasia, six gains, four losses, 12 amplifications, and four homozygous deletions were detected. Amplifications of 7p11.2 and 11q13.2-11q13.3 (CCND1) and homozygous deletion at 9p21.3 (CDKN2A) were consistent genomic changes in both dysplasia and carcinoma. ANO1 at 11q13.3 was overexpressed at the mRNA and protein levels in tumors, and higher mRNA expression was correlated with the copy number increase. In particular, ANO1 expression was elevated in moderate dysplasia compared with normal esophageal epithelium. IHC revealed that ANO1 overexpression was positively correlated with lymph node metastasis and advanced clinical stage. Knockdown of ANO1 significantly inhibited the proliferation of KYSE30 and KYSE510 cells.
CONCLUSION: Copy number aberrations in both esophageal dysplasia and ESCC may be useful as potential biomarkers for early detection. In addition, ANO1 may be a candidate target gene in esophageal tumorigenesis.

Ubby I, Bussani E, Colonna A, et al.
TMEM16A alternative splicing coordination in breast cancer.
Mol Cancer. 2013; 12:75 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: TMEM16A, also known as Anoctamin-1, is a calcium-activated chloride channel gene overexpressed in many tumors. The role of TMEM16A in cancer is not completely understood and no data are available regarding the potential tumorigenic properties of the multiple isoforms generated by alternative splicing (AS).
METHODS: We evaluated TMEM16A AS pattern, isoforms distribution and Splicing Coordination (SC), in normal tissues and breast cancers, through a semi-quantitative PCR-assay that amplifies transcripts across three AS exons, 6b, 13 and 15.
RESULTS: In breast cancer, we did not observe an association either to AS of individual exons or to specific TMEM16A isoforms, and induced expression of the most common isoforms present in tumors in the HEK293 Flp-In Tet-ON system had no effect on cellular proliferation and migration. The analysis of splicing coordination, a mechanism that regulates AS of distant exons, showed a preferential association of exon 6b and 15 in several normal tissues and tumors: isoforms that predominantly include exon 6b tend to exclude exon 15 and vice versa. Interestingly, we found an increase in SC in breast tumors compared to matched normal tissues.
CONCLUSIONS: As the different TMEM16A isoforms do not affect proliferation or migration and do not associate with tumors, our results suggest that the resulting channel activities are not directly involved in cell growth and motility. Conversely, the observed increase in SC in breast tumors suggests that the maintenance of the regulatory mechanism that coordinates distant alternative spliced exons in multiple genes other than TMEM16A is necessary for cancer cell viability.

Wang C, Jin MS, Zou YB, et al.
Diagnostic significance of DOG-1 and PKC-θ expression and c-Kit/PDGFRA mutations in gastrointestinal stromal tumours.
Scand J Gastroenterol. 2013; 48(9):1055-65 [PubMed] Related Publications
OBJECTIVE: To investigate discovered on gastrointestinal stromal tumor (GIST)-1 (DOG-1) and protein kinase C-θ (PKC-θ) expression in a series of GISTs and determine the sensitivity, specificity, and diagnostic value of these two antigens.
METHODS: Immnunohistochemistry (IHC) was used to detect CD117, DOG-1, PKC-θ, CD34, Ki-67, α-smooth muscle actin (SMA), S100, and Desmin expression in 147 GISTs and 51 non-GISTs. c-Kit gene (exons 9, 11, 13, and 17) and platelet-derived growth factor receptor-alpha (PDGFRA) gene (exons 12 and 18) mutations were also detected.
RESULTS: About 94.5% GISTs were CD117 positive, 96% were DOG-1 positive, and 90.5% were PKC-θ positive. DOG-1 had a specificity of 100%, while CD117 and PKC-θ had a specificity of 90% and 80%, respectively. There was no significant difference between DOG-1 and PKC-θ expressions when compared to CD117 expression. In 30 out of 42 (71.5%) GISTs, a c-Kit gene mutation was found, and in 3 out of 42 cases (7%), PDGFRA was mutated. Wild-type c-Kit/PDGFRA genes accounted for 21.5% (9/42). Most c-Kit gene mutations were found to be located at exon 11, mainly as in-frame deletions. Mutations in exon 9 were all missense mutations. Most PDGFRA gene mutations were found in exon 18, codon 842. c-Kit gene mutations in exons 13 and 17, and the PDGFRA gene mutation in exon 12 were not detected.
CONCLUSIONS: Compared to CD117, DOG-1 is a biomarker with higher sensitivity and specificity. The combination of CD117 and DOG-1 can be used to improve the diagnosis of GIST. Although PKC-θ has a lower specificity than DOG-1, it can be a useful biomarker, especially in CD117(-) and/or DOG-1(-) cases.

