Research IndicatorsGraph generated 15 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (8)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
TICdb, Universidad de Navarra
Search the database of Translocation breakpoints In Cancer for "NFIB"
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: NFIB (cancer-related)
Vallonthaiel AG, Jain D, Singh V, et al.c-Myb Overexpression in Cytology Smears of Tracheobronchial and Pulmonary Adenoid Cystic Carcinomas.
Acta Cytol. 2017; 61(1):77-83 [PubMed
] Related Publications
AIMS: Adenoid cystic carcinoma (AdCC) is a malignant epithelial neoplasm that occurs rarely in the lower respiratory tract (LRT). AdCC at various sites is associated with the novel fusion transcript MYB-NFIB, along with the overexpression of the Myb protein. The expression of the Myb protein in AdCC of the LRT has not been evaluated much.
STUDY DESIGN: Cases of AdCC of the LRT diagnosed on cytology or histology were retrieved from our institutional archives. c-Myb expression was analyzed on immunocytochemistry/immunohistochemistry (ICC/IHC) and was correlated with clinicopathological parameters.
RESULTS: Twenty-three samples of AdCC originating from the LRT were included in the study. Four cases were diagnosed on cytology, 3 of which had corresponding histology specimens. The remaining 19 cases had either biopsy or resection. Most of the patients presented with endobronchial mass. The mean age was 49.4 years and a male predominance was seen. ICC and IHC for c-Myb showed positivity in 75 and 59% of the cases, respectively. Western blot was used to validate IHC results.
CONCLUSION: AdCC of the LRT is rare and hence poses diagnostic difficulty. Cytology smears can be utilized for c-Myb ICC. The presence of c-Myb immunopositivity in most cases may possibly make Myb a diagnostic biomarker and a therapeutic target for personalized treatment.
Denny SK, Yang D, Chuang CH, et al.Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility.
Cell. 2016; 166(2):328-42 [PubMed
] Article available free on PMC
after 14/07/2017 Related Publications
Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression.
Rettig EM, Talbot CC, Sausen M, et al.Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma.
Cancer Prev Res (Phila). 2016; 9(4):265-74 [PubMed
] Article available free on PMC
after 01/04/2017 Related Publications
Adenoid cystic carcinomas (ACC) of the salivary glands are challenging to understand, treat, and cure. To better understand the genetic alterations underlying the pathogenesis of these tumors, we performed comprehensive genome analyses of 25 fresh-frozen tumors, including whole-genome sequencing and expression and pathway analyses. In addition to the well-described MYB-NFIB fusion that was found in 11 tumors (44%), we observed five different rearrangements involving the NFIB transcription factor gene in seven tumors (28%). Taken together, NFIB translocations occurred in 15 of 25 samples (60%, 95% CI, 41%-77%). In addition, mRNA expression analysis of 17 tumors revealed overexpression of NFIB in ACC tumors compared with normal tissues (P = 0.002). There was no difference in NFIB mRNA expression in tumors with NFIB fusions compared with those without. We also report somatic mutations of genes involved in the axonal guidance and Rho family signaling pathways. Finally, we confirm previously described alterations in genes related to chromatin regulation and Notch signaling. Our findings suggest a separate role for NFIB in ACC oncogenesis and highlight important signaling pathways for future functional characterization and potential therapeutic targeting.
Gonda TJ, Ramsay RGAdenoid Cystic Carcinoma Can Be Driven by MYB or MYBL1 Rearrangements: New Insights into MYB and Tumor Biology.
Cancer Discov. 2016; 6(2):125-7 [PubMed
] Related Publications
A majority of adenoid cystic carcinomas (AdCC)-rare tumors of the salivary gland and some other organs-have recently been found to be driven by chromosomal translocations resulting in MYB-NFIB fusions. Brayer and colleagues and Mitani and colleagues have now reported that AdCCs can alternatively be driven by similar rearrangements involving a second MYB family gene, MYBL1, and that these two drivers act in remarkably similar ways.
Kumar-Sinha C, Kalyana-Sundaram S, Chinnaiyan AMLandscape of gene fusions in epithelial cancers: seq and ye shall find.
Genome Med. 2015; 7:129 [PubMed
] Article available free on PMC
after 01/04/2017 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.
