Gene Summary

Gene:NKX2-2; NK2 homeobox 2
Aliases: NKX2B, NKX2.2
Summary:The protein encoded by this gene contains a homeobox domain and may be involved in the morphogenesis of the central nervous system. This gene is found on chromosome 20 near NKX2-4, and these two genes appear to be duplicated on chromosome 14 in the form of TITF1 and NKX2-8. The encoded protein is likely to be a nuclear transcription factor. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:homeobox protein Nkx-2.2
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Latest Publications: NKX2-2 (cancer-related)

Anderson WJ, Hornick JL
Immunohistochemical correlates of recurrent genetic alterations in sarcomas.
Genes Chromosomes Cancer. 2019; 58(2):111-123 [PubMed] Related Publications
Accurate diagnosis of sarcomas relies on the integration of clinical, histopathological and molecular features. Our understanding of the latter has increased dramatically in recent years with the application of high-throughput sequencing. Concomitantly, the role of immunohistochemistry has expanded as genomic alterations have been exploited by the development of diagnostic markers that serve as surrogates for their detection. Herein, we review selected immunohistochemical markers that can infer the presence of diverse molecular events. These include gene fusions in vascular neoplasms (FOSB, CAMTA1 and TFE3), round cell sarcomas (BCOR, DUX4 and WT1), and fibroblastic/myofibroblastic tumors (STAT6, ALK and Pan-TRK); amplifications in well-differentiated and dedifferentiated liposarcomas (MDM2 and CDK4); and deletions in several aggressive neoplasms (SMARCB1 and SMARCA4). Protein correlates of single nucleotide variants (beta-catenin in desmoid fibromatosis) and epigenetic alterations (histone H3K27me3 in malignant peripheral nerve sheath tumor) and markers discovered through gene expression profiling (NKX2.2 and MUC4) are also discussed.

Nagel S, MacLeod RAF, Meyer C, et al.
NKL homeobox gene activities in B-cell development and lymphomas.
PLoS One. 2018; 13(10):e0205537 [PubMed] Free Access to Full Article Related Publications
Homeobox genes encode transcription factors which regulate basic processes in development and cell differentiation. Several members of the NKL subclass are deregulated in T-cell progenitors and support leukemogenesis. We have recently described particular expression patterns of nine NKL homeobox genes in early hematopoiesis and T-cell development. Here, we screened NKL homeobox gene activities in normal B-cell development and extended the NKL-code to include this lymphoid lineage. Analysis of public expression profiling datasets revealed that HHEX and NKX6-3 were the only members differentially active in naïve B-cells, germinal center B-cells, plasma cells and memory B-cells. Subsequent examination of different types of B-cell malignancies showed both aberrant overexpression of NKL-code members and ectopic activation of subclass members physiologically silent in lymphopoiesis including BARX2, DLX1, EMX2, NKX2-1, NKX2-2 and NKX3-2. Based on these findings we performed detailed studies of the B-cell specific NKL homeobox gene NKX6-3 which showed enhanced activity in patient subsets of follicular lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL), and in three DLBCL cell lines to serve as in vitro models. While excluding genomic and chromosomal rearrangements at the locus of NKX6-3 (8p11) promoter studies demonstrated that B-cell factors MYB and PAX5 activated NKX6-3 transcription. Furthermore, aberrant BMP7/SMAD1-signalling and deregulated expression of chromatin complex components AUTS2 and PCGF5 promoted NKX6-3 activation. Finally, NKL homeobox genes HHEX, HLX, MSX1 and NKX6-3 were expressed in B-cell progenitors and generated a regulatory gene network in cell lines which we propose may provide physiological support for NKL-code formation in early B-cell development. Together, we identified an NKL-code in B-cell development whose violation may deregulate differentiation and promote malignant transformation.

Dugnani E, Sordi V, Pellegrini S, et al.
Gene expression analysis of embryonic pancreas development master regulators and terminal cell fate markers in resected pancreatic cancer: A correlation with clinical outcome.
Pancreatology. 2018; 18(8):945-953 [PubMed] Related Publications
BACKGROUND: Despite the recent introduction of new drugs and the development of innovative multi-target treatments, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains very poor. Even when PDAC is resectable, the rate of local or widespread disease recurrence remains particularly high. Currently, reliable prognostic biomarkers of recurrence are lacking. We decided to explore the potential usefulness of pancreatic developmental regulators as biomarkers of PDAC relapse.
METHODS: We analyzed by quantitative real-time PCR the mRNA of selected factors involved either in pancreatic organogenesis (ISL1, NEUROD1, NGN3, NKX2.2, NKX6.1, PAX4, PAX6, PDX1 and PTF1α) or associated with terminally committed pancreatic cells (CHGA, CHGB, GAD2, GCG, HNF6α, INS, KRT19, SYP) in 17 PDAC cell lines and in frozen tumor samples from 41 PDAC patients.
RESULTS: High baseline levels of the ISL1, KRT19, PAX6 and PDX1 mRNAs in PDAC cell lines, were risk factors for time-dependent xenograft appearance after subcutaneous injection in CD1-Nude mice. Consistently, in human PDAC samples, high levels of KRT19 mRNA were associated with reduced overall survival and earlier recurrence. Higher levels of PDX1 or PAX6 mRNAs were instead associated with a higher frequency of local recurrence.
CONCLUSIONS: Our findings suggest that selected factors associated with pancreas development or its terminal differentiation might be implicated in mechanisms of PDAC progression and/or metastatic spread and that the measurement of their mRNA in tumors might be potentially used to improve patient prognostic stratification and prediction of the relapse site.