Pinto A, Nosé V, Rojas C, et al.
Searching for mammary analogue [corrected] secretory carcinoma of salivary gland among its mimics.
Mod Pathol. 2014; 27(1):30-7 [PubMed] Related Publications
Mammary analog secretory carcinoma of salivary gland is a recently described entity with unique morphologic, clinical, and genetic characteristics, including the characteristic t(12;15)(p13;q25) with ETV6-NTRK3 translocation found in secretory carcinomas of the breast. Before their initial description, these salivary gland tumors were generally diagnosed as acinic cell carcinoma or adenocarcinoma. For the purpose of this study, all cases of salivary gland acinic cell carcinoma, cribriform cystadenocarcinoma, and adenocarcinoma, not otherwise specified (NOS), diagnosed over a 10-year period were retrieved from our surgical pathology files. There were a total of 11 cases diagnosed as acinic cell carcinoma, 10 cases of adenocarcinoma, NOS, and 6 cases of cribriform cystadenocarcinoma. All slides were reviewed by two pathologists (AP, CGF) and tumors that show morphologic features of mammary analog secretory carcinoma according to the recent literature were selected. This process narrowed down the initial number to six cases originally diagnosed as acinic cell carcinoma, three cases originally diagnosed as adenocarcinoma, NOS, and one case originally diagnosed as cribriform cystadenocarcinoma. The 10 cases were subjected to immunohistochemistry for S-100, mammaglobin, and ANO1, as well as fluorescence in situ hybridization analysis for t(12;15)(p13;q25) with ETV6-NTRK3 fusion rearrangement. The ETV6-NTRK3 gene rearrangement was detected in three tumors. These three tumors, initially diagnosed as acinic cell carcinomas, stained positive for S-100 and mammaglobin, and negative for ANO1 by immunohistochemistry. Two of the three patients were male (2/3). In summary, mammary analog secretory carcinoma is a newly described diagnostic entity that should be in the differential diagnosis of salivary gland tumors that morphologically mimic other neoplasms, mainly acinic cell carcinomas. They differ from conventional acinic cell tumors immunohistochemically and molecularly. Positivity for mammaglobin and S-100, and negativity for ANO1 are useful screening tools before confirmatory molecular studies.

Simon S, Grabellus F, Ferrera L, et al.
DOG1 regulates growth and IGFBP5 in gastrointestinal stromal tumors.
Cancer Res. 2013; 73(12):3661-70 [PubMed] Free Access to Full Article Related Publications
Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor α(PDGFRA), which can be therapeutically targeted by tyrosine kinase inhibitors (TKI) such as imatinib. Despite long-lasting responses, most patients eventually progress after TKI therapy. The calcium-dependent chloride channel DOG1 (ANO1/TMEM16A), which is strongly and specifically expressed in GIST, is used as a diagnostic marker to differentiate GIST from other sarcomas. Here, we report that loss of DOG1 expression occurs together with loss of KIT expression in a subset of GIST resistant to KIT inhibitors, and we illustrate the functional role of DOG1 in tumor growth, KIT expression, and imatinib response. Although DOG1 is a crucial regulator of chloride balance in GIST cells, we found that RNAi-mediated silencing or pharmacologic inhibition of DOG1 did not alter cell growth or KIT signaling in vitro. In contrast, DOG1 silencing delayed the growth of GIST xenografts in vivo. Expression profiling of explanted tumors after DOG1 blockade revealed a strong upregulation in the expression of insulin-like growth factor-binding protein 5 (IGFBP5), a potent antiangiogenic factor implicated in tumor suppression. Similar results were obtained after selection of imatinib-resistant DOG1- and KIT-negative cells derived from parental DOG1 and KIT-positive GIST cells, where a 5,000-fold increase in IGFBP5 mRNA transcripts were documented. In summary, our findings establish the oncogenic activity of DOG1 in GIST involving modulation of IGF/IGF receptor signaling in the tumor microenvironment through the antiangiogenic factor IGFBP5.