A functional complex consisting of androgen receptor (AR) and forkhead box A1 (FOXA1) proteins supports prostatic development, differentiation, and disease. In addition, the interaction of FOXA1 with cofactors such as nuclear factor I (NFI) family members modulates AR target gene expression. However, the global role of specific NFI family members has yet to be described in the prostate. In these studies, chromatin immunoprecipitation followed by DNA sequencing in androgen-dependent LNCaP prostate cancer cells demonstrated that 64.3% of NFIB binding sites are associated with AR and FOXA1 binding sites. Interrogation of published data revealed that genes associated with NFIB binding sites are predominantly induced after dihydrotestosterone treatment of LNCaP cells, whereas NFIB knockdown studies demonstrated that loss of NFIB drives increased AR expression and superinduction of a subset of AR target genes. Notably, genes bound by NFIB only are associated with cell division and cell cycle. To define the role of NFIB in vivo, mouse Nfib knockout prostatic tissue was rescued via renal capsule engraftment. Loss of Nfib expression resulted in prostatic hyperplasia, which did not resolve in response to castration, and an expansion of an intermediate cell population in a small subset of grafts. In human benign prostatic hyperplasia, luminal NFIB loss correlated with more severe disease. Finally, some areas of intermediate cell expansion were also associated with NFIB loss. Taken together, these results show a fundamental role for NFIB as a coregulator of AR action in the prostate and in controlling prostatic hyperplasia.
PURPOSE: Adenoid cystic carcinoma (ACC) is an indolent salivary gland malignancy, characterized by t(6;9) translocations and MYB-NFIB gene fusions in approximately 50% of the tumors. The genetic alterations underlying t(6;9)-negative and t(6;9)-positive/MYB-NFIB fusion-negative ACC remain unknown. To uncover the genetic alterations in ACC lacking the canonical translocation and fusion transcript and identify new abnormalities in translocation positive tumors.
EXPERIMENTAL DESIGN: We performed whole-genome sequencing in 21 salivary ACCs and conducted targeted molecular analyses in a validation set (81 patients). Microarray gene-expression data were also analyzed to explore the biologic differences between fusion positive and negative tumors.
RESULTS: We identified a novel MYBL1-NFIB gene fusion as a result of t(8;9) translocation and multiple rearrangements in the MYBL1 gene in 35% of the t(6;9)-negative ACCs. All MYBL1 alterations involved deletion of the C-terminal negative regulatory domain and were associated with high MYBL1 expression. Reciprocal MYB and MYBL1 expression was consistently found in ACCs. In addition, 5'-NFIB fusions that did not involve MYB/MYBL1 genes were identified in a subset of t(6;9)-positive/fusion-negative tumors. We also delineated distinct gene-expression profiles in ACCs associated with the length of the MYB or MYBL1 fusions, suggesting a biologic importance of the C-terminal part of these fusions.
CONCLUSIONS: Our study defines new molecular subclasses of ACC characterized by MYBL1 rearrangements and 5'-NFIB gene fusions.
Brayer KJ, Frerich CA, Kang H, Ness SARecurrent Fusions in MYB and MYBL1 Define a Common, Transcription Factor-Driven Oncogenic Pathway in Salivary Gland Adenoid Cystic Carcinoma.
Cancer Discov. 2016; 6(2):176-87 [PubMed
] Free Access to Full Article Related Publications
UNLABELLED: Adenoid cystic carcinoma (ACC), the second most common malignancy of salivary glands, is a rare tumor with a bleak prognosis for which therapeutic targets are unavailable. We used RNA sequencing (RNA-seq) to analyze low-quality RNA from archival, formaldehyde-fixed, paraffin-embedded samples. In addition to detecting the most common ACC translocation, t(6;9) fusing the MYB proto-oncogene to NFIB, we also detected previously unknown t(8;9) and t(8;14) translocations fusing the MYBL1 gene to the NFIB and RAD51B genes, respectively. RNA-seq provided information about gene fusions, alternative RNA splicing, and gene expression signatures. Interestingly, tumors with MYB and MYBL1 translocations displayed similar gene expression profiles, and the combined MYB and MYBL1 expression correlated with outcome, suggesting that the related MYB proteins are interchangeable oncogenic drivers in ACC. Our results provide important details about the biology of ACC and illustrate how archival tissue samples can be used for detailed molecular analyses of rare tumors.