Machiela MJ, Grünewald TGP, Surdez D, et al.
Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility.
Nat Commun. 2018; 9(1):3184 [PubMed] Free Access to Full Article Related Publications
Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

Boulay G, Volorio A, Iyer S, et al.
Epigenome editing of microsatellite repeats defines tumor-specific enhancer functions and dependencies.
Genes Dev. 2018; 32(15-16):1008-1019 [PubMed] Free Access to Full Article Related Publications
Various types of repetitive sequences are dysregulated in cancer. In Ewing sarcoma, the oncogenic fusion protein EWS-FLI1 induces chromatin features typical of active enhancers at GGAA microsatellite repeats, but the function of these sites has not been directly demonstrated. Here, by combining nascent transcription profiling with epigenome editing, we found that a subset of GGAA microsatellite repeats is transcriptionally active in Ewing sarcoma and that silencing individual repeats abolishes local nascent transcription and leads to markedly reduced expression of putative target genes. Epigenome silencing of these repeat sites does not affect gene expression in unrelated cells, can prevent the induction of gene expression by EWS-FLI1, and, in the case of a GGAA repeat that controls

Toki S, Wakai S, Sekimizu M, et al.
PAX7 immunohistochemical evaluation of Ewing sarcoma and other small round cell tumours.
Histopathology. 2018; 73(4):645-652 [PubMed] Related Publications
AIMS: Ewing sarcoma is a small round cell tumour that affects bone and soft tissues. Although the detection of the specific fusion gene is a robust method of its diagnosis, immunohistochemistry may serve as a practical surrogate. Recent tissue microarray studies suggested that PAX7 is a novel marker, because it was expressed consistently in Ewing sarcoma, in addition to rhabdomyosarcoma and synovial sarcoma. Here, we evaluated the utility of PAX7 immunohistochemistry in whole-tissue sections of an expanded array of round cell malignancies with adequate molecular characterisation.
METHODS AND RESULTS: We stained 30 molecularly confirmed Ewing sarcomas, one EWSR1-NFATC2 sarcoma and 141 non-Ewing round cell tumours by a monoclonal antibody against PAX7. Staining was considered positive if at least 5% of tumour cells were stained. PAX7 was expressed in 27 of 30 Ewing sarcomas (90%), mainly in a diffuse and strong manner. Although NKX2-2 showed similar sensitivity, PAX7 showed more extensive and strong reactivity. One EWSR1-NFATC2 sarcoma co-expressed PAX7 and NKX2-2. PAX7 was also expressed in 24 of 141 non-Ewing tumours, including alveolar rhabdomyosarcomas (seven of 10), poorly differentiated synovial sarcomas (seven of 10), BCOR-CCNB3 sarcomas (eight of 10), small-cell osteosarcoma (one of five) and desmoplastic small round cell tumour (one of 10), one-third of which showed diffuse strong reactivity.
CONCLUSIONS: Although we confirmed that PAX7 is a sensitive marker for Ewing sarcoma, anti-PAX7 antibody also stained several Ewing sarcoma mimics, whose spectrum was distinct from NKX2-2-positive non-Ewing entities. Further studies are required to determine how PAX7 could be integrated into practice to classify small round cell tumours efficiently.

Yang Y, Zhou Y, Xiong X, et al.
ALG3 Is Activated by Heat Shock Factor 2 and Promotes Breast Cancer Growth.
Med Sci Monit. 2018; 24:3479-3487 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Previous research found that ALG3 is associated with cervical cancer, but the role of ALG3 in breast cancer was still unknown. MATERIAL AND METHODS The expression of ALG3 in breast carcinoma tissues was determined by immunochemistry. The ability of cellular proliferation, migration, and invasion was determined by CCK-8 assay, wound healing migration assay, and cell invasion assays, respectively. The binding between HSF2 and promoter of ALG3 was determined by ChIP assay. RESULTS There was an increased expression of ALG3 in breast cancer tissues compared to normal breast tissues (p<0.05). High expression of ALG3 was significantly correlated with poor OS (p<0.05). ALG3 expression was significantly increased in cancer samples with advanced stages (stage III/IV) compared with those in the early stages of disease (stage I/II) (p<0.05). The staining intensity of ALG3 was significantly correlated to the tumor grade (grades 2-3 versus 1, p<0.05). Silencing ALG3 or HSF2 inhibited the proliferation, migration, and invasion abilities of MCF-7 cells. Silencing ALG3 retarded the growth of MCF-7 cells in vivo. CONCLUSIONS Silencing ALG3 inhibited MCF-7 cells growth in vitro and in vivo. HSF2 activated ALG3 and promoted the growth of breast carcinoma.

Liao YS, Chiang IH, Gao HW
A mesenteric primary peripheral Ewing's sarcoma/primitive neuroectodermal tumor with molecular cytogenetic analysis: Report of a rare case and review of literature.
Indian J Pathol Microbiol. 2018 Apr-Jun; 61(2):248-251 [PubMed] Related Publications
Rare cases of Ewing's sarcoma/primitive neuroectodermal tumors (EWS/PNETs) arising from mesenteric tissue have been reported. This report describes an EWS/PNET in a 25-year-old woman who presented with abdominal pain lasting 3 days. Radiologic evaluation revealed a 9 cm × 6 cm homogeneous mass in the lower abdomen with homogeneous enhancement and invasion of the ileum. Surgical resection was completed during exploratory laparotomy. Immunohistochemically, the tumor cells revealed CD99, friend leukemia virus integration-1 and NKX2.2 (NK2 Homeobox 2, a protein coding gene) and subsequently showed EWSR1 rearrangement. The histological feature, immunohistochemical results and genetic fluorescence in situ hybridization analysis of this case were confirming the diagnosis of EWS/PNET. Adjuvant chemotherapy was suggested, but the patient was lost to follow-up.