Britschgi A, Bill A, Brinkhaus H, et al.
Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling.
Proc Natl Acad Sci U S A. 2013; 110(11):E1026-34 [PubMed] Free Access to Full Article Related Publications
The calcium-activated chloride channel anoctamin 1 (ANO1) is located within the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human cancer, but its functional role in tumorigenesis has remained unclear. The 11q13 region is amplified in ∼15% of breast cancers. Whether ANO1 is amplified in breast tumors, the extent to which gene amplification contributes to ANO1 overexpression, and whether overexpression of ANO1 is important for tumor maintenance have remained unknown. We have found that ANO1 is amplified and highly expressed in breast cancer cell lines and primary tumors. Amplification of ANO1 correlated with disease grade and poor prognosis. Knockdown of ANO1 in ANO1-amplified breast cancer cell lines and other cancers bearing 11q13 amplification inhibited proliferation, induced apoptosis, and reduced tumor growth in established cancer xenografts. Moreover, ANO1 chloride channel activity was important for cell viability. Mechanistically, ANO1 knockdown or pharmacological inhibition of its chloride-channel activity reduced EGF receptor (EGFR) and calmodulin-dependent protein kinase II (CAMKII) signaling, which subsequently attenuated AKT, v-src sarcoma viral oncogene homolog (SRC), and extracellular signal-regulated kinase (ERK) activation in vitro and in vivo. Our results highlight the involvement of the ANO1 chloride channel in tumor progression and provide insights into oncogenic signaling in human cancers with 11q13 amplification, thereby establishing ANO1 as a promising target for therapy in these highly prevalent tumor types.

Yuen HF, McCrudden CM, Huang YH, et al.
TAZ expression as a prognostic indicator in colorectal cancer.
PLoS One. 2013; 8(1):e54211 [PubMed] Free Access to Full Article Related Publications
The Hippo pathway restricts the activity of transcriptional coactivators TAZ (WWTR1) and YAP. TAZ and YAP are reported to be overexpressed in various cancers, however, their prognostic significance in colorectal cancers remains unstudied. The expression levels of TAZ and YAP, and their downstream transcriptional targets, AXL and CTGF, were extracted from two independent colon cancer patient datasets available in the Gene Expression Omnibus database, totaling 522 patients. We found that mRNA expressions of both TAZ and YAP were positively correlated with those of AXL and CTGF (p<0.05). High level mRNA expression of TAZ, AXL or CTGF significantly correlated with shorter survival. Importantly, patients co-overexpressing all 3 genes had a significantly shorter survival time, and combinatorial expression of these 3 genes was an independent predictor for survival. The downstream target genes for TAZ-AXL-CTGF overexpression were identified by Java application MyStats. Interestingly, genes that are associated with colon cancer progression (ANTXR1, EFEMP2, SULF1, TAGLN, VCAN, ZEB1 and ZEB2) were upregulated in patients co-overexpressing TAZ-AXL-CTGF. This TAZ-AXL-CTGF gene expression signature (GES) was then applied to Connectivity Map to identify small molecules that could potentially be utilized to reverse this GES. Of the top 20 small molecules identified by connectivity map, amiloride (a potassium sparing diuretic), and tretinoin (all-trans retinoic acid) have shown therapeutic promise in inhibition of colon cancer cell growth. Using MyStats, we found that low level expression of either ANO1 or SQLE were associated with a better prognosis in patients who co-overexpressed TAZ-AXL-CTGF, and that ANO1 was an independent predictor of survival together with TAZ-AXL-CTGF. Finally, we confirmed that TAZ regulates Axl, and plays an important role in clonogenicity and non-adherent growth in vitro and tumor formation in vivo. These data suggest that TAZ could be a therapeutic target for the treatment of colon cancer.

Takahashi RH, Matsubayashi J, Yokotsuka M, et al.
An intrapelvic extraintestinal gastrointestinal stromal tumor of undetermined origin: diagnosis by prostate needle biopsy.
Pathol Res Pract. 2012; 208(12):736-40 [PubMed] Related Publications
We herein report a case of intrapelvic gastrointestinal stromal tumor (GIST) of undetermined origin in a 48-year-old male who presented with dysuria. An enlarged tumor was detected on digital rectal examination. Imaging studies showed a solid and lobular homogenous tumor of 7.0 cm in diameter. The tumor was attached to the right dorsal aspect of the prostate with compression of the seminal vesicles and rectum. It was considered that the tumor had arisen from the prostate, although the patient's serum prostate-specific antigen level was low (0.436 ng/mL). The histological diagnosis by prostate needle biopsy was a spindle cell tumor. At cystoprostatectomy, the tumor was confirmed to be separated from the prostate by a fibrous band, and showed spindle cells with a fascicular growth pattern, but without necrotic areas. Mitotic figures were noted in 12 of 50 high-power fields. The tumor cells were immunoreactive for the KIT protein (CD117), CD34, Discovered on GIST-1 (DOG-1), and vimentin. In contrast, they were negative for desmin, α-smooth muscle actin, pancytokeratin (AE1/AE3), and S100 protein. The Ki-67 labeling index was 5%. The genetic analyses targeting the c-kit gene revealed a point mutation at codon 559 (GTT→GAT). The diagnosis of GIST was confirmed on the basis of the morphological features, immunoprofile, and results of the molecular analyses. Since extraintestinal GIST can resemble a prostatic tumor clinically, KIT (CD117) and DOG-1 should be considered for inclusion in the immunohistochemical panel for spindle cell tumors obtained by prostate needle biopsy.