SIGNIFICANCE: Using RNA-seq to perform whole-transcriptome analysis of archival ACC tumor samples, we identified novel, recurrent gene fusions, detected alternative RNA splicing, and established gene expression signatures that provide detailed information about the biology of ACC tumors.
Adenoid cystic carcinoma (ACC) is a rare cancer with high potential for recurrence and metastasis. Efficacy of current treatment options, particularly for advanced disease, is very limited. Recent whole genome and exome sequencing has dramatically improved our understanding of ACC pathogenesis. A balanced translocation resulting in the MYB-NFIB fusion gene appears to be a fundamental signature of ACC. In addition, sequencing has identified a number of other driver genes mutated in downstream pathways common to other well-studied cancers. Overexpression of oncogenic proteins involved in cell growth, adhesion, cell cycle regulation, and angiogenesis are also present in ACC. Collectively, studies have identified genes and proteins for targeted, mechanism-based, therapies based on tumor phenotypes, as opposed to nonspecific cytotoxic agents. In addition, although few studies in ACC currently exist, immunotherapy may also hold promise. Better genetic understanding will enable treatment with novel targeted agents and initial exploration of immune-based therapies with the goal of improving outcomes for patients with ACC.
Dadone B, Refae S, Lemarié-Delaunay C, et al.Molecular cytogenetics of pediatric adipocytic tumors.
Cancer Genet. 2015; 208(10):469-81 [PubMed
] Related Publications
Both epidemiologic and cytogenetic data on pediatric adipose tissue tumors are scarce. Pediatric adipose tumors are mainly represented by lipomas, though only 28 cytogenetic descriptions of pediatric lipoma have been reported to date. Similar to adult cases, most of these pediatric lipomas harbored rearrangements of the chromosomal regions 12q14-q15 and 6p21, involving the HMGA2 and HMGA1 genes. Further cytogenetic studies of pediatric lipoma would be useful to determinate whether some partner genes of HMGA2, such as NFIB, may have a specific role in the early onset of these tumors. Cytogenetically, the best documented pediatric adipose tumor is lipoblastoma, which is the second most frequent adipose tumor in children. Chromosomal alterations in lipoblastoma, observed in 61% of cases studied by conventional cytogenetics, typically involve the 8q11-q12 region. The target gene of this rearrangement is PLAG1. Anomalies of PLAG1 have been observed in 70% of cases of pediatric adipose tumors studied by molecular cytogenetics methods, such as fluorescence in situ hybridization (FISH) or comparative genomic hybridization on array (array-CGH). The rare described cases of malignant pediatric adipose tumors in children are mostly myxoid liposarcomas. In the 27 cases explored at the genetic level, all pediatric myxoid liposarcomas showed the classical rearrangement of the DDIT3 gene at 12q13. In conclusion, the epidemiology and the prevalence of histological types of adipose tissue tumors differ in the pediatric population compared with adults, whereas chromosomal and genic rearrangements are similar to those of adult cases in each histological type.
Roden AC, Greipp PT, Knutson DL, et al.Histopathologic and Cytogenetic Features of Pulmonary Adenoid Cystic Carcinoma.
J Thorac Oncol. 2015; 10(11):1570-5 [PubMed
] Related Publications
INTRODUCTION: A significant portion of adenoid cystic carcinoma (ACC) cases are characterized by a t(6;9)(q22-23;p23-24) translocation that originates a MYB-NFIB fusion oncogene. The MYB-NFIB fusion oncoprotein activates transcription of MYB-mediated pathways that impact cell cycle control, DNA repair, and apoptosis. This translocation seems highly specific for ACC. Moreover, therapies targeting MYB-activated pathways to treat ACC are being explored. Pulmonary ACC (PACC) has not been thoroughly studied for rearrangements of the MYB gene.
METHODS: Mayo Clinic Rochester surgical pathology archives (1972-2011) were searched for PACC. All cases were reviewed and classified according to the predominant histologic pattern (cribriform, solid, and tubular) by two surgical pathologists. Fluorescence in situ hybridization (FISH) was employed using a break-apart strategy to detect MYB rearrangement (at 6q23.3). Medical records were studied.