Machado I, Yoshida A, Morales MGN, et al.
Review with novel markers facilitates precise categorization of 41 cases of diagnostically challenging, "undifferentiated small round cell tumors". A clinicopathologic, immunophenotypic and molecular analysis.
Ann Diagn Pathol. 2018; 34:1-12 [PubMed] Related Publications
BACKGROUND: Despite extensive immunohistochemical (IHC) and molecular studies combined with morphologic findings, a group of round/ovoid cell tumors histologically similar to Ewing sarcomas (ES) but lacking EWSR1-rearrangements may remain unclassifiable.
DESIGN: We retrospectively analyzed 41 Ewing-like tumors (formalin-fixed, paraffin-embedded) previously determined as negative or non-informative for EWSR1-rearrangements by FISH and/or RT-PCR. A new histopathology revision and additional IHC and molecular analyses were carried out in order to investigate whether additional IHC and/or molecular testing in combination with the morphological findings may help in reaching a definitive diagnosis.
RESULTS: Almost all the tumors (n=40) involved soft tissue and/or bone and half the patients died of disease. In the archival cases all diagnoses were Ewing sarcoma (ES), Ewing-like sarcoma (ELS), myoepithelial tumor and undifferentiated sarcoma (US). In the new review all the tumors were re-classified as, ES (n=16), Ewing-like tumor with EWSR1 rearrangement and amplification and possible EWSR1-NFATC2 gene fusion (n=1), CIC-rearranged sarcomas or undifferentiated sarcoma, most consistent with CIC-rearranged sarcoma (n=7), sarcoma with BCOR-alteration or undifferentiated sarcoma, consistent with BCOR-associated sarcoma (n=3), neuroblastoma (n=2), unclassifiable neoplasm with neuroblastic differentiation (n=1), malignant rhabdoid tumor (n=2), lymphoblastic lymphoma (n=1), clear cell sarcoma of the gastrointestinal tract (n=1), small cell carcinoma (n=1), sclerosing rhabdomyosarcoma (n=1), desmoplastic small round cell tumor (n=1), malignant peripheral sheath nerve tumor (n=1), poorly-differentiated synovial sarcoma (n=1), Possible gastrointestinal stromal tumor/GIST with predominant round cells (n=1) and possible SMARCA4-deficient-sarcoma (n=1). NKX2.2, ETV4 and BCOR immunoreactivity was observed in all ES, CIC-rearranged sarcomas and sarcomas with BCOR alteration, respectively. CIC-rearrangement by FISH was observed in many of the CIC-rearranged sarcomas.
CONCLUSION: Our analysis of 41 Ewing-like tumors confirms that there may be a significant pathological and IHC overlap among Ewing-like tumors, with prognostic and therapeutic impacts. Additional IHC (NKX2.2, ETV4 and BCOR) and molecular studies including FUS, CIC or BCOR analysis may support the final diagnosis when FISH or RT-PCR fail to detect EWSR1-rearrangements. Any molecular findings should always be interpreted in relation to the specific clinical and pathological context.

Machado I, Yoshida A, López-Guerrero JA, et al.
Immunohistochemical analysis of NKX2.2, ETV4, and BCOR in a large series of genetically confirmed Ewing sarcoma family of tumors.
Pathol Res Pract. 2017; 213(9):1048-1053 [PubMed] Related Publications
Ewing sarcoma is an aggressive neoplasm of pediatric and adolescent patients. Immunohistochemistry (IHC) can be used to support the morphologic diagnosis of Ewing sarcoma family of tumors (ESFT) in a convincing clinical/radiological context. Although neither NKX2.2 nor CD99 alone are entirely specific, when combined, the diagnostic specificity is high. The aim of the present study was to investigate the IHC expression of NKX2.2, ETV4 and BCOR in a large series of genetically confirmed ESFT. The results for CD99 and CAV-1 immunoreactivity, and the histological and fusion gene subtypes were retrieved from our previous study. NKX2.2 demonstrated moderate or strong nuclear positivity in 91.2% of the tumors. The staining intensity was heterogeneous. Many of the ESFT with negative NKX2.2 immunoreactivity were in bone. Strong/moderate ETV4 nuclear expression was detected in two small round cell tumors, both were negative for NKX2.2. No relationships could be found between expression of NKX2.2 and the histological subgroups or ESFT gene fusion subtypes. BCOR was negative in all ESFT. In conclusion, NKX2.2, ETV4 and BCOR IHC may be helpful in daily practice for distinguishing ESFT from CIC or BCOR-associated sarcomas, especially in hospitals without access to molecular assays. In addition, the combination of strong CD99 membranous positivity and nuclear NKX2.2 positivity seems to be very reliable for ESFT diagnosis in an appropriate clinicoradiological setting. So far no antibody is entirely specific for ESFT diagnosis, and the IHC or molecular results in round cell tumors of bone may be strongly influenced by decalcification processes.

Yoshida A, Arai Y, Kobayashi E, et al.
CIC break-apart fluorescence in-situ hybridization misses a subset of CIC-DUX4 sarcomas: a clinicopathological and molecular study.
Histopathology. 2017; 71(3):461-469 [PubMed] Related Publications
AIMS: Approximately 60-70% of high-grade round-cell sarcomas that lack the Ewing sarcoma breakpoint region 1 (EWSR1) rearrangement harbour a rearrangement of the CIC gene, most commonly CIC-DUX4. Recent studies have established that CIC-rearranged sarcomas constitute a distinct group characterized by recognizable histology and immunoprofiles, such as positivity for ETV4 and WT1 and negativity for NKX2.2. Although these sarcomas are diagnosed increasingly in practice by fluorescence in-situ hybridization (FISH) with CIC break-apart probes, the optimal modality to diagnose these sarcomas has not been determined. In this study, we describe four round-cell sarcomas that showed false-negative results by CIC break-apart FISH assays.
METHODS AND RESULTS: These sarcomas showed characteristic histology of CIC-rearranged sarcomas, and all were immunohistochemically positive for ETV4 and WT1 and negative for NKX2.2. Although FISH showed non-atypical negative signals for CIC rearrangement, high-throughput RNA sequencing identified CIC-DUX4 and its fusion breakpoint in all cases. Their clinical and histological findings, as well as fusion points determined by RNA sequencing, did not differ significantly from those of nine FISH-positive CIC-DUX4 sarcoma cases. We estimated that the FISH false-negative rate for CIC-rearranged sarcomas was 14%. Although neither histology nor immunoprofiles (e.g. ETV4 and WT1) are entirely sensitive or specific for CIC-rearranged sarcomas, the observation that these four cases were identified successfully by such phenotypes suggested their practical utility.
CONCLUSIONS: CIC break-apart FISH assays missed a significant minority of CIC-DUX4 sarcomas, and full awareness of typical morphology and judicious immunohistochemical work-ups, including analyses of ETV4 and WT1, should complement diagnostic assessment.

