Gene Summary

Gene:NUTM1; NUT midline carcinoma family member 1
Aliases: NUT, FAM22H, C15orf55
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:NUT family member 1
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
NUTM1 is implicated in:
- cytoplasm
- nucleus
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: NUTM1 (cancer-related)

Multani S, Saranath D
Genotypic distribution of single nucleotide polymorphisms in oral cancer: global scene.
Tumour Biol. 2016; 37(11):14501-14512 [PubMed] Related Publications
Globocan 2012 reports the global oral cancer incidence of 300,373 new oral cancer cases annually, contributing to 2.1 % of the world cancer burden. The major well-established risk factors for oral cancer include tobacco, betel/areca nut, alcohol and high-risk oncogenic human papilloma virus (HPV) 16/18. However, only 5-10 % of individuals with high-risk lifestyle develop oral cancer. Thus, genomic variants in individuals represented as single nucleotide polymorphisms (SNPs) influence susceptibility to oral cancer. With a view to understanding the role of genomic variants in oral cancer, we reviewed SNPs in case-control studies with a minimum of 100 cases and 100 controls. PubMed and HuGE navigator search engines were used to obtain data published from 1990 to 2015, which identified 67 articles investigating the role of SNPs in oral cancer. Single publications reported 93 SNPs in 55 genes, with 34 SNPs associated with a risk of oral cancer. Meta-analysis of data in multiple studies defined nine SNPs associated with a risk of oral cancer. The genes were associated with critical functions deregulated in cancers, including cell proliferation, immune function, inflammation, transcription, DNA repair and xenobiotic metabolism.

Yaming P, Urs AB, Saxena A, Zuberi M
Roles of CYP1A1 and CYP2E1 Gene Polymorphisms in Oral Submucous Fibrosis.
Asian Pac J Cancer Prev. 2016; 17(7):3335-40 [PubMed] Related Publications
BACKGROUND: Oral submucous fibrosis (OSF) is a precancerous condition with a 4 to13% malignant transformation rate. Related to the habit of areca nut chewing it is mainly prevalent in Southeast Asian countries where the habit of betel quid chewing is frequently practised. On chewing, alkaloids and polyphenols are released which undergo nitrosation and give rise to Nnitrosamines which are cytotoxic agents. CYP450 is a microsomal enzyme group which metabolizes various endogenous and exogenous chemicals including those released by areca nut chewing. CYP1A1 plays a central role in metabolic activation of these xenobiotics, whereas CYP2E1 metabolizes nitrosamines and tannins. Polymorphisms in genes that code for these enzymes may alter their expression or function and may therefore affect an individuals susceptibility regarding OSF and oral cancer. The present study was therefore undertaken to investigate the association of polymorphisms in CYP1A1 m2 and CYP2E1 (RsaI/PstI) sites with risk of OSF among areca nut chewers in the Northern India population. A total of 95 histopathologically confirmed cases of OSF with history of areca nut chewing not less than 1 year and 80, age and sex matched controls without any clinical signs and symptoms of OSF with areca nut chewing habit not less than 1 year were enrolled. DNA was extracted from peripheral blood samples and polymorphisms were analyzed by PCRRFLP method. Gene polymorphism of CYP1A1 at NcoI site was observed to be significantly higher (p = 0.016) in cases of OSF when compared to controls. Association of CYP1A1 gene polymorphism at NcoI site and the risk of OSF (Odd's Ratio = 2.275) was also observed to be significant. However, no such association was observed for the CYP2E1 gene polymorphism (Odd's Ratio = 0.815). Our results suggest that the CYP1A1 gene polymorphism at the NcoI site confers an increased risk for OSF.

Klijanienko J, Le Tourneau C, Rodriguez J, et al.
Cytological features of NUT midline carcinoma arising in sino-nasal tract and parotid gland: Report of two new cases and review of the literature.
Diagn Cytopathol. 2016; 44(9):753-6 [PubMed] Related Publications
Nuclear Protein in Testis (NUT) Midline Carcinoma (NMC) represents a recently described, uncommon, high-grade and extremely lethal malignancy mainly occurring in children and young adults. Such tumors are genetically characterized by chromosomal rearrangements of the NUT gene. Cytological description of NUT carcinoma is limited and only seven cases were reported up to date. We show here another two cases studied cytologically with molecular and immunohistochemical confirmation. In both cases smears were hypercellular and composed of isolated or clustered small to medium-sized in size with roundish and oval shape cells. Nuclei were either regular or roundish containing dusty chromatin and prominent nucleoli. Mitotic figures were prominent. Cytoplasm was scant, strongly basophilic. Cell debris, necrosis, and apoptosis were also prominent. One of the cases was studied by FISH and the second case was studied by RT-PCR and BRD4-NUT translocation was found in both cases. Moreover, the clinical evolution was aggressive in both cases with rapid fatal clinical outcome. NUT carcinomas are an underdiagnosed entity which should be taken into consideration when poorly differentiated carcinomas was diagnosed in children or young adults. Cytology material may be successfully used for morphological and molecular diagnosis. Diagn. Cytopathol. 2016;44:753-756. © 2016 Wiley Periodicals, Inc.