RESULTS: Forty cases of PACC were studied; tissue blocks were available for FISH analysis in 35 cases. Six cases failed to hybridize. In 12 of 29 cases (41%), the MYB gene region was disrupted, whereas 17 cases (59%) showed no evidence of rearrangement. FISH studies performed on other histologic subtypes of lung cancer (10 squamous cell carcinomas, 10 adenocarcinomas, and 10 small-cell carcinomas) failed to show MYB rearrangement. There was no significant difference in MYB rearrangement status with respect to predominant histologic pattern, clinical features, or clinical outcome.
CONCLUSIONS: A MYB rearrangement was identified in 41% of PACC and was 100% specific. FISH studies for MYB may be of diagnostic utility in PACC, particularly on small biopsy specimens. MYB rearrangement in PACC does not seem to be associated with clinical features or prognosis.
Adenoid cystic carcinoma (AdCC) is a rare type of triple-negative breast cancer (TNBC) characterized by the presence of the MYB-NFIB fusion gene. The molecular underpinning of breast AdCCs other than the MYB-NFIB fusion gene remains largely unexplored. Here we sought to define the repertoire of somatic genetic alterations of breast AdCCs. We performed whole-exome sequencing, followed by orthogonal validation, of 12 breast AdCCs to determine the landscape of somatic mutations and gene copy number alterations. Fluorescence in situ hybridization and reverse-transcription PCR were used to define the presence of MYB gene rearrangements and MYB-NFIB chimeric transcripts. Unlike common forms of TNBC, we found that AdCCs have a low mutation rate (0.27 non-silent mutations/Mb), lack mutations in TP53 and PIK3CA and display a heterogeneous constellation of known cancer genes affected by somatic mutations, including MYB, BRAF, FBXW7, SMARCA5, SF3B1 and FGFR2. MYB and TLN2 were affected by somatic mutations in two cases each. Akin to salivary gland AdCCs, breast AdCCs were found to harbour mutations targeting chromatin remodelling, cell adhesion, RNA biology, ubiquitination and canonical signalling pathway genes. We observed that, although breast AdCCs had rather simple genomes, they likely display intra-tumour genetic heterogeneity at diagnosis. Taken together, these findings demonstrate that the mutational burden and mutational repertoire of breast AdCCs are more similar to those of salivary gland AdCCs than to those of other types of TNBCs, emphasizing the importance of histological subtyping of TNBCs. Furthermore, our data provide direct evidence that AdCCs harbour a distinctive mutational landscape and genomic structure, irrespective of the disease site of origin.
Bishop JA, Yonescu R, Epstein JI, Westra WHA subset of prostatic basal cell carcinomas harbor the MYB rearrangement of adenoid cystic carcinoma.
Hum Pathol. 2015; 46(8):1204-8 [PubMed
] Related Publications
Adenoid cystic carcinoma (ACC) is a basaloid tumor consisting of myoepithelial and ductal cells typically arranged in a cribriform pattern. Adenoid cystic carcinoma is generally regarded as a form of salivary gland carcinoma, but it can arise from sites unassociated with salivary tissue. A rare form of prostate carcinoma exhibits ACC-like features; it is no longer regarded as a true ACC but rather as prostatic basal cell carcinoma (PBCC) and within the spectrum of basaloid prostatic proliferations. True ACCs often harbor MYB translocations resulting in the MYB-NFIB fusion protein. MYB analysis could clarify the true nature of prostatic carcinomas that exhibit ACC features and thus help refine the classification of prostatic basaloid proliferations. Twelve PBCCs were identified from the pathology consultation files of Johns Hopkins Hospital. The histopathologic features were reviewed, and break-apart fluorescence in situ hybridization for MYB was performed. All 12 cases exhibited prominent basaloid histology. Four were purely solid, 7 exhibited a cribriform pattern reminiscent of salivary ACC, and 1 had a mixed pattern. The MYB rearrangement was detected in 2 (29%) of 7 ACC-like carcinomas but in none (0%) of the 5 PBCCs with a prominent solid pattern. True ACCs can arise in the prostate as is evidenced by the presence of the characteristic MYB rearrangement. When dealing with malignant basaloid proliferations in the prostate, recommendations to consolidate ACCs with other tumor types may need to be reassessed, particularly in light of the rapidly advancing field of biologic therapy where the identification of tumor-specific genetic alterations presents novel therapeutic targets.
UNLABELLED: Metastasis is the leading cause of death in patients with osteosarcoma, the most common pediatric bone malignancy. We conducted a multistage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified an SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P = 1.2 × 10(-9); OR, 2.43; 95% confidence interval, 1.83-3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. In addition, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib and with lowered NFIB expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis and that NFIB is an osteosarcoma metastasis susceptibility gene.