Xue M, Liu H, Zhang L, et al.
Computational identification of mutually exclusive transcriptional drivers dysregulating metastatic microRNAs in prostate cancer.
Nat Commun. 2017; 8:14917 [PubMed] Free Access to Full Article Related Publications
Androgen-ablation therapies, which are the standard treatment for metastatic prostate cancer, invariably lead to acquired resistance. Hence, a systematic identification of additional drivers may provide useful insights into the development of effective therapies. Numerous microRNAs that are critical for metastasis are dysregulated in metastatic prostate cancer, but the underlying molecular mechanism is poorly understood. We perform an integrative analysis of transcription factor (TF) and microRNA expression profiles and computationally identify three master TFs, AR, HOXC6 and NKX2-2, which induce the aberrant metastatic microRNA expression in a mutually exclusive fashion. Experimental validations confirm that the three TFs co-dysregulate a large number of metastasis-associated microRNAs. Moreover, their overexpression substantially enhances cell motility and is consistently associated with a poor clinical outcome. Finally, the mutually exclusive overexpression between AR, HOXC6 and NKX2-2 is preserved across various tissues and cancers, suggesting that mutual exclusivity may represent an intrinsic characteristic of driver TFs during tumorigenesis.

Bhat S, Kabekkodu SP, Varghese VK, et al.
Aberrant gene-specific DNA methylation signature analysis in cervical cancer.
Tumour Biol. 2017; 39(3):1010428317694573 [PubMed] Related Publications
Multicomponent molecular modifications such as DNA methylation may offer sensitive and specific cervical intraepithelial neoplasia and cervical cancer biomarkers. In this study, we tested cervical tissues at various stages of tumor progression for 5-methylcytosine and 5-hydroxymethylcytosine levels and also DNA promoter methylation profile of a panel of genes for its diagnostic potential. In total, 5-methylcytosine, 5-hydroxymethylcytosine, and promoter methylation of 33 genes were evaluated by reversed-phase high-performance liquid chromatography, enzyme-linked immunosorbent assay based technique, and bisulfate-based next generation sequencing. The 5-methylcytosine and 5-hydroxymethylcytosine contents were significantly reduced in squamous cell carcinoma and receiver operating characteristic curve analysis showed a significant difference in (1) 5-methylcytosine between normal and squamous cell carcinoma tissues (area under the curve = 0.946) and (2) 5-hydroxymethylcytosine levels among normal, squamous intraepithelial lesions and squamous cell carcinoma. Analyses of our next generation sequencing results and data from five independent published studies consisting of 191 normal, 10 low-grade squamous intraepithelial lesions, 21 high-grade squamous intraepithelial lesions, and 335 malignant tissues identified a panel of nine genes ( ARHGAP6, DAPK1, HAND2, NKX2-2, NNAT, PCDH10, PROX1, PITX2, and RAB6C) which could effectively discriminate among the various groups with sensitivity and specificity of 80%-100% (p < 0.05). Furthermore, 12 gene promoters (ARHGAP6, HAND2, LHX9, HEY2, NKX2-2, PCDH10, PITX2, PROX1, TBX3, IKBKG, RAB6C, and DAPK1) were also methylated in one or more of the cervical cancer cell lines tested. The global and gene-specific methylation of the panel of genes identified in our study may serve as useful biomarkers for the early detection and clinical management of cervical cancer.

Yamada Y, Kuda M, Kohashi K, et al.
Histological and immunohistochemical characteristics of undifferentiated small round cell sarcomas associated with CIC-DUX4 and BCOR-CCNB3 fusion genes.
Virchows Arch. 2017; 470(4):373-380 [PubMed] Related Publications
CIC-DUX4 and BCOR-CCNB3 fusion-gene-associated small round cell sarcomas account for a proportion of pediatric small round cell sarcomas, but their pathological features have not been sufficiently clarified. We reviewed a large number of soft tissue tumors registered at our institution, retrieved the cases of unclassified tumors with a small round cell component, and subjected them to histopathological, immunohistochemical, and gene profile analysis. We reviewed 164 cases of unclassified tumors with a small round cell component and analyzed them by RT-PCR and FISH. Tumors positive for a specific fusion-gene were also subjected to histopathological and immunohistochemical examinations. We identified 16 cases of BCOR-CCNB3/CIC-associated (CIC-DUX4 or CIC gene rearrangement-positive) sarcomas. These included seven BCOR-CCNB3 sarcomas and nine CIC-associated sarcomas. Heterogeneous elements included a myxoid spindle cell component in three BCOR-CCNB3 sarcomas and an epithelioid cell component in two CIC-associated sarcomas (one CIC-DUX4-positive and one CIC-DUX4-negative sarcomas). Mitotic activity was low in both heterogeneous components. By immunohistochemistry, in seven BCOR-CCNB3 sarcomas expression of EMA was positive in two cases, of p63 in three, of CD56 in six, of TLE1 in seven, of NKX2.2 in two, of CCNB3 in seven, and of BCOR in six cases (one case could not be tested for BCOR). In nine cases of CIC-associated sarcoma, CD56 was expressed in five, alpha-smooth muscle actin in one, ERG in three, and CD99, WT1 and TLE1 each in eight cases. Both sarcoma types showed not only a small round cell component, but also a myxoid/epithelioid component with low mitotic activity.