Celestino R, Lima J, Faustino A, et al.
Molecular alterations and expression of succinate dehydrogenase complex in wild-type KIT/PDGFRA/BRAF gastrointestinal stromal tumors.
Eur J Hum Genet. 2013; 21(5):503-10 [PubMed] Free Access to Full Article Related Publications
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, disclosing somatic KIT, PDGFRA and BRAF mutations. Loss of function of succinate dehydrogenase (SDH) complex is an alternative molecular mechanism in GISTs, namely in carriers of germline mutations of the SDH complex that develop Carney-Stratakis dyad characterized by multifocal GISTs and multicentric paragangliomas (PGLs). We studied a series of 25 apparently sporadic primary wild-type (WT) KIT/PDGFRA/BRAF GISTs occurring in patients without personal or familial history of PGLs, re-evaluated clinicopathological features and analyzed molecular alterations and immunohistochemistry expression of SDH complex. As control, we used a series of well characterized 49 KIT/PDGFRA/BRAF-mutated GISTs. SDHB expression was absent in 20% and SDHB germline mutations were detected in 12% of WT GISTs. Germline SDHB mutations were significantly associated to younger age at diagnosis. A significant reduction in SDHB expression in WT GISTs was found when compared with KIT/PDGFRA/BRAF-mutated GISTs. No significant differences were found when comparing DOG-1 and c-KIT expression in WT, SDHB-mutated and KIT/PDGFRA/BRAF-mutated GISTs. Our results confirm the occurrence of germline SDH genes mutations in isolated, apparently sporadic WT GISTs. WT KIT/PDGFRA/BRAF GISTs without SDHB or SDHA/SDHB expression may correspond to Carney-Stratakis dyad or Carney triad. Most importantly, the possibility of PGLs (Carney-Stratakis dyad) and/or pulmonary chondroma (Carney triad) should be addressed in these patients and their kindred.

Ruiz C, Martins JR, Rudin F, et al.
Enhanced expression of ANO1 in head and neck squamous cell carcinoma causes cell migration and correlates with poor prognosis.
PLoS One. 2012; 7(8):e43265 [PubMed] Free Access to Full Article Related Publications
Head and neck squamous cell carcinoma (HNSCC) has the potential for early metastasis and is associated with poor survival. Ano1 (Dog1) is an established and sensitive marker for the diagnosis of gastrointestinal stromal tumors (GIST) and has recently been identified as a Ca(2+) activated Cl(-) channel. Although the ANO1 gene is located on the 11q13 locus, a region which is known to be amplified in different types of human carcinomas, a detailed analysis of Ano1 amplification and expression in HNSCC has not been performed. It is thus still unclear how Ano1 contributes to malignancy in HNSCC. We analyzed genomic amplification of the 11q13 locus and Ano1 together with Ano1-protein expression in a large collection of HNSCC samples. We detected a highly significant correlation between amplification and expression of Ano1 and showed that HNSCC patients with Ano1 protein expression have a poor overall survival. We further analyzed the expression of the Ano1 protein in more than 4'000 human samples from 80 different tumor types and 76 normal tissue types and detected that besides HNSCC and GISTs, Ano1 was rarely expressed in other tumor samples or healthy human tissues. In HNSCC cell lines, expression of Ano1 caused Ca(2+) activated Cl(-) currents, which induced cell motility and cell migration in wound healing and in real time migration assays, respectively. In contrast, knockdown of Ano1 did not affect intracellular Ca(2+) signaling and surprisingly did not reduce cell proliferation in BHY cells. Further, expression and activity of Ano1 strongly correlated with the ability of HNSCC cells to regulate their volume. Thus, poor survival in HNSCC patients is correlated with the presence of Ano1. Our results further suggest that Ano1 facilitates regulation of the cell volume and causes cell migration, which both can contribute to metastatic progression in HNSCC.