SIGNIFICANCE: Metastasis at diagnosis in osteosarcoma is the leading cause of death in these patients. Here we show data that are supportive for the NFIB locus as associated with metastatic potential in osteosarcoma.
North JP, McCalmont TH, Fehr A, et al.Detection of MYB Alterations and Other Immunohistochemical Markers in Primary Cutaneous Adenoid Cystic Carcinoma.
Am J Surg Pathol. 2015; 39(10):1347-56 [PubMed
] Related Publications
Adenoid cystic carcinoma (ACC) can arise in several organs, and prognosis is highly dependent on the primary tumor site. Primary cutaneous ACC has an excellent prognosis compared with salivary or lacrimal ACC. Activation of MYB by gene fusion or other mechanisms has been found in salivary, breast, and lacrimal ACCs but has not been described in cutaneous ACC. We analyzed the histopathologic and immunohistochemical features of 19 primary cutaneous ACCs, 2 periorbital ACCs, and 12 salivary gland ACCs and assessed for MYB activation in primary cutaneous ACC by immunohistochemistry and molecular methods. The presence of perineural invasion differed significantly among ACCs of various sites (83% salivary, 50% eyelid, 11% skin, P=0.0002). Over 90% of all ACCs were grade 1 or 2 and exhibited diffuse (>50%) positivity with CD117, SOX-10, and smooth muscle actin immunostains. CK15 and vimentin showed diffuse positivity in 36% and 57% of cutaneous ACCs, respectively, and were negative or only focally positive in all salivary ACCs (P=0.04 and 0.002). Six of the 11 cutaneous and periorbital ACCs tested with reverse transcriptase polymerase chain reaction and/or fluorescence in situ hybridization had MYB rearrangements including 2 cases that expressed MYB-NFIB fusion transcripts. Diffuse expression of MYB protein assessed by immunostaining was present in 8 of 9 cutaneous ACCs, including cases both with and without MYB rearrangements. These results indicate that cutaneous ACCs possess the same types of MYB alterations as ACCs of other anatomic sites. Vimentin and CK15 appear to have some discriminatory value in differentiating between primary cutaneous and salivary gland ACCs.
Fonseca FP, Sena Filho M, Altemani A, et al.Molecular signature of salivary gland tumors: potential use as diagnostic and prognostic marker.
J Oral Pathol Med. 2016; 45(2):101-10 [PubMed
] Related Publications
Salivary gland tumors are a highly heterogeneous group of lesions with diverse microscopic appearances and variable clinical behavior. The use of clinical and histological parameters to predict patient prognosis and survival rates has been of limited utility, and the search for new biomarkers that could not only aid in a better understanding of their pathogenesis but also be reliable auxiliaries for prognostic determination and useful diagnostic tools has been performed in the last decades with very exciting results. Hence, gene rearrangements such as CRTC1-MAML2 in mucoepidermoid carcinomas have shown excellent specificity, and more than that, it has been strongly correlated with low-grade tumors and consequently with an increased survival rate and better prognosis of patients affected by neoplasms carrying this translocation. Moreover, MYB-NFIB and EWSR1-ATF1 gene fusions were shown to be specifically found in cases of adenoid cystic carcinomas and hyalinizing clear cell carcinomas, respectively, in the context of salivary gland tumors, becoming reliable diagnostic tools for these entities and potential therapeutic targets for future therapeutic protocols. Finally, the identification of ETV6-NTRK3 in cases previously diagnosed as uncommon acinic cell carcinomas, cystadenocarcinomas, and adenocarcinomas not otherwise specified led to the characterization of a completely new and now widely accepted entity, including, therefore, mammary analogue secretory carcinoma in the list of well-recognized salivary gland carcinomas. Thus, further molecular investigations of salivary gland tumors are warranted, and the recognition of other genetic abnormalities can lead to the acknowledgment of new entities and the acquirement of reliable biomarkers.
Kobayashi K, Ando M, Saito Y, et al.Nerve Growth Factor Signals as Possible Pathogenic Biomarkers for Perineural Invasion in Adenoid Cystic Carcinoma.