Sugita S, Arai Y, Aoyama T, et al.
NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma.
Hum Pathol. 2017; 65:225-230 [PubMed] Related Publications
CIC-rearranged sarcoma is a new entity of undifferentiated small round cell sarcoma characterized by chimeric fusions with CIC rearrangement. We report a NUTM2A-CIC fusion sarcoma in a 43-year-old woman who died of rapidly progressive disease. Histologic analysis revealed multinodular proliferation of small round tumor cells with mild nuclear pleomorphism. The sclerotic fibrous septa separated the tumor into multiple nodules. Immunohistochemistry showed that the tumor cells were diffusely positive for vimentin, focally positive for cytokeratin, and negative for CD99 and NKX2.2. Tumor cells were also negative for ETV4, which was recently identified as a specific marker for CIC-rearranged sarcoma. High-throughput RNA sequencing of a formalin-fixed, paraffin-embedded clinical sample unveiled a novel NUTM2A-CIC fusion between NUTM2A exon 7 and CIC exon 12, and fluorescence in situ hybridization identified CIC and NUTM2A split signals. This case shared several clinicopathological findings with previously reported CIC-rearranged cases. We recognized the tumor as a genetically distinct variant of CIC-rearranged sarcomas with a novel NUTM2A-CIC fusion.

Ishiguro M, Yuki M, Fukushige T, et al.
Molecular cytogenetic characterization of two established ESFT cell lines.
Hum Cell. 2017; 30(1):41-48 [PubMed] Related Publications
Ewing's sarcoma/primitive neuroectodermal tumor/Askin's tumor (Ewing`s sarcoma family of tumors: ESFT) is the most common type of malignant tumor of bone and soft tissue in children and young adults, and morphologically is a member of a group of small round cell tumors. We report, here, on the establishment of two human ESFT cell lines, FU-PNET-3 and FU-PNET-4, from the iliac and the chest wall, respectively, the cells of both cell lines were tumorigenic in immunodeficient mice. Histologically, both original and xenograft tumors and cultured cells were composed of small round cells with positive immunoreactivity for CD99 and Nkx2.2. Molecular biological examination demonstrated chimeric transcripts of EWSR1 exon 7 to FLI1 exon 6 in FU-PNET-3 cells, and EWSR1 exon 10 to FLI1 exon 6 in FU-PNET-4 cells. Cytogenetic analysis revealed chromosome translocation t(11;22)(q24;q12) and some secondary changes in both cultured cells. These histological, molecular biological, and cytogenetical findings indicate ESFT in both cell lines. ESFT is well studied, but its recurrent fusion genes are heterogeneous and its biological behaviors are unclear. The FU-PNET-3 and FU-PNET-4 cell lines have been well examined and may become useful tools for studying the genetic and biological behavioral properties of ESFT.

Bailey P, Chang DK, Nones K, et al.
Genomic analyses identify molecular subtypes of pancreatic cancer.
Nature. 2016; 531(7592):47-52 [PubMed] Related Publications
Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Yoshida A, Goto K, Kodaira M, et al.
CIC-rearranged Sarcomas: A Study of 20 Cases and Comparisons With Ewing Sarcomas.
Am J Surg Pathol. 2016; 40(3):313-23 [PubMed] Related Publications
The CIC gene rearrangement exists in a subset of small round cell sarcomas. As the nosologic relationship of these sarcomas to Ewing sarcomas remains undetermined, we examined 20 CIC-rearranged sarcomas to compare their clinicopathologic features with those of Ewing sarcomas. The CIC-rearranged sarcomas were from a group of 14 men and 6 women with a median age of 24.5 years. The primary tumor sites included the limbs, trunk wall, internal trunk, lung, cerebrum, and pharynx. A comparison of the demographic and clinical characteristics of the 20 patients with CIC-rearranged sarcomas with those of the 53 near-consecutive patients with EWSR1-rarranged Ewing sarcomas showed that there were no differences with respect to their ages and sexes. Although none of the CIC-rearranged sarcomas arose in the bone, 40% of the Ewing sarcomas primarily affected the skeleton. The overall survival of patients with Ewing sarcomas was significantly better than that for patients with CIC-rearranged sarcomas. A histologic comparison of the CIC-rearranged sarcomas with 20 EWSR1-rearranged Ewing sarcomas showed significantly higher degrees of lobulation, nuclear pleomorphism, the prominence of the nucleoli, spindle cell elements, and myxoid changes in the CIC-rearranged sarcomas. Distinguishing immunohistochemical features included heterogenous CD99 reactivity, nuclear WT1 expression, and calretinin expression in the CIC-rearranged sarcomas and NKX2.2 expression in the Ewing sarcomas. CIC-rearranged sarcomas are distinct from Ewing sarcomas clinically, morphologically, and immunohistochemically, and they should be considered a separate entity rather than being grouped within the same family of tumors.

Fan H, Zhao H, Pang L, et al.
Systematically Prioritizing Functional Differentially Methylated Regions (fDMRs) by Integrating Multi-omics Data in Colorectal Cancer.
Sci Rep. 2015; 5:12789 [PubMed] Free Access to Full Article Related Publications
While genome-wide differential DNA methylation regions (DMRs) have been extensively identified, the comprehensive prioritization of their functional importance is still poorly explored. Here, we aggregated multiple data resources rooted in the genome, epigenome and transcriptome to systematically prioritize functional DMRs (fDMRs) in colorectal cancer (CRC). As demonstrated, the top-ranked fDMRs from all of the data resources showed a strong enrichment for known methylated genes. Additionally, we analyzed those top 5% DMR-coupled coding genes using functional enrichment, which resulted in significant disease-related biological functions in contrast to the tail 5% genes. To further confirm the functional importance of the top-ranked fDMRs, we applied chromatin modification alterations of CRC cell lines to characterize their functional regulation. Specifically, we extended the utility of the top-ranked DMR-coupled genes to serve as classification and survival biomarkers, which showed a robust performance across diverse independent data sets. Collectively, our results established an integrative framework to prioritize fDMRs, which could help characterize aberrant DNA methylation-induced potential mechanisms underlying tumorigenesis and uncover epigenome-based biomarkers for clinical diagnosis and prognosis.