Rizzardi C, Marzinotto S, Avellini C, et al.
A KIT-negative, DOG1-positive epithelioid GIST of the stomach harboring a novel PDGFRA exon 14 single nucleotide deletion.
Anticancer Res. 2012; 32(5):1775-8 [PubMed] Related Publications
Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal tumors of the gastrointestinal tract, and most of them harbor KIT or platelet-derived growth factor receptor alpha (PDGFRA) gain-of-function mutations. Proper diagnostic assessment of GISTs has become very important since the availability of the molecular-targeted therapy with imatinib mesylate. Histopathology remains the gold standard in GIST diagnosis, and immunohistochemistry plays the major confirmatory role. Moreover, genetic sequencing not only further confirms the diagnosis of GIST, but also provides information for the optimal treatment of patients. Herein, we describe a gastric GIST harboring a novel PDGFRA exon 14 frameshift mutation caused by a single-nucleotide deletion. The case reported here represents further evidence regarding the existence of a distinct subset of GISTs characterized by the PDGFRA mutation, the gastric localisation, the epithelioid morphology, and the weak or negative immunohistochemical expression of KIT. DOG1 is emerging as a promising biomarker for this subgroup of GISTs.

Duvvuri U, Shiwarski DJ, Xiao D, et al.
TMEM16A induces MAPK and contributes directly to tumorigenesis and cancer progression.
Cancer Res. 2012; 72(13):3270-81 [PubMed] Free Access to Full Article Related Publications
Frequent gene amplification of the receptor-activated calcium-dependent chloride channel TMEM16A (TAOS2 or ANO1) has been reported in several malignancies. However, its involvement in human tumorigenesis has not been previously studied. Here, we show a functional role for TMEM16A in tumor growth. We found TMEM16A overexpression in 80% of head and neck squamous cell carcinoma (SCCHN), which correlated with decreased overall survival in patients with SCCHN. TMEM16A overexpression significantly promoted anchorage-independent growth in vitro, and loss of TMEM16A resulted in inhibition of tumor growth both in vitro and in vivo. Mechanistically, TMEM16A-induced cancer cell proliferation and tumor growth were accompanied by an increase in extracellular signal-regulated kinase (ERK)1/2 activation and cyclin D1 induction. Pharmacologic inhibition of MEK/ERK and genetic inactivation of ERK1/2 (using siRNA and dominant-negative constructs) abrogated the growth effect of TMEM16A, indicating a role for mitogen-activated protein kinase (MAPK) activation in TMEM16A-mediated proliferation. In addition, a developmental small-molecule inhibitor of TMEM16A, T16A-inh01 (A01), abrogated tumor cell proliferation in vitro. Together, our findings provide a mechanistic analysis of the tumorigenic properties of TMEM16A, which represents a potentially novel therapeutic target. The development of small-molecule inhibitors against TMEM16A may be clinically relevant for treatment of human cancers, including SCCHN.

Hemminger J, Marsh WL, Iwenofu OH, Frankel WL
DOG1 (clone K9) is seldom expressed and not useful in the evaluation of pancreatic neoplasms.
Appl Immunohistochem Mol Morphol. 2012; 20(4):397-401 [PubMed] Related Publications
DOG1, a transmembrane calcium-regulated chloride channel protein, is a sensitive and specific marker for gastrointestinal stromal tumors compared with other spindle cell and epithelioid neoplasms. Overexpression has also been described in a variety of both benign and malignant epithelial neoplasms. Recently, DOG1 immunoreactivity has been reported in pancreatic solid pseudopapillary tumors (SPT), suggesting a role as a marker for SPT. Utilizing immunohistochemistry, we evaluated DOG1 expression in pancreatic neoplasms to determine the prevalence of staining and establish diagnostic utility. Multiple tissue microarrays (TMA) were created from cores of formalin-fixed paraffin-embedded blocks containing pancreatic adenocarcinomas (n=112), neuroendocrine tumors (n=99), serous cystadenomas (n=28), and SPT (n=14) as well as normal pancreas (n=12). Immunoreactivity for DOG1 (clone K9) was assessed for intensity (1 to 3+), percentage of tumor positivity and location. Of the 99 cases of neuroendocrine tumors, only 2 (2%) were focally positive. Patchy staining was identified in 8 cases (7%) of adenocarcinoma of 1 to 2+ intensity, involving 15% to 80% of the tumor cells and primarily seen in a membranous and luminal distribution. In contrast to a previous report, no DOG1 positivity was observed in SPT, evaluated by both TMA and full sections. The TMAs of serous cystadenomas and normal pancreas were negative for DOG1. Rarely, pancreatic islets displayed granular, cytoplasmic staining. DOG1 antibody clone K9 is not a useful marker for SPT or other primary pancreatic neoplasms. Additional studies may be helpful to evaluate differences between clones of DOG1.