Otolaryngol Head Neck Surg. 2015; 153(2):218-24 [PubMed
] Related Publications
OBJECTIVE: The molecular mechanisms underlying perineural invasion (PNI)-a characteristic pathological feature of adenoid cystic carcinoma (ACC)-remain largely unclear. Recently, nerve growth factor (NGF) has been implicated in perineural invasion in certain malignancies. Overexpression of Myb related to the MYB-NFIB fusion gene in ACC has also been correlated with perineural invasion and survival. However, this concept is controversial. The aim of this study was to examine the expression of NGF together with its receptors, tropomyosin receptor kinase A (TrkA) and p75NRT, and Myb in ACC and assess their relationship with perineural invasion and survival.
STUDY DESIGN: Case series with chart review.
SETTING: The University of Tokyo Hospital.
SUBJECTS AND METHODS: We retrospectively analyzed 37 patients with ACC surgically treated from 1991 to 2011. We examined expression levels of NGF, TrkA, p75NRT, and Myb in the ACC specimens and their correlations with PNI and prognosis.
RESULTS: NGF, TrkA, p75NRT, and Myb overexpression rates were 65%, 65%, 30%, and 62%, respectively. Pearson product-moment correlation coefficient revealed a strong correlation between NGF/TrkA immunostaining and PNI (NGF: r = 0.68, P < .0001; TrkA: r = 0.53, P = .0007). Moreover, NGF overexpression was significantly associated with worse 8-year local control rate (27% vs 80%, P = .005). However, p75NRT and Myb expression was related to neither perineural invasion nor survival.
CONCLUSION: Our findings demonstrated that NGF and TrkA overexpression, but not Myb and p75NRT overexpression, may contribute to PNI and thus cause local recurrence in patients with ACC.
OBJECTIVES: Salivary gland adenoid cystic carcinoma (ACC) is rare, aggressive, and challenging to treat. Many ACCs have a t(6;9) chromosomal translocation resulting in a MYB-NFIB fusion gene, but the clinical significance is unclear. The purposes of this study were to describe the clinicopathologic factors impacting survival and to determine the prevalence and clinical significance of MYB-NFIB fusion.
STUDY DESIGN: Case series.
METHODS: Medical records of patients treated for ACC of the head and neck from 1974 to 2011 were reviewed and clinicopathologic data recorded. Fluorescence in situ hybridization (FISH) was used to detect MYB rearrangement in archival tumor tissue as a marker of MYB-NFIB fusion.
RESULTS: One hundred fifty-eight patients were included, with median follow-up 75.1 months. Median overall survival was 171.5 months (95% confidence interval [CI] = 131.9-191.6), and median disease-free survival was 112.0 months (95% CI = 88.7-180.4). Advanced stage was associated with decreased overall survival (adjusted ptrend < 0.001), and positive margins were associated with decreased disease-free survival (adjusted hazard ratio [aHR] = 8.80, 95% CI = 1.25-62.12, P = 0.029). Ninety-one tumors were evaluable using FISH, and 59 (65%) had evidence of a MYB-NFIB fusion. MYB-NFIB positive tumors were more likely than MYB-NFIB negative tumors to originate in minor salivary glands (adjusted prevalence ratios = 1.51, 95% CI = 1.07-2.12, P = 0.019). MYB-NFIB tumor status was not significantly associated with disease-free or overall survival (hazard ratio [HR] = 1.53, 95% CI = 0.77-3.02, P = 0.22 and HR = 0.91, 95% CI = 0.46-1.83, P = 0.80, respectively, for MYB-NFIB positive compared with MYB-NFIB negative tumors).
CONCLUSION: Stage and margin status were important prognostic factors for ACC. Tumors with evidence of MYB-NFIB fusion were more likely to originate in minor salivary glands, but MYB-NFIB tumor status was not significantly associated with prognosis.
LEVEL OF EVIDENCE: 4.
Zhang Q, Cao LY, Cheng SJ, et al.p53-induced microRNA-1246 inhibits the cell growth of human hepatocellular carcinoma cells by targeting NFIB.