Sarver AE, Sarver AL, Thayanithy V, Subramanian S
Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors.
Lab Invest. 2015; 95(9):1077-88 [PubMed] Related Publications
Human sarcomas comprise a heterogeneous group of more than 50 subtypes broadly classified into two groups: bone and soft tissue sarcomas. Such heterogeneity and their relative rarity have made them challenging targets for classification, biomarker identification, and development of improved treatment strategies. In this study, we used RNA sequencing to analyze 35 primary human tissue samples representing 13 different sarcoma subtypes, along with benign schwannoma, and normal bone and muscle tissues. For each sarcoma subtype, we detected unique messenger RNA (mRNA) expression signatures, which we further subjected to bioinformatic functional analysis, upstream regulatory analysis, and microRNA (miRNA) targeting analysis. We found that, for each sarcoma subtype, significantly upregulated genes and their deduced upstream regulators included not only previously implicated known players but also novel candidates not previously reported to be associated with sarcoma. For example, the schwannoma samples were characterized by high expression of not only the known associated proteins GFAP and GAP43 but also the novel player GJB6. Further, when we integrated our expression profiles with miRNA expression data from each sarcoma subtype, we were able to deduce potential key miRNA-gene regulator relationships for each. In the Ewing's sarcoma and fibromatosis samples, two sarcomas where miR-182-5p is significantly downregulated, multiple predicted targets were significantly upregulated, including HMCN1, NKX2-2, SCNN1G, and SOX2. In conclusion, despite the small number of samples per sarcoma subtype, we were able to identify key known players; concurrently, we discovered novel genes that may prove to be important in the molecular classification of sarcomas and in the development of novel treatments.

Ozaki Y, Miura Y, Koganemaru S, et al.
Ewing sarcoma of the liver with multilocular cystic mass formation: a case report.
BMC Cancer. 2015; 15:16 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ewing sarcoma is a rare tumor that occurs commonly in the long bones of children or adolescents that can also arise in soft tissues including the extremities, retroperitoneum, chest wall, and rarely in the liver as primary sites. We report a case of Ewing sarcoma arising primarily in the liver and, to our knowledge, this is the fourth reported case of Ewing sarcoma occurring in the liver.
CASE PRESENTATION: A 27-year-old Japanese woman was admitted with sudden onset right upper abdominal pain. Clinical examination revealed a multilocular cystic mass consisting of thickened, irregular septa and nodal walls in the right hepatic lobe. Ultrasound-guided aspiration biopsy of the liver mass showed clusters of small atypical round cells and the clinical preoperative diagnosis was mucinous cystadenoma of the liver. The patient underwent an extended right hepatectomy and histopathological findings revealed sheet-like proliferation of small- to medium-sized round cells. Tumor cells were positive for periodic acid-Schiff reaction and immunoreactive for glycoprotein C99 and gene NKX2.2, as well as the neuroendocrine markers, CD56 and synaptophysin. EWS-FLI-1 fusion transcript type 1 was detected by reverse transcriptase polymerase chain reaction. Pathological and molecular analysis confirmed the diagnosis of Ewing sarcoma arising primarily in the liver and the patient received adjuvant systemic chemotherapy with vincristine, doxorubicin, and cyclophosphamide, alternating with ifosfamide and etoposide. We found no evidence of recurrence 15 months after completing chemotherapy.
CONCLUSION: We present an extremely rare case of Ewing sarcoma arising primarily in the liver. To our knowledge, this is the fourth reported case of Ewing sarcoma occurring in the liver, and the first case with a multilocular cystic liver mass. Imaging examinations of the other three reported cases showed solid tumors and a diffuse enlarged liver without mass lesion. Clinicians should consider the possibility of Ewing sarcoma in young patients with a multilocular cystic mass with thick and/or irregular cyst walls in the liver.

Shibuya R, Matsuyama A, Nakamoto M, et al.
The combination of CD99 and NKX2.2, a transcriptional target of EWSR1-FLI1, is highly specific for the diagnosis of Ewing sarcoma.
Virchows Arch. 2014; 465(5):599-605 [PubMed] Related Publications
Ewing sarcoma (ES) is a high-grade malignant neoplasm primarily affecting children and young adults. The diagnosis of ES is often difficult because of its broad differential diagnosis comprising a diverse group of small round cell tumors (SRCTs). Although the identification of tumor type-specific fusion genes by molecular testing is the gold standard for the diagnosis of ES, such approaches are not always available in a routine pathology practice. Thus, a reliable immunohistochemical marker is required. A recent study using a limited number of tumor samples has shown that NKX2.2, a putative transcriptional target of EWSR1-FLI1, is a useful marker for the diagnosis of ES. In the present study, the immunohistochemical expression of NKX2.2 was evaluated on 46 genetically confirmed ES and 85 non-ES SRCTs, together with comparative assessment of CD99 and other molecular targets of EWSR1-FLI1, including NR0B1, E2F3, and EZH2. NKX2.2 was expressed in 37 (80 %) of the ES samples with a mostly diffuse and strong staining pattern, and 14 (16 %) of the non-ES SRCTs, including olfactory neuroblastomas, extraskeletal myxoid chondrosarcoma, mesenchymal chondrosarcoma, small cell carcinomas, and Merkel cell carcinoma, also expressed this marker. The sensitivity and specificity of the NKX2.2 expression in this cohort were 80 and 84 %, respectively. The specificity when combined with CD99 was 98 %, with exceptional expression of both markers in only two non-ES SRCTs, including one case each of mesenchymal chondrosarcoma and small cell carcinoma. NR0B1, E2F3, and EZH2 were less sensitive for specific markers for ES when applied singly or in any combination. In conclusion, the study reinforces that NKX2.2 is a useful immunohistochemical marker for ES, and that the combination of CD99 and NKX2.2 is a powerful diagnostic tool that can differentiate ES from other SRCTs.