Speleman F, Park JR, Henderson TO
Neuroblastoma: A Tough Nut to Crack.
Am Soc Clin Oncol Educ Book. 2016; 35:e548-57 [PubMed] Related Publications
Neuroblastoma, an embryonal tumor arising from neural crest-derived progenitor cells, is the most common solid tumor in childhood, with more than 700 cases diagnosed per year in the United States. In the past several decades, significant advances have been made in the treatment of neuroblastoma. Treatment advances reflect improved understanding of the biology of neuroblastoma. Although amplification of MYCN was discovered in the early 1980s, our understanding of neuroblastoma oncogenesis has advanced in the last decade as a result of high-throughput genomic analysis, exome and whole-genome sequencing, genome-wide association studies, and synthetic lethal drug screens. Our refined understanding of neuroblastoma biology and genetics is reflected in improved prognostic stratification and appropriate tailoring of therapy in recent clinical trials. Moreover, for high-risk neuroblastoma, a disease that was uniformly fatal 3 decades ago, recent clinical trials incorporating autologous hematopoietic transplant and immunotherapy utilizing anti-GD2 antibody plus cytokines have shown improved event-free and overall survival. These advances have resulted in a growing population of long-term survivors of neuroblastoma. Examination of the late effects and second malignant neoplasms (SMNs) in both older generations of survivors and more recently treated survivors will inform both design of future trials and surveillance guidelines for long-term follow-up. As a consequence of advances in understanding of the biology of neuroblastoma, successful clinical trials, and refined understanding of the late effects and SMNs of survivors, the promise of precision medicine is becoming a reality for patients with neuroblastoma.

Saikia S, Barooah P, Bhattacharyya M, et al.
Polymorphisms in Heat Shock Proteins A1B and A1L (HOM) as Risk Factors for Oesophageal Carcinoma in Northeast India.
Asian Pac J Cancer Prev. 2015; 16(18):8227-33 [PubMed] Related Publications
BACKGROUND: To investigate polymorphisms in heat shock proteins A1B and A1L (HOM) and associated risk of oesophageal carcinoma in Northeast India.
MATERIALS AND METHODS: The study includes oesophageal cancer (ECA) patients attending general outpatient department (OPD) and endoscopic unit of Gauhati Medical College. Patients were diagnosed based on endoscopic and histopathological findings. Genomic DNA was typed for HSPA1B1267 and HSPA1L2437 SNPs using the polymerase chain reaction with restriction fragment length polymorphisms.
RESULTS: A total of 78 cases and 100 age-sex matched healthy controls were included in the study with a male: female ratio of 5:3 and a mean age of 61.4±8.5 years. Clinico-pathological evaluation showed 84% had squamous cell carcinoma and 16% were adenocarcinoma. Dysphagia grades 4 (43.5%) and 5 (37.1%) were observed by endoscopic and hispathological evaluation. The frequency of genomic variation of A1B from wild type A/A to heterozygous A/G and mutant G/G showed a positive association [chi sq=19.9, p= <0.05] and the allelic frequency also showed a significant correlation [chi sq=10.3, with cases vs. controls, OR=0.32, p≤0.05]. The genomic variation of A1L from wild T/T to heterozygous T/C and mutant C/C were found positively associated [chi sq= 7.02, p<0.05] with development of ECA. While analyzing the allelic frequency, there was no significant association [chi sq= 3.19, OR=0.49, p=0.07]. Among all the risk factors, betel quid [OR =9.79, Chi square= 35.0, p<0.05], tobacco [OR = 2.95, chi square=10.6, p<0.05], smoking [OR=3.23, chi square=10.1, p<0.05] demonstrated significant differences between consumers vs. non consumers regarding EC development. Alcohol did not show any significant association [OR= 1.34, chi square=0.69, p=0.4] independently.
CONCLUSIONS: It can be concluded that the present study provides marked evidence that polymorphisms of HSP70 A1B and HSP70 A1L genes are associated with the development of ECA in a population in Northeast India, A1B having a stronger influence. Betel quid consumption was found to be a highly significant risk factor, followed by smoking and tobacco chewing. Although alcohol was not a potent risk factor independently, alcohol consumption along with tobacco, smoking and betel nut was found to contribute to development of ECA.

Kumar-Sinha C, Kalyana-Sundaram S, Chinnaiyan AM
Landscape of gene fusions in epithelial cancers: seq and ye shall find.
Genome Med. 2015; 7:129 [PubMed] Free Access to Full Article Related Publications
Enabled by high-throughput sequencing approaches, epithelial cancers across a range of tissue types are seen to harbor gene fusions as integral to their landscape of somatic aberrations. Although many gene fusions are found at high frequency in several rare solid cancers, apart from fusions involving the ETS family of transcription factors which have been seen in approximately 50% of prostate cancers, several other common solid cancers have been shown to harbor recurrent gene fusions at low frequencies. On the other hand, many gene fusions involving oncogenes, such as those encoding ALK, RAF or FGFR kinase families, have been detected across multiple different epithelial carcinomas. Tumor-specific gene fusions can serve as diagnostic biomarkers or help define molecular subtypes of tumors; for example, gene fusions involving oncogenes such as ERG, ETV1, TFE3, NUT, POU5F1, NFIB, PLAG1, and PAX8 are diagnostically useful. Tumors with fusions involving therapeutically targetable genes such as ALK, RET, BRAF, RAF1, FGFR1-4, and NOTCH1-3 have immediate implications for precision medicine across tissue types. Thus, ongoing cancer genomic and transcriptomic analyses for clinical sequencing need to delineate the landscape of gene fusions. Prioritization of potential oncogenic "drivers" from "passenger" fusions, and functional characterization of potentially actionable gene fusions across diverse tissue types, will help translate these findings into clinical applications. Here, we review recent advances in gene fusion discovery and the prospects for medicine.