Oncol Rep. 2015; 33(3):1335-41 [PubMed
] Related Publications
In recent years, miR-1246 has been identified as a transcriptional target of p53 in Down syndrome and may provide a new p53-miR-1246-DYRK1A-NFAT pathway in cancer. The present study aimed to explore the role of miR-1246 in the tumorigenesis of human hepatocellular carcinoma (HCC). We found that wild-type p53 regulated the expression of miR-1246 in HCC cell lines, and alteration of miR-1246 modulated cell proliferation, colony formation ability and apoptosis. The nuclear factor I/B (NFIB), an oncogene, was identified as a direct target gene of miR-1246 using a fluorescent reporter assay. Overexpression of NFIB abolished the regulation of cell apoptosis caused by miR-1246 in HepG2 cells. This finding suggests that miR-1246 is regulated by p53 and suppresses the growth of human HCC by targeting NFIB. Here, we propose a new p53-miR-1246-NFIB pathway in HCC.
MYB activation is proposed to underlie development of adenoid cystic cancer (ACC), an aggressive salivary gland tumor with no effective systemic treatments. To discover druggable targets for ACC, we performed global mRNA/miRNA analyses of 12 ACC with matched normal tissues, and compared these data with 14 mucoepidermoid carcinomas (MEC) and 11 salivary adenocarcinomas (ADC). We detected a unique ACC gene signature of 1160 mRNAs and 22 miRNAs. MYB was the top-scoring gene (18-fold induction), however we observed the same signature in ACC without detectable MYB gene rearrangements. We also found 4 ACC tumors (1 among our 12 cases and 3 from public databases) with negligible MYB expression that retained the same ACC mRNA signature including over-expression of extracellular matrix (ECM) genes. Integration of this signature with somatic mutational analyses suggests that NOTCH1 and RUNX1 participate with MYB to activate ECM elements including the VCAN/HAPLN1 complex. We observed that forced MYB-NFIB expression in human salivary gland cells alters cell morphology and cell adhesion in vitro and depletion of VCAN blocked tumor cell growth of a short-term ACC tumor culture. In summary, we identified a unique ACC signature with parallel MYB-dependent and independent biomarkers and identified VCAN/HAPLN1 complexes as a potential target.
Dillon PM, Chakraborty S, Moskaluk CA, et al.Adenoid cystic carcinoma: A review of recent advances, molecular targets, and clinical trials.
Head Neck. 2016; 38(4):620-7 [PubMed
] Related Publications
BACKGROUND: Adenoid cystic carcinoma (ACC) is a rare tumor of secretory glands. In this study, recent advances in molecular characterization and in therapeutics are reviewed.
METHODS: A search of articles in PubMed and of abstracts from national meetings was performed regarding ACC.
RESULTS: Recent genetic analyses found that recurrent chromosome 6:9 translocations in ACC generate an MYB:NFIB gene fusion resulting in overexpression of the MYB oncoprotein. Several other frequent mutations are recently published that may be relevant for drug development. Several trials of targeted drugs are reviewed. Some agents delay tumor progression, but tumor responses remain rare.
CONCLUSION: ACCs have a characteristic chromosomal translocation, but also frequently pick up additional mutations. Clinical research is limited by the rarity and slow growth of ACC. Several ongoing trials are testing agents that inhibit fibroblast growth factor receptor signaling or other signaling pathways. Novel treatments based on the recently sequenced tumor genome are under development.
D'Alfonso TM, Mosquera JM, MacDonald TY, et al.MYB-NFIB gene fusion in adenoid cystic carcinoma of the breast with special focus paid to the solid variant with basaloid features.
Hum Pathol. 2014; 45(11):2270-80 [PubMed
] Related Publications
Adenoid cystic carcinomas (ACCs) from various anatomical sites harbor a translocation t(6;9)(q22-23;p23-24), resulting in MYB-NFIB gene fusion. This gene fusion is not well studied in mammary ACCs, and there are no studies examining this abnormality in solid variant of ACC with basaloid features (SBACC), a high-grade variant thought to behave more aggressively than ACCs with conventional histologic growth. Our aim was to investigate the frequency of MYB-NFIB gene fusion in mammary ACCs with a focus paid to SBACC. MYB rearrangement and MYB-NFIB fusion were assessed by fluorescence in situ hybridization and reverse-transcription polymerase chain reaction, respectively. Histologic features and the presence of MYB rearrangement were correlated with clinical outcome. MYB rearrangement was present in 7 (22.6%) of 31 mammary ACCs (5/15 [33.3%] ACCs with conventional growth; 2/16 [12.5%] SBACCs). One patient with conventional ACC developed distant metastasis, and no patients had axillary lymph node involvement by ACC (mean follow-up, 34 months; range, 12-84 months). Two patients with SBACC had axillary lymph node involvement at initial surgery, and 2 additional patients experienced disease recurrence (1 local, 1 distant; mean follow-up, 50 months; range, 9-192 months). MYB-NFIB fusion status did not correlate with clinical outcome in studied patients. We confirm that MYB-NFIB gene fusion is observed in mammary ACCs and that a subset lacks this abnormality. This study is the first to confirm the presence of MYB rearrangement in SBACC. Additional validation with long-term follow-up is needed to determine the relationship, if any, between MYB-NFIB gene fusion and clinical outcome.