Kim KH, Nelson SD, Kim DH, et al.
Diagnostic relevance of overexpressions of PKC-θ and DOG-1 and KIT/PDGFRA gene mutations in extragastrointestinal stromal tumors: a Korean six-centers study of 28 cases.
Anticancer Res. 2012; 32(3):923-37 [PubMed] Related Publications
BACKGROUND: We investigated the clinicopathological and immunohistochemical characteristics, genetic aberrations and prognostic factors in 28 patients with extragastrointestinal stromal tumors (EGISTs) from six centers in South Korea.
PATIENTS AND METHODS: Immunohistochemistry was performed for c-KIT (CD117), PKC-θ (protein kinase C theta), DOG-1 (discovered on GIST-1), CD34, alpha-smooth muscle actin (α-SMA), vimentin, desmin and S-100 protein. Genetic analyses for the KIT gene (exon 9, 11, 13 and 17) and the platelet-derived growth factor receptor alpha (PDGFRA) gene (exons 12 and 18) were performed by direct sequencing of PCR products. The relationships of various clinicopathological characteristics and outcomes were also examined.
RESULTS: Of the tumor samples, 78.6% (22/28) were located in the intra-abdominal cavity including the omentum and mesentery, and 10.7% (3/28) were located in the retroperitoneum. All patients were older than 39 years. The median size of the tumors was 10 cm for the maximum diameter. When first detected, 57.1% of EGISTs were large in size, measuring more than 10 cm. Tumors that were larger than 10 cm were found more frequently among tumors with more than 10 mitoses per 50 high-power fields (HPFs) and this finding was statistically significant (p<0.05). Based on immunohistochemical results, the EGISTs were positive for c-KIT in 96.4% (27/28) of samples, PKC-θ in 82.1% (23/28), DOG-1 in 85.7% (24/28), PDGFRA in 82.1% (23/28), CD34 in 67.9% (19/28), vimentin in 100% (28/28), α-SMA in 28.6% (8/28), S-100 protein in 39.3% (11/28) and desmin in 28.6% (8/28). c-KIT, DOG-1 and PKC-θ immunostains were sensitive and specific, but the PDGFRA stain was not specific for EGISTs. c-KIT expression was correlated with DOG-1 expression (p<0.05). One c-KIT-negative EGIST was also negative for DOG-1, but positive for PDGFRA and PKC-θ immunostains. Out of all EGISTs, 57.1% had tumor necrosis and most of these were more than 10 cm in size, and had obvious nuclear atypia and high mitotic counts (>10/50 HPFs). Overall survival (OS) was correlated with tumor size >10 cm, tumor necrosis, obvious nuclear atypia, mitotic counts >10/50 HPFs and epithelioid or mixed cell type (p<0.05). Eleven EGISTs (44.0%) had mutations in the KIT gene and 6 (24.0%) had mutations in the PDGFRA gene, the most common being missense mutations or deletions affecting exon 11 of the KIT gene (n=9) or exon 18 of the PDGFRA gene (n=6). Three cases showed co-existence of both KIT and PDGFRA gene mutations. There were no mutations of exon 17 of KIT and exon 12 of PDGFRA genes.
CONCLUSION: The c-KIT, PKC-θ and DOG-1 antigens are the most sensitive and specific immunomarkers for confirming EGISTs. PKC-θ and PDGFRA immunostains are helpful markers for c-KIT-negative EGISTs. Survival analyses indicated that tumor size >10 cm, mitotic rate >10/50 HPFs, tumor necrosis, obvious nuclear atypia, and epithelioid or mixed cell type were significant predictors of survival. We found that the combination of these parameters helped to predict aggressive tumor behavior and may be useful for predicting the prognosis of EGISTs. The majority of gene mutations were identified in exon 11 of the KIT gene or exon 18 of the PDGFRA gene. The pattern of KIT and PDGFRA mutations in EGISTs was essentially similar to the one in GISTs. From the immunohistochemistry and molecular genetics perspective, EGISTs may be a special subtype of GISTs. Both immunohistochemical and molecular evaluation are useful for classifying tumors as EGISTs.

Ríos-Moreno MJ, Jaramillo S, Pereira Gallardo S, et al.
Gastrointestinal stromal tumors (GISTs): CD117, DOG-1 and PKCθ expression. Is there any advantage in using several markers?
Pathol Res Pract. 2012; 208(2):74-81 [PubMed] Related Publications
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. Expression of CD117, DOG1 and PKCθ was investigated immunohistochemically in a series of 99 paraffin-embedded GISTs in order to determine the sensitivity and diagnostic value of these markers. KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were amplified by PCR and sequenced. A total of 94/99 (94%) GISTs stained positive for CD117, 81/99 (82%) for PKCθ and 90/99 (91%) for DOG-1. A significant correlation was noted between CD117 and DOG-1 expression (p=0.0001). All three markers were expressed in 74% (73/99) of GISTs. Of the five CD117-negative cases, two were PKCθ-negative/DOG1-negative and had mutations in KIT exon 11. Two were PKCθ-positive/DOG1-positive and had mutations in PDGFRA (one each in exons 12 and 18), and one was DOG1-negative/PKCθ-positive, with a PDGFRA exon 18 mutation. The most sensitive marker was CD117, followed by DOG-1 and PKCθ. Although PKCθ was less sensitive, and its staining is more challenging and difficult to interpret, the use of this marker is highly recommended, particularly in CD117-negative/DOG-1-negative GISTs.