Samples S, Gleditsch K, Polimenakos A
Intrapericardial NUT Midline Carcinoma: Unusual Presentation of a Rare Tumor and Literature Review with Management Considerations.
Pediatr Cardiol. 2016; 37(1):208-11 [PubMed] Related Publications
Rearrangements in the nuclear protein in testis (NUT) gene cause carcinomas that represent a rare but aggressive tumor type that often present at advanced stages in midline structures. Survival rarely exceeds 12 months from the time of diagnosis. There have been no reports of a primary cardiac presentation, and few studies have reported on the numerous treatment strategies. Given their aggressive and invasive nature, NUT midline carcinomas present a therapeutic dilemma. Treatment may include surgical resection, chemotherapy, or radiotherapy, but no consistently successful treatment has been established. Surgical resection is indicated to reduce symptomatic mass effect whenever present. Novel therapies with bromodomain extra-terminal inhibitors may be associated with potential survival benefit. Here, we describe an unusual presentation of this tumor. Literature review with management considerations is underlying.

Sun H, McGuire MF, Zhang S, Brown RE
NUT Midline Carcinoma: Morphoproteomic Characterization with Genomic and Therapeutic Correlates.
Ann Clin Lab Sci. 2015; 45(6):692-701 [PubMed] Related Publications
NUT midline carcinoma is a rare entity arising primarily in the midline of teenagers and young adults. Genomically, it is associated with a translocation involving a nuclear protein in testis (NUT) gene with other genes, most commonly, the BRD4 gene. The resultant is a partial or near total block in differentiation of tumor cells into mature squamous elements. Such tumors are resistant to conventional therapy with a reported mean survival at less than 1 year. In this study, we investigated two cases with genomic confirmation as NUT midline carcinoma by morphoproteomic analysis using immunohistochemical antibodies. Our results showed overexpression, largely in the undifferentiated cells of the tumors of: 1) Stemness marker, SRY (sex determining region Y)-box 2 (Sox2); 2) Constitutive activation of the mTORC2 pathway with expression of total insulin-like growth factor-1 receptor (IGF-1R[Tyr1165/1166]), and nuclear p-mTOR (Ser 2448) and p-Akt (Ser 473); and 3) c-Myc, silent mating type information regulation 2 homolog 1 (Sirt1) and histone methyltransferase enhancer of Zeste, Drosophila, homolog 2 (EZH2) as molecular impediments to differentiation. These data were analyzed through the use of QIAGEN's Ingenuity(®) Pathway Analysis (IPA(®), QIAGEN Redwood City, The results established the interconnection of these pathways and molecules, and identified several pharmacogenomic agents--melatonin, metformin, vorinostat, curcumin, and sulforaphane--that have the potential to remove the block in differentiation and lead to the establishment of a more benign form of NUT midline carcinoma.

He Z, Chen AY, Rojanasakul Y, et al.
Gallic acid, a phenolic compound, exerts anti-angiogenic effects via the PTEN/AKT/HIF-1α/VEGF signaling pathway in ovarian cancer cells.
Oncol Rep. 2016; 35(1):291-7 [PubMed] Free Access to Full Article Related Publications
Gallic acid (GA), a polyphenol, is widely found in numerous fruits and vegetables, particularly in hickory nuts. In the present study, we found that gallic acid, a natural phenolic compound isolated from fruits and vegetables, had a more potent growth inhibitory effect on two ovarian cancer cell lines, OVCAR-3 and A2780/CP70, than the effect on a normal ovarian cell line, IOSE-364. These results demonstrated that GA selectively inhibits the growth of cancer cells. Gene expression was examined by ELISA and western blot analysis, and gene pathways were examined by luciferase assay. It was found that GA inhibited VEGF secretion and suppressed in vitro angiogenesis in a concentration-dependent manner. GA downregulated AKT phosphorylation as well as HIF-1α expression but promoted PTEN expression. The luciferase assay results suggest that the PTEN/AKT/HIF-1α pathway accounts for the inhibitory effect of GA on VEGF expression and in vitro angiogenesis. These findings provide strong support for the high potential of GA in the prevention and therapy of ovarian cancer.

Harms A, Herpel E, Pfarr N, et al.
NUT carcinoma of the thorax: Case report and review of the literature.
Lung Cancer. 2015; 90(3):484-91 [PubMed] Related Publications
NUT (nuclear protein in testis) carcinomas are exceedingly rare neoplasms with specific molecular alterations and often follow a devastating course. Thus, a precise early diagnosis is of utmost importance. Known from the sinonasal region for years, the new 2015 WHO classification now also recognizes the existence of this entity in the thorax, specifically the lungs and the mediastinum. However, yet available data on this entity are sparse. Here, we report on a 31 years old female patient with an aggressively growing tumor localized in the median line that was initially sampled by endobronchial ultrasound-guided transbronchial biopsies. Pathological assessment of the biopsy specimens revealed a NUT carcinoma with typical morphological characteristics and an uncommon NUT translocation variant with a NSD3-NUT fusion. Diagnosis was further confirmed in the subsequent resection specimen. We describe specific clinical, histomorphological, and molecular characteristics of this tumor and provide a comprehensive review of the current literature on these rare neoplasms.

Raza A, Cao H, Conrad R, et al.
Nuclear protein in testis midline carcinoma with unusual elevation of α-fetoprotein and synaptophysin positivity: a case report and review of the literature.
Expert Rev Anticancer Ther. 2015; 15(10):1199-213 [PubMed] Related Publications
Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare cancer that displays a characteristic chromosomal rearrangement of BRD4-NUT t(15;19)(q14;q13.1). Despite occasional dramatic responses to radiation and chemotherapy, NMC usually behaves aggressively and becomes rapidly progressive. Immunohistochemical staining is usually limited to p63, cytokeratins, and monoclonal NUT antibody. Here, we report a NMC case in a 36-year-old man with elevated serum α-fetoprotein (AFP), synaptophysin positivity, and a 9.0 cm mass involving the right lung and mediastinum. Tumor cells demonstrated BRD4-NUT fusion on fluorescence in situ hybridization. To our knowledge, only one other case with elevated serum AFP and one case with synaptophysin positivity have been described. This diagnosis will undoubtedly grow more common as informed physicians become more aware of the disease and begin testing for NMC. Further study is needed to establish the prevalence of NMC and to elucidate the significance of elevated AFP and synaptophysin positivity in this rare tumor.