Hsiao CC, Wang WC, Kuo WL, et al.CD97 inhibits cell migration in human fibrosarcoma cells by modulating TIMP-2/MT1- MMP/MMP-2 activity--role of GPS autoproteolysis and functional cooperation between the N- and C-terminal fragments.
FEBS J. 2014; 281(21):4878-91 [PubMed
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CD97 is a tumor-associated adhesion-class G-protein-coupled receptor involved in modulating cell migration. Adhesion-class G-protein-coupled receptors are characterized by proteolytic cleavage at a G-protein-coupled receptor proteolysis site (GPS) into an N-terminal fragment (NTF) and a C-terminal fragment (CTF), which remain associated noncovalently. The molecular mechanism and the role of GPS proteolysis in CD97-modulated cell migration are not completely understood. We report here that CD97 expression in HT1080 fibrosarcoma cells enhanced tissue inhibitor of metalloproteinase-2 secretion, leading to reduced membrane type 1 matrix metalloproteinase and matrix metalloproteinase 2 activities. This, in turn, impaired cell migration and invasion in vitro and lung macrometastasis in vivo. CD97 expression also upregulated the expression of integrins, promoting cell adhesion. Importantly, these cellular functions absolutely required the presence of both the NTF and the CTF of CD97, confirming functional cooperation between the two receptor subunits. CD97 gene knockdown reversed these phenotypic changes. We conclude that GPS proteolysis and the functional interplay between the NTF and the CTF are indispensible for CD97 to inhibit HT1080 cell migration by suppressing matrix metalloproteinase activity.
Aberrant expression of microRNAs plays vital roles in tumor development and progression. As transcription factors (TFs) are the critical components of signaling cascades, specific targeting effects of microRNAs to specific TFs may determine the role of microRNAs in different cancers. In this study, we identified Nuclear Factor I/B (NFIB) as one of the targets of miR-365 which was previously verified as an onco-miR in cutaneous squamous cell carcinoma (CSCC). Down-regulation of NFIB was a general feature in both CSCC cell lines and tumors from patients which show drastically up-regulated miR-365 expression levels. The siRNA-based knockdown of NFIB mimic the carcinogenic transformation of normal cells by ectopically expression of miR-365 which indicates depletion of NFIB is necessary for miR-365 to exert its pro-carcinogenic function. NFIB may represent a functional barrier targeted by miR-365 to the development of CSCC. Further studies also discovered a conserved feedback regulatory circuitry formed by NFIB and miR-365 in CSCC development which may be potentially utilized as therapeutic target to improve the clinical CSCC treatment.
von Holstein SLTumours of the lacrimal gland. Epidemiological, clinical and genetic characteristics.
Acta Ophthalmol. 2013; 91 Thesis 6:1-28 [PubMed
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Tumours of the lacrimal gland are rare, but the prognosis may be grave. To date, no population-based incidence and distribution data on lacrimal gland tumours exist. In addition, almost nothing is known about the genetic profile of epithelial tumours of the lacrimal gland. We collected specimens and clinical files on all biopsied lacrimal gland lesions in Denmark over a 34-year period and re-evaluated the diagnosis to provide updated population-based incidence rates and epidemiological characteristics. Clinical data regarding symptoms, clinical examinations, treatment and follow-up were collected for patients with adenoid cystic carcinoma (ACC), pleomorphic adenoma (PA), carcinoma ex pleomorphic adenoma (Ca-ex-PA) and mucoepidermoid carcinoma (MEC). Using RT-PCR, FISH, immunohistochemistry, Q-PCR and high-resolution array-based comparative genomic hybridization (arrayCGH) we explored the genetic characteristics including copy number alterations (