Kidd M, Modlin IM, Drozdov I
Gene network-based analysis identifies two potential subtypes of small intestinal neuroendocrine tumors.
BMC Genomics. 2014; 15:595 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumor transcriptomes contain information of critical value to understanding the different capacities of a cell at both a physiological and pathological level. In terms of clinical relevance, they provide information regarding the cellular "toolbox" e.g., pathways associated with malignancy and metastasis or drug dependency. Exploration of this resource can therefore be leveraged as a translational tool to better manage and assess neoplastic behavior. The availability of public genome-wide expression datasets, provide an opportunity to reassess neuroendocrine tumors at a more fundamental level. We hypothesized that stringent analysis of expression profiles as well as regulatory networks of the neoplastic cell would provide novel information that facilitates further delineation of the genomic basis of small intestinal neuroendocrine tumors.
RESULTS: We re-analyzed two publically available small intestinal tumor transcriptomes using stringent quality control parameters and network-based approaches and validated expression of core secretory regulatory elements e.g., CPE, PCSK1, secretogranins, including genes involved in depolarization e.g., SCN3A, as well as transcription factors associated with neurodevelopment (NKX2-2, NeuroD1, INSM1) and glucose homeostasis (APLP1). The candidate metastasis-associated transcription factor, ST18, was highly expressed (>14-fold, p < 0.004). Genes previously associated with neoplasia, CEBPA and SDHD, were decreased in expression (-1.5 - -2, p < 0.02). Genomic interrogation indicated that intestinal tumors may consist of two different subtypes, serotonin-producing neoplasms and serotonin/substance P/tachykinin lesions. QPCR validation in an independent dataset (n = 13 neuroendocrine tumors), confirmed up-regulated expression of 87% of genes (13/15).
CONCLUSIONS: An integrated cellular transcriptomic analysis of small intestinal neuroendocrine tumors identified that they are regulated at a developmental level, have key activation of hypoxic pathways (a known regulator of malignant stem cell phenotypes) as well as activation of genes involved in apoptosis and proliferation. Further refinement of these analyses by RNAseq studies of large-scale databases will enable definition of individual master regulators and facilitate the development of novel tissue and blood-based tools to better understand diagnose and treat tumors.

Chiang JH, Cheng WS, Hood L, Tian Q
An epigenetic biomarker panel for glioblastoma multiforme personalized medicine through DNA methylation analysis of human embryonic stem cell-like signature.
OMICS. 2014; 18(5):310-23 [PubMed] Free Access to Full Article Related Publications
Alterations of DNA methylation occur during the course of both stem cell development and tumorigenesis. We present a novel strategy that can be used to stratify glioblastoma multiforme (GBM) patients through the epigenetic states of genes associated with human embryonic stem cell (hESC) identity in order to 1) assess linkages between the methylation signatures of these stem cell genes and survival of GBM patients, and 2) delineate putative mechanisms leading to poor prognosis in some patient subgroups. A DNA methylation signature was established for stratifying GBM patients into several hESC methylator subgroups. The hESC methylator-negative phenotype has demonstrated poor survival and upregulation of glioma stem cell (GSC) markers, and is enriched in one of the previously defined transcriptomic phenotypes-the mesenchymal phenotype. We further identified a refined signature of 36 genes as the gene panel, including SOX2, POU3F2, FGFR2, GAP43, NTRK2, NTRK3, and NKX2-2, which are highly enriched in the nervous system. Both signatures outperformed the O6-methylguanine-DNA methyltransferase (MGMT) methylation test in predicting patient's outcome. These findings were also validated through an independent dataset of patients. Furthermore, through statistical analyses, both signatures were examined significantly. Hypomethylation of hESC-associated genes predicted poorer clinical outcome in GBM, supporting the idea that epigenetic activation of stem cell genes contributes to GBM aggression. The gene panel presented herein may be developed into clinical assays for patient stratification and future personalized medicine interventions.

Li C, Shen W, Shen S, Ai Z
Gene expression patterns combined with bioinformatics analysis identify genes associated with cholangiocarcinoma.
Comput Biol Chem. 2013; 47:192-7 [PubMed] Related Publications
To explore the molecular mechanisms of cholangiocarcinoma (CC), microarray technology was used to find biomarkers for early detection and diagnosis. The gene expression profiles from 6 patients with CC and 5 normal controls were downloaded from Gene Expression Omnibus and compared. As a result, 204 differentially co-expressed genes (DCGs) in CC patients compared to normal controls were identified using a computational bioinformatics analysis. These genes were mainly involved in coenzyme metabolic process, peptidase activity and oxidation reduction. A regulatory network was constructed by mapping the DCGs to known regulation data. Four transcription factors, FOXC1, ZIC2, NKX2-2 and GCGR, were hub nodes in the network. In conclusion, this study provides a set of targets useful for future investigations into molecular biomarker studies.

Lee K, Byun K, Hong W, et al.
Proteome-wide discovery of mislocated proteins in cancer.
Genome Res. 2013; 23(8):1283-94 [PubMed] Free Access to Full Article Related Publications
Several studies have sought systematically to identify protein subcellular locations, but an even larger task is to map which of these proteins conditionally relocates in disease (the mislocalizome). Here, we report an integrative computational framework for mapping conditional location and mislocation of proteins on a proteome-wide scale, called a conditional location predictor (CoLP). Using CoLP, we mapped the locations of over 10,000 proteins in normal human brain and in glioma. The prediction showed 0.9 accuracy using 100 location tests of 20 randomly selected proteins. Of the 10,000 proteins, over 150 have a strong likelihood of mislocation under glioma, which is striking considering that few mislocation events have been identified in this disease previously. Using immunofluorescence and Western blotting in both primary cells and tissues, we successfully experimentally confirmed 15 mislocations. The most common type of mislocation occurs between the endoplasmic reticulum and the nucleus; for example, for RNF138, TLX3, and NFRKB. In particular, we found that the gene for the mislocating protein GFRA4 had a nonsynonymous point mutation in exon 2. Moreover, redirection of GFRA4 to its normal location, the plasma membrane, led to marked reductions in phospho-STAT3 and proliferation of glioma cells. This framework has the potential to track changes in protein location in many human diseases.