Wasserman JK, Purgina B, Sekhon H, et al.
The Gross Appearance of a NUT Midline Carcinoma.
Int J Surg Pathol. 2016; 24(1):85-8 [PubMed] Related Publications
The NUT midline carcinoma (NMC) is a recently described and highly aggressive tumor that usually involves the head and neck and anterior mediastinum. Most patients with NMC present with metastases and are often treated with neoadjuvant chemotherapy and/or radiation therapy. As a consequence, surgical specimens are often piecemeal excisions demonstrating treatment effect. In this report, we provide what is to the best of our knowledge the first complete gross description of NMC resected in toto and without prior treatment. The patient in this case underwent a pneumonectomy for a lung mass with curative intent. On gross examination, the tumor was found to be arising from the mediastinum with a smooth border, and demonstrated only minimal invasion of the surrounding structures. However, lymphovascular invasion was present throughout and there was extensive involvement of surrounding lymph nodes. The gross appearance of the tumor in this case reaffirms that NMC is an aggressive malignancy that usually metastasizes before it invades locally.

Lund-Iversen M, Grøholt KK, Helland Å, et al.
NUT expression in primary lung tumours.
Diagn Pathol. 2015; 10:156 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Nuclear protein in testis (NUT) midline carcinomas (NMC) are rare, highly aggressive epithelial neoplasms, characterised by protein expression of NUT-fusion proteins which reflects the genetic translocation between chromosome 15 and 19. NMC occurs mainly in midline structures, but there are reports regarding occurrence in structures outside the midline. We investigated specimens from 519 surgically resected lung carcinomas and carcinoid tumours for the presence of NUT protein using immunohistochemistry. Normal testis and two previously confirmed NMCs served as positive controls.
FINDINGS: All 483 evaluable cases (278 adenocarcinomas, 140 squamous cell carcinomas, 30 large cell carcinomas, 7 small cell carcinomas, 10 undifferentiated carcinomas and 18 carcinoids) were completely negative for expression of NUT protein.
CONCLUSION: NUT gene rearrangement does not seem to be relevant in primary pulmonary carcinomas or carcinoid tumours of the lung.

Alekseyenko AA, Walsh EM, Wang X, et al.
The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains.
Genes Dev. 2015; 29(14):1507-23 [PubMed] Free Access to Full Article Related Publications
NUT midline carcinoma (NMC), a subtype of squamous cell cancer, is one of the most aggressive human solid malignancies known. NMC is driven by the creation of a translocation oncoprotein, BRD4-NUT, which blocks differentiation and drives growth of NMC cells. BRD4-NUT forms distinctive nuclear foci in patient tumors, which we found correlate with ∼100 unprecedented, hyperacetylated expanses of chromatin that reach up to 2 Mb in size. These "megadomains" appear to be the result of aberrant, feed-forward loops of acetylation and binding of acetylated histones that drive transcription of underlying DNA in NMC patient cells and naïve cells induced to express BRD4-NUT. Megadomain locations are typically cell lineage-specific; however, the cMYC and TP63 regions are targeted in all NMCs tested and play functional roles in tumor growth. Megadomains appear to originate from select pre-existing enhancers that progressively broaden but are ultimately delimited by topologically associating domain (TAD) boundaries. Therefore, our findings establish a basis for understanding the powerful role played by large-scale chromatin organization in normal and aberrant lineage-specific gene transcription.

Policarpio-Nicolas ML, de Leon EM, Jagirdar J
Cytologic findings of NUT midline carcinoma in the hilum of the lung.
Diagn Cytopathol. 2015; 43(9):739-42 [PubMed] Related Publications
Nuclear protein in testis (NUT) midline carcinoma (NMC) is a clinically lethal malignancy affecting all age group often located in the midline structures such as mediastinum, larynx and nasopharynx. It is characterized by chromosomal translocation between chromosomes 15 and 19 with the formation of chimeric gene BRD-NUT. We present the cytologic findings of NMC including the immunohistochemical stains performed. The patient is a 34-year-old man who presented with 1 month history of dyspnea and interscapular pain followed by nonproductive cough a week before consultation. He was initially diagnosed with pneumonia. Due to progression of symptoms, a chest CT scan was performed revealing a large hilar mass and mediastinal adenopathy. A core biopsy with touch preparations of the hilar mass was performed which revealed cohesive malignant cells with ovoid to elongated nuclei, fine to coarse chromatin pattern, irregular nuclear contour, prominent nucleoli, and scant ill-defined cytoplasm arranged in sheets and focally pseudoglandular pattern. Although focal nuclear overlapping and crush artifact were identified, karyorrhectic debris and mitotic figures were rare. Squamous differentiation was absent. The core biopsy showed discohesive malignant cells with tumor necrosis. No nuclear molding, glandular or squamous differentiation was identified. The tumor was immunoreactive for p63 and NUT with high Ki-67 (>80%). The tumor was negative for keratin, lymphoid, myeloid, neuroendocrine markers and S-100. This case emphasizes that cytologic features of NMC can mimic poorly differentiated, undifferentiated and neuroendocrine carcinomas and the importance of immunohistochemical stains especially NUT monoclonal antibody in arriving at the diagnosis.