Miettinen M, Wang ZF, Sarlomo-Rikala M, et al.
Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age.
Am J Surg Pathol. 2011; 35(11):1712-21 [PubMed] Free Access to Full Article Related Publications
Most gastrointestinal stromal tumors (GISTs) are driven by KIT or PDGFRA-activating mutations, but a small subset is associated with loss of function of the succinate dehydrogenase (SDH) complex of mitochondrial inner membrane proteins. This occurs by germline mutations of the SDH subunit genes and hitherto unknown mechanisms. SDH-deficient GISTs especially include pediatric GISTs and those associated with Carney triad (CT) or Carney-Stratakis syndromes (CSSs); the latter 2 also include paraganglioma as a component. SDH-deficient GISTs were identified in this study on the basis of immunohistochemical loss of succinate dehydrogenase subunit B (SDHB), which signals functional loss of the SDH complex. We found 66 SDH-deficient GISTs among 756 gastric GISTs, with an estimated frequency of 7.5% of unselected cases. Nearly, all gastric GISTs in patients <20 years, and a substantial percentage of those in patients <40 years, but only rare GISTs in older adults were SDH deficient. There was a female predominance of over 2:1. Two patients each had either pulmonary chondroma or paraganglioma (CT), but none of the examined cases had SDH germline mutations (CSS) or somatic KIT/PDGFRA or BRAF mutations. SDH-deficient GISTs were often multiple and typically showed plexiform muscularis propria involvement and epithelioid hypercellular morphology. They were consistently KIT-positive and DOG1/Ano 1-positive and almost always smooth muscle actin negative. Tumor size and mitotic activity varied, and the tumors were somewhat unpredictable with low mitotic rates developing metastases. Gastric recurrences occurred in 11 patients, and peritoneal and liver metastases occurred in 8 and 10 patients, respectively. Lymph node metastases were detected in 5 patients, but lymphovascular invasion was present in >50% of cases studied; these 2 were not related to adverse outcome. Seven patients died of disease, but many had long survivals, even with peritoneal or liver metastases. All 378 nongastric GISTs and 34 gastric non-GIST mesenchymal tumors were SDHB positive. SDH-deficient GISTs constitute a small subgroup of gastric GISTs; they usually occur in children and young adults, often have a chronic course similar to that of pediatric and CT GISTs, and have potential association with paraganglioma, necessitating long-term follow-up.

Cho H, Watanabe T, Aoyama T, et al.
Small bud of probable gastrointestinal stromal tumor within a laparoscopically-resected gastric schwannoma.
Int J Clin Oncol. 2012; 17(3):294-8 [PubMed] Related Publications
Submucosal tumors (SMTs) of the gastrointestinal (GI) tract can be potentially difficulty to diagnose pathologically. We report a case of a gastric SMT that was resected by laparoscopic partial gastrectomy. Although the initial histological and immunohistochemical examinations considered the tumor as a schwannoma, mRNA-based KIT genotyping indicated that the tumor included cells with KIT gene expression, and that a small number of cells carried a deletion mutation in exon 11. Additional histopathological investigations revealed small aggregates of enlarged spindle to epithelioid cells, which were positive for KIT, CD34 and DOG1, and negative for S-100, scattered among the S-100-positive schwannoma cells. We consider that the cells carrying the KIT gene mutation are microscopic buds of a gastrointestinal stroma tumor (GIST), and to the best of our knowledge, this is the first report of probable GIST tissues identified in a schwannoma. Our observations raised the significance of genotyping for diagnosis of GI tract SMTs.