Jully B, Vijayalakshmi R, Gopal G, et al.
Junction region of EWS-FLI1 fusion protein has a dominant negative effect in Ewing's sarcoma in vitro.
BMC Cancer. 2012; 12:513 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ewing's sarcoma is a malignancy characterized by a specific 11:22 chromosomal translocation which generates a novel EWS-FLI1 fusion protein functioning as an aberrant transcription factor. In the present study, we have further characterized the junction region of the EWS-FLI1 fusion protein.
METHODS: In-silico model of EWS-FLI1 fusion protein was analysed for ligand binding sites, and a putative region (amino acid (aa) 251-343 of the type 1 fusion protein) in the vicinity of the fusion junction was cloned and expressed using bacterial expression. The recombinant protein was characterized by Circular Dichroism (CD). We then expressed aa 251-280 ectopically in Ewing's sarcoma cell-line and its effect on cell proliferation, tumorigenicity and expression of EWS-FLI1 target genes were analysed.
RESULTS: Our modelling analysis indicated that Junction region (aa 251-343) encompasses potential ligand biding sites in the EWS-FLI1 protein and when expressed in bacteria was present as soluble form. Ectopically expressing this region in Ewing's sarcoma cells inhibited tumorigenicity, and EWS-FLI1 target genes indicating a dominant negative biological effect.
CONCLUSIONS: Junction region can be exploited further as target for drug development in future to specifically target EWS-FLI1 in Ewing's Sarcoma.

Shahi MH, Rey JA, Castresana JS
The sonic hedgehog-GLI1 signaling pathway in brain tumor development.
Expert Opin Ther Targets. 2012; 16(12):1227-38 [PubMed] Related Publications
INTRODUCTION: The sonic hedgehog (Shh) pathway is a regulatory network involved in development and cancer. Proteins like Ptch, SMO, and Gli are central to the Shh pathway. Other proteins like HHIP, SUFU, Bmi-1, Cyclin D2, Plakoglobin, PAX6, Nkx2.2, and SFRP1 are not so well understood in Shh regulation as Gli-1 downstream target genes.
AREAS COVERED: In this review we try to explain the Shh pathway components and their role in development and cancer, mainly of the brain. A summary of each of the proteins is presented together with an overview of their involvement in cancer.
EXPERT OPINION: Genetic alterations of the Shh pathway have been detected in cancer stem cells, a subgroup of tumor cells implicated in the origin and maintenance of tumors, being responsible for cancer recurrence and chemotherapy resistance. Cancer stem cells constitute a novel target for biomedical researchers. Specifically, the Shh pathway is being explored as a new opportunity for targeted therapies against tumors. Therefore, a better knowledge of every of the regulators of the Shh pathway is needed.

Yoshida A, Sekine S, Tsuta K, et al.
NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma.
Am J Surg Pathol. 2012; 36(7):993-9 [PubMed] Related Publications
Ewing sarcoma is a high-grade round cell sarcoma that affects bones and soft tissues in children and young adults. Its diagnosis can be challenging, and the differential diagnoses include a wide variety of small round cell tumors. CD99 and FLI-1 are the currently accepted immunohistochemical markers for Ewing sarcoma, but their accuracy has been controversial. NKX2.2 is a homeodomain-containing transcription factor that plays a critical role in neuroendocrine/glial differentiation. The NKX2.2 gene was recently identified as a target of EWS-FLI-1, the fusion protein specific to Ewing sarcoma, and was shown to be differentially upregulated in Ewing sarcoma on the basis of array-based gene expression analysis. However, the immunohistochemical diagnostic potential of this marker has not been tested. We immunostained representative sections of 30 genetically confirmed Ewing sarcomas and 130 non-Ewing small round cell tumors by using an antibody to NKX2.2. Nuclear staining in at least 5% of the cells was deemed positive. Twenty-eight (93%) of the 30 Ewing sarcomas were positive for NKX2.2. The staining was diffuse (>50%) in all the positive cases and was moderate or strong in intensity for most cases (25 of 28). NKX2.2 was also positive in 14 non-Ewing tumors, including all the olfactory neuroblastomas and a minor subset of small cell carcinomas, synovial sarcomas, mesenchymal chondrosarcomas, and malignant melanomas. All the other non-Ewing tumors tested were negative for this marker. NKX2.2 is a valuable marker for Ewing sarcoma, with a sensitivity of 93% and a specificity of 89%, and aids in the differential diagnosis of small round cell tumors.

Deutsch L, Wrage M, Koops S, et al.
Opposite roles of FOXA1 and NKX2-1 in lung cancer progression.
Genes Chromosomes Cancer. 2012; 51(6):618-29 [PubMed] Related Publications
Gene copy number profiles of primary lung tumors were screened for high-level amplifications. We detected 22 high-level amplifications in various loci, including 14q13. This locus is known to harbor the adenocarcinoma (AC) lineage-specific target gene NKX2-1, which is not expressed in squamous cell carcinoma (SCC). As the 14q amplification was also found in SCC, we investigated whether or not FOXA1 might be the corresponding target gene for SCC. Focusing on these two target genes, we assessed gene amplifications and protein expression of NKX2-1 and FOXA1 in primary lung tumors (n = 554) and brain metastases (n = 68). Primary AC (n = 194) showed positive protein expression of NKX2-1 in 58.2% of the samples compared with 4.2% of primary SCC samples (n = 212). Positive staining for FOXA1 was seen in 34.7% of the SCC samples, which was comparable with 39.6% in the AC samples. For brain metastases, FOXA1 expression was slightly higher in the SCC samples (55.6%) compared with the non-matched primary SCC tumor samples (43.4%), whereas NKX2-1 expression was comparable in both primary tumors and brain metastases. Positive FOXA1 and NKX2-1 expression was associated with a gain or amplification in 34.6% and 28.6% of cases, respectively. The expression of NKX2-1 was associated with early stage and grade among the AC cases. In contrast, FOXA1 expression in SCC was associated with distant metastases as well as an unfavorable survival rate (P = 0.039). These results suggest that both FOXA1 and NKX2-1 may act as lineage-specific target genes within the 14q amplicon with opposite functions in lung cancer.

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