Pant I, Kumar N, Khan I, et al.
Role of Areca Nut Induced TGF-β and Epithelial-Mesenchymal Interaction in the Pathogenesis of Oral Submucous Fibrosis.
PLoS One. 2015; 10(6):e0129252 [PubMed] Free Access to Full Article Related Publications
Areca nut consumption has been implicated in the progression of Oral Submucous fibrosis (OSF); an inflammatory precancerous fibrotic condition. Our previous studies have demonstrated the activation of TGF-β signaling in epithelial cells by areca nut components and also propose a role for epithelial expressed TGF-β in the pathogenesis of OSF. Although the importance of epithelial cells in the manifestation of OSF has been proposed, the actual effectors are fibroblast cells. However, the role of areca nut and TGF-β in the context of fibroblast response has not been elucidated. Therefore, to understand their role in the context of fibroblast response in OSF pathogenesis, human gingival fibroblasts (hGF) were treated with areca nut and/or TGF-β followed by transcriptome profiling. The gene expression profile obtained was compared with the previously published transcriptome profiles of OSF tissues and areca nut treated epithelial cells. The analysis revealed regulation of 4666 and 1214 genes by areca nut and TGF-β treatment respectively. The expression of 413 genes in hGF cells was potentiated by areca nut and TGF-β together. Further, the differentially expressed genes of OSF tissues compared to normal tissues overlapped significantly with areca nut and TGF-β induced genes in epithelial and hGF cells. Several positively enriched pathways were found to be common between OSF tissues and areca nut +TGF-β treated hGF cells. In concordance, areca nut along with TGF-β enhanced fibroblast activation as demonstrated by potentiation of αSMA, γSMA and collagen gel contraction by hGF cells. Furthermore, TGF-β secreted by areca nut treated epithelial cells influenced fibroblast activation and other genes implicated in fibrosis. These data establish a role for areca nut influenced epithelial cells in OSF progression by activation of fibroblasts and emphasizes the importance of epithelial-mesenchymal interaction in OSF.

Li YC, Chang JT, Chiu C, et al.
Areca nut contributes to oral malignancy through facilitating the conversion of cancer stem cells.
Mol Carcinog. 2016; 55(5):1012-23 [PubMed] Related Publications
Oral cancer is one of the most frequent malignant diseases worldwide, and areca nut is a primary carcinogen causing this cancer in Southeast Asia. Previous studies to examine the effects of this carcinogen often used short-term and high-dose treatment of area nut extract as a research model, which do not recapitulate the conditions of patients with long-term and habitual use of this substance. To approach authentic mechanism of areca nut-induced oral carcinogenesis that occurs in human, we established four isogenic sublines of oral cells which were chronic exposed to areca nut extract. Without eliciting cytotoxicity or senescence, these four sublines cells exhibited significant increase in invasive ability, along with epithelial-mesenchymal transition. These cells also showed resistance to chemotherapeutic drug and irradiation, accompanying with the augmentation of ABCG2 protein efflux and increased ROS clearance. Moreover, these sublines possessed the characteristics of cancer stemness, as demonstrated by enriched CD24-/CD44+ and CD133+ sub-populations, enhanced spheroid cell formation, and induced expressions of pluripotent stemness regulators, including Gp96, Grp78, Slug, Sox9, Snail, and Foxc2. These stemness regulators were further shown up-regulations in oral cancer patients with areca nut-chewing habit, and were statistically correlated with CD44 expression, a stemness marker. In conclusion, our findings suggested that areca nut contributes to oral malignancy through facilitating the conversion of cancer stem cells. This study may further contribute to clinical applications in disease prevention, risk assessment or molecular therapeutics on areca nut- associated diseases.

Wang X, Zhang Y, Nilsson CL, et al.
Association of chromosome 19 to lung cancer genotypes and phenotypes.
Cancer Metastasis Rev. 2015; 34(2):217-26 [PubMed] Related Publications
The Chromosome 19 Consortium, a part of the Chromosome-Centric Human Proteome Project (C-HPP, ), is tasked with the understanding chromosome 19 functions at the gene and protein levels, as well as their roles in lung oncogenesis. Comparative genomic hybridization (CGH) studies revealed chromosome aberration in lung cancer subtypes, including ADC, SCC, LCC, and SCLC. The most common abnormality is 19p loss and 19q gain. Sixty-four aberrant genes identified in previous genomic studies and their encoded protein functions were further validated in the neXtProt database ( ). Among those, the loss of tumor suppressor genes STK11, MUM1, KISS1R (19p13.3), and BRG1 (19p13.13) is associated with lung oncogenesis or remote metastasis. Gene aberrations include translocation t(15, 19) (q13, p13.1) fusion oncogene BRD4-NUT, DNA repair genes (ERCC1, ERCC2, XRCC1), TGFβ1 pathway activation genes (TGFB1, LTBP4), Dyrk1B, and potential oncogenesis protector genes such as NFkB pathway inhibition genes (NFKBIB, PPP1R13L) and EGLN2. In conclusion, neXtProt is an effective resource for the validation of gene aberrations identified in genomic studies. It promises to enhance our understanding of lung cancer oncogenesis.