Yamamoto H, Kojima A, Nagata S, et al.
KIT-negative gastrointestinal stromal tumor of the abdominal soft tissue: a clinicopathologic and genetic study of 10 cases.
Am J Surg Pathol. 2011; 35(9):1287-95 [PubMed] Related Publications
Gastrointestinal stromal tumor (GIST) typically occurs in the gastrointestinal (GI) tract, and expresses KIT protein that is associated with KIT or platelet-derived growth factor receptor-α (PDGFRA) gene mutation. Extragastrointestinal stromal tumors (EGISTs) are a minor subset of GIST that occurs in the soft tissue outside the GI tract, and in very rare cases, these tumors can be KIT negative. We examined the clinicopathologic and molecular characteristics of 10 cases of KIT-negative EGIST by using immunohistochemical staining and gene mutation analysis. The tumors occurred in the omentum (n=5), mesentery (n=2), retroperitoneum (n=1), pelvic cavity (n=1), and not otherwise specified regions of the abdominal cavity (n=1). They ranged from 4 to 33 cm (median, 15 cm) in maximum diameter with relatively low mitotic counts (median, 3.5 per 50 high-power fields). Morphologically, most cases were of epithelioid cell (n=9) or mixed epithelioid and spindle cell (n=1) type, accompanied by variable amounts of myxoid stroma. By immunohistochemical staining, the tumors were positive for CD34 (80%), protein kinase C (PKC) θ (90%), and discovered on GIST-1 (DOG1) (90%), but were negative for KIT (0%). The majority of the examined cases (7 of 9 cases; 78%) had PDGFRA mutations in exon 12 (n=1) or exon 18 (n=6). One case (11%) had a mutation in KIT exon 11, and the remaining 1 had no mutation in either KIT or PDGFRA. Distant metastasis and local recurrence occurred in 1 (10%) and 2 (20%) patients, respectively, and adverse outcome was correlated with larger (>10 cm) tumor size and high mitotic counts (>5/50 high-power fields). Therefore, KIT-negative EGISTs can be characterized by preferential omental origin, epithelioid cell type, low mitotic activity, and mutation of the PDGFRA gene, and these features are similar to those of KIT-negative gastric GISTs. As KIT-negative EGISTs should be considered to be a potential abdominal soft tissue neoplasm, immunohistochemical staining panel and molecular analysis are necessary not only to confirm the diagnosis but also to determine the therapeutic strategy.

Sugahara K, Michikawa Y, Ishikawa K, et al.
Combination effects of distinct cores in 11q13 amplification region on cervical lymph node metastasis of oral squamous cell carcinoma.
Int J Oncol. 2011; 39(4):761-9 [PubMed] Related Publications
Lymph node metastasis (LNM) in oral squamous cell carcinoma (OSCC) is known to associate with a significant decrease of 5-year survival. Genetic factors related to the difference of the LNM status in the OSCC have been not fully elucidated. Array-based comparative genomic hybridization (CGH) with individual gene-level resolution and real-time quantitative polymerase chain reaction (QPCR) were conducted using primary tumor materials resected from 54 OSCC patients with (n=22) or without (n=32) cervical LNM. Frequent gain was observed at the 11q13 region exclusively in patients with cervical LNM, which was confirmed by real-time QPCR experiments using 11 genes (TPCN2, MYEOV, CCND1, ORAOV1, FGF4, TMEM16A, FADD, PPFIA1, CTTN, SHANK2 and DHCR7) in this region. It was revealed that two distinct amplification cores existed, which were separated by a breakpoint between MYEOV and CCND1 in the 11q13 region. The combination of copy number amplification at CTTN (core 2) and/or TPCN2/MYEOV (core 1), selected from each core, was most significantly associated with cervical LNM (P=0.0035). Two amplification cores at the 11q13 region may have biological impacts on OSCC cells to spread from the primary site to local lymph nodes. Further study of a larger patient series should be conducted to validate these results.

Dei Tos AP, Laurino L, Bearzi I, et al.
Gastrointestinal stromal tumors: the histology report.
Dig Liver Dis. 2011; 43 Suppl 4:S304-9 [PubMed] Related Publications
Gastrointestinal stromal tumors (GISTs) represent a mesenchymal neoplasm occurring primarily in the gastrointestinal tract, and showing differentiation toward the interstitial cell of Cajal. Its incidence is approximately 15 case/100,000/year. Stomach and small bowel are the most frequently affected anatomic sites. GIST represents a morphological, immunophenotypical and molecular distinct entity, the recognition of which has profound therapeutic implications. In fact, they have shown an exquisite sensitivity to treatment with the tyrosine kinase inhibitor imatinib. Diagnosis relies upon morphology along with immunodetection of KIT and/or DOG1. When dealing with KIT negative cases, molecular analysis of KIT/PDGFRA genes may help in confirming diagnosis. Molecular evaluation of both genes are in any case recommended as mutational status provides key predictive information. Pathologists also play a key role in providing an estimation of the risk of biological aggressiveness, which is currently based on anatomic location of the tumor, size, and mitotic activity.

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