Sánchez-González C, Ciudad CJ, Izquierdo-Pulido M, Noé V
Urolithin A causes p21 up-regulation in prostate cancer cells.
Eur J Nutr. 2016; 55(3):1099-112 [PubMed] Related Publications
PURPOSE: Walnuts contain several bioactive compounds, including pedunculagin, a polyphenol metabolized by microbiota to form urolithins, namely urolithin A (UA). The aim of this study was to determine gene expression changes in prostate cancer cells after incubation with UA.
METHODS: We performed a genomic analysis to study the effect of UA on LNCaP prostate cells. Cells were incubated with 40 µM UA for 24 h, and RNA was extracted and hybridized to Affymetrix Human Genome U219 array. Microarray results were analyzed using GeneSpring v13 software. Differentially expressed genes (p < 0.05, fold change > 2) were used to perform biological association networks. Cell cycle was analyzed by flow cytometry and apoptosis measured by the rhodamine method and by caspases 3 and 7 activation. Cell viability was determined by MTT assay.
RESULTS: We identified two nodes, FN-1 and CDKN1A, among the differentially expressed genes upon UA treatment. CDKN1A was validated, its mRNA and protein levels were significantly up-regulated, and the promoter activation measured by luciferase. Cell cycle analysis showed an increase in G1-phase, and we also observed an induction of apoptosis and caspases 3 and 7 activation upon UA treatment.
CONCLUSION: Our results indicate a potential role of UA as a chemopreventive agent for prostate cancer.

Jeong JB, Lee J, Lee SH
TCF4 Is a Molecular Target of Resveratrol in the Prevention of Colorectal Cancer.
Int J Mol Sci. 2015; 16(5):10411-25 [PubMed] Free Access to Full Article Related Publications
The Wnt/β-catenin pathway plays an essential role in the tumorigenesis of colorectal cancer. T-cell factor-4 (TCF4) is a member of the TCF/LEF (lymphoid enhancer factor) family of transcription factors, and dysregulation of β-catenin is decisive for the initiation and progression of colorectal cancer. However, the role of TCF4 in the transcriptional regulation of its target gene remained poorly understood. Resveratrol is a dietary phytoalexin and present in many plants, including grape skin, nuts and fruits. Although resveratrol has been widely implicated in anti-tumorigenic and pro-apoptotic properties in several cancer models, the underlying cellular mechanisms are only partially understood. The current study was performed to elucidate the molecular mechanism of the anti-cancer activity of resveratrol in human colorectal cancer cells. The treatment of resveratrol and other phytochemicals decreased the expression of TCF4. Resveratrol decreases cellular accumulation of exogenously-introduced TCF4 protein, but did not change the TCF4 transcription. The inhibition of proteasomal degradation using MG132 (carbobenzoxy-Leu-Leu-leucinal) and lactacystin ameliorates resveratrol-stimulated down-regulation of TCF4. The half-life of TCF4 was decreased in the cells exposed to resveratrol. Resveratrol increased phosphorylation of TCF4 at serine/threonine residues through ERK (extracellular signal-regulated kinases) and p38-dependent pathways. The TCF4 knockdown decreased TCF/β-catenin-mediated transcriptional activity and sensitized resveratrol-induced apoptosis. The current study provides a new mechanistic link between resveratrol and TCF4 down-regulation and significant benefits for further preclinical and clinical practice.

Tsoukas MA, Ko BJ, Witte TR, et al.
Dietary walnut suppression of colorectal cancer in mice: Mediation by miRNA patterns and fatty acid incorporation.
J Nutr Biochem. 2015; 26(7):776-83 [PubMed] Related Publications
Colorectal cancer, unlike many other malignancies, may be preventable. Recent studies have demonstrated an inverse association between nut consumption and incidence of colon cancer; however, the underlying mechanisms are not fully understood. An emerging concept suggests that microribonucleic acids (miRNAs) may help explain the relationship between walnut consumption and decreased colorectal neoplasia risk. Seven days after HT-29 colon cancer cell injection, mice were randomized to either control or walnut diets for 25 days of diet treatment. Thirty samples of tumor and of omental adipose were analyzed to determine changes in lipid composition in each dietary group. In the tumors of the walnut-containing diet, we found significant increases in α-linolenic, eicosapentaenoic, docosahexaenoic and total omega-3 acids, and a decrease in arachidonic acid, as compared to the control diet. Final tumor size measured at sacrifice was negatively associated with percentage of total omega-3 fatty acid composition (r=-0.641, P=.001). MicroRNA expression analysis of colorectal tumor tissue revealed decreased expression of miRNAs 1903, 467c and 3068 (P<.05) and increased expression of miRNA 297a* (P=.0059) in the walnut-treated group as compared to control diet. Our results indicate that changes in the miRNA expression profiles likely affect target gene transcripts involved in pathways of anti-inflammation, antivascularization, antiproliferation and apoptosis. We also demonstrate the incorporation of protective fatty acids into colonic epithelium of walnut-fed mice, which may independently alter miRNA expression profiles itself. Future studies of the mechanism of widespread miRNA regulation by walnut consumption are needed to offer potential prognostic and therapeutic targets.

Watanabe S, Hirano S, Mine S, et al.
A case of endobronchial NUT midline carcinoma with intraluminal growth.
Anticancer Res. 2015; 35(3):1607-12 [PubMed] Related Publications
BACKGROUND: NUT midline carcinoma (NMC) is a rare, lethal form of differentiated squamous cell carcinoma characterized by chromosomal rearrangement of the NUT gene. Its highly aggressive nature commonly leads to unresectable and metastatic lesions.
CASE REPORT: We report on a case of endobronchial NMC in a middle-aged man who was treated by bronchoscopic electrocautery followed by Ewing sarcoma-based chemotherapy with concurrent chemoradiotherapy. The patient's disease continued to be stable 31 months after diagnosis.
REVIEW: NMC is a challenging disease entity, which is difficult to diagnose and treat, and has a dismal overall survival. Most cases of NMC are widely metastatic or unresectable when diagnosed.
DISCUSSION: This is the first reported case that involves intraluminal tumour growth of NMC and demonstrates the effectiveness of early intensive local therapy aided by bronchoscopic techniques.

Lee CP, Chiang SL, Lee CH, et al.
AURKA Phe31Ile polymorphism interacted with use of alcohol, betel quid, and cigarettes at multiplicative risk of oral cancer occurrence.
Clin Oral Investig. 2015; 19(8):1825-32 [PubMed] Related Publications
OBJECTIVES: The expression levels of two DNA repair genes (CHAF1A and CHAF1B) and a chromosome segregation gene (AURKA) were susceptible to arecoline exposure, a major alkaloid of areca nut. We hypothesize that genetic variants of these genes might also be implicated in the risk of oral cancer and could be modified by substance use of betel quid or alcohol and cigarettes.
MATERIAL AND METHODS: A case-control study, which included 507 patients with oral cancer and 717 matched controls, was performed in order to evaluate the cancer susceptibility by the tagging single-nucleotide polymorphisms (tagSNPs) in AURKA, CHAF1A, and CHAF1B using a genotyping assay and gene-environment interaction analysis.
RESULTS: The Phe31Ile polymorphism (rs2273535, T91A) of AURKA was significantly associated with an increased risk of oral cancer (odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.2-3.5). The gene dosage of the 91A allele also showed a significant trend in risk of oral cancer (P = 0.008). Furthermore, we found the AURKA 91AA homozygote was modifiable by substance use of alcohol, betel quid, and cigarettes (ABC), leading to increased risk of oral cancer in an additive or a multiplicative model (combined effect indexes = 1.2-4.0 and 1.5-2.2, respectively). However, no association was observed between the genetic variants of CHAF1A or CHAF1B and oral cancer risk in the study.
CONCLUSION: These findings reveal the functional Phe31Ile polymorphism tagSNP of AURKA may be a strong susceptibility gene in ABC-related oral cancer occurrence.
CLINICAL RELEVANCE: The results of this betel-related oral cancer study provide the evidence of environment-gene interaction for early prediction and molecular diagnosis.

French C
NUT midline carcinoma.
Nat Rev Cancer. 2014; 14(3):149-50 [PubMed] Related Publications
NUT midline carcinoma, a squamous cell carcinoma, is one of the most aggressive human cancers, and there is a desperate need for effective therapies for patients with this disease. Will the new bromodomain and extra terminal (BET) inhibitors prove to be one such treatment for this rare and enigmatic cancer?

Dragoescu E, French C, Cassano A, et al.
NUT midline carcinoma presenting with bilateral ovarian metastases: a case report.
Int J Gynecol Pathol. 2015; 34(2):136-42 [PubMed] Related Publications
Nuclear protein of the testis (NUT) midline carcinoma (NMC) is an uncommon, relatively recently characterized carcinoma, which is defined by NUT gene rearrangements. We are reporting a case of NMC in a 38-year-old female who presented with pleural effusion and bilateral ovarian masses. We also discuss some of the difficulties encountered by the practicing pathologist in reaching the diagnosis and the role of ancillary studies. Immunohistochemical staining using a commercially available monoclonal antibody showing nuclear expression of the NUT protein is diagnostic of NMC. Dual-color split-apart fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) can be used to characterize the fusion gene, whether BRD4-NUT or BRD3-NUT, or NUT-variant.

Su S, Chien M, Lin C, et al.
RAGE gene polymorphism and environmental factor in the risk of oral cancer.
J Dent Res. 2015; 94(3):403-11 [PubMed] Free Access to Full Article Related Publications
Oral squamous cell carcinoma is a common neoplasm that is known to be causally associated with genetic factors and environmental carcinogens. The receptor for advanced glycosylation endproducts (RAGE) is a transmembrane protein of the immunoglobulin superfamily with broad specificity for multiple ligands, and it has been shown to play vital roles in several pathophysiologic processes, including diabetes, Alzheimer disease, renal disease, cardiovascular disease, and cancer. The present study aimed to assess the influences of RAGE gene polymorphisms, combined with environmental carcinogens on the predisposition to oral tumorigenesis. Five polymorphisms of the RAGE gene-including -374T>A (rs1800624), -429T>C (rs1800625), 1704G>T (rs184003), Gly82Ser (rs2070600), and a 63-bp deletion allele (-407 to -345)-were examined from 592 controls and 618 patients with oral cancer. We found that individuals carrying the polymorphic allele of rs1800625 are more susceptible to oral cancer (odds ratio [OR], 1.899; 95% confidence interval [CI], 1.355 to 2.661; adjusted OR [AOR], 2.053; 95% CI, 1.269 to 3.345) after adjustment for age, sex, betel nut chewing, and tobacco consumption. Moreover, we observed a significant association of rs1800625 variants with late-stage tumors (stage III/IV, OR, 1.736; 95% CI, 1.126 to 2.677; AOR, 1.771; 95% CI, 1.101 to 2.851) and large-size tumors (>2 cm in the greatest dimension; OR, 1.644; 95% CI, 1.083 to 2.493; AOR, 1.728; 95% CI, 1.089 to 2.741). Based on behavioral exposure of environmental carcinogens, the presence of 4 RAGE single-nucleotide polymorphisms (SNPs), combined with betel quid chewing and/or tobacco use, greatly augmented the risk of oral cancer. In addition, carriers of particular haplotypes of the 4 RAGE SNPs examined are more prone to develop oral cancer. These results indicate an involvement of RAGE SNP rs1800625 in the development of oral squamous cell carcinoma and implicate the interaction between RAGE gene polymorphisms and environmental mutagens as a predisposing factor of oral carcinogenesis.

Maher OM, Christensen AM, Yedururi S, et al.
Histone deacetylase inhibitor for NUT midline carcinoma.
Pediatr Blood Cancer. 2015; 62(4):715-7 [PubMed] Related Publications
NUT Midline carcinoma (NMC) is a rare and invariably fatal poorly differentiated carcinoma characterized by chromosomal rearrangement involving the nuclear protein of the testis (NUT) gene. Current approaches do not provide durable response. We report a case of widely metastatic NMC in a 17-year-old female who, following an initial response to combination chemotherapy developed rapid disease progression. Treatment with vorinostat, a histone deacetylase inhibitor (HDACi) resulted in an objective response, yet she died in less than one year from initial diagnosis. This report shows a potentially promising activity of HDACi in the treatment of NMC that needs further exploration.

Kurkalang S, Banerjee A, Dkhar H, et al.
Precocious anaphase and expression of Securin and p53 genes as candidate biomarkers for the early detection in areca nut-induced carcinogenesis.
Mutagenesis. 2015; 30(3):381-9 [PubMed] Related Publications
Research over the years has generated enough evidence to implicate areca nut, as a carcinogen in humans. Besides oral, significant rise in the incidence of cancers of the oesophagus, liver and stomach was seen among areca nut chewers. Early diagnosis seems key to understand the initial processes of carcinogenesis which is highly curable. In North-East India, betel quid contains raw areca nut (RAN), lime and small portion of betel leaf without any other constituents. This study was not intended to isolate any active ingredients from the RAN and to look its action. The present objective is to validate the screening of precocious anaphase and analysis of expression of Securin and p53 in non-target cells like human peripheral blood lymphocytes (PBLs) and mouse bone marrow cells (BMCs) as early indicative parameters of RAN + lime-induced cancers. A total of 35 mice were examined at different time points for following ad libitum administration of RAN extract in drinking water with lime. Peripheral blood was collected from 32 human donors of which, 24 were RAN + lime heavy chewers. Expression of genes was assessed by immunoblotting and/or by immunohistochemistry. Histological preparation of stomach tissue of mice revealed that RAN + lime induced stomach cancer. A gradual increase in the frequency of precocious anaphases and aneuploid cells was observed in both RAN + lime-treated mouse BMC and human PBL of RAN heavy chewers. Levels of p53 and Securin were increased in these cells during early days of RAN + lime exposure. The level of Securin was significantly higher in human tumour samples than their adjacent normal counterpart. The expression of Securin was increased significantly in RAN + lime-administered mice as well as in stomach tumour. Present study revealed that precocious anaphase and expression of p53 and Securin in non-target cells are significantly associated with an increased risk of RAN-induced cancer and thus these parameters can be of early diagnostic value.

Suzuki S, Kurabe N, Ohnishi I, et al.
NSD3-NUT-expressing midline carcinoma of the lung: first characterization of primary cancer tissue.
Pathol Res Pract. 2015; 211(5):404-8 [PubMed] Related Publications
BACKGROUND: Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare, aggressive malignancy. Only two pediatric and three adult cases of pulmonary NMCs have been documented. In more than two-thirds of NMC cases, a gene fusion between NUT and BRD4 or BRD3 has been documented; other fusions are rare.
CASE PRESENTATION: A 36-year-old woman was admitted because of a rapidly progressing tumor of the lung with metastases to the breast and bone. A biopsy from the lung tumor revealed an undifferentiated neoplasm exhibiting round to oval nuclei with vesicular chromatin, prominent nucleoli, and scant cytoplasm. Immunohistochemical staining demonstrated focal EMA, cytokeratin AE1/AE3, cytokeratin CAM 5.2, p63, CD138, and vimentin positivity. Finally, the nuclear staining pattern for NUT confirmed a histopathological diagnosis of NMC. A 5'- rapid amplification of the cDNA end (RACE) procedure successfully identified the partner of the NUT translocation as NSD3, a recently discovered partner. Fluorescence in situ hybridization confirmed the NSD3-NUT gene rearrangement, whereas a BRD3/4-NUT fusion gene was not detected.
CONCLUSION: We herein describe the first case of an NSD3-NUT-expressing NMC of the lung. The further accumulation of variant NMCs should provide clues to the establishment of new individualized therapy for NMCs.

Nakamura H, Tsuta K, Tsuda H, et al.
NUT midline carcinoma of the mediastinum showing two types of poorly differentiated tumor cells: a case report and a literature review.
Pathol Res Pract. 2015; 211(1):92-8 [PubMed] Related Publications
Nuclear protein in testis (NUT) midline carcinoma (NMC) is an extremely aggressive carcinoma that is genetically defined by rearrangement of the NUT gene. Herein, we describe a case of NMC in a young Japanese man, and review 31 cases of NMC in the literature. The present case was of a massive tumor of the anterior and middle mediastinum in a 26-year-old man. The tumor included 2 types of poorly differentiated tumor cells and was immunohistochemically positive for the NUT-specific antigen, epithelial membrane antigen (EMA), cluster of differentiation 99 (CD99) antigen, CD45RO antigen, keratins, p63, and p40. The patient died 2 months after the initial diagnosis. At least two-thirds of the 31 NMC cases in the literature were immunohistochemically positive for EMA, p63, and AE1/AE3. However, some exceptional NMC cases are keratins-negative/CD99-positive like Ewing sarcoma or CD45RO-positive like the present case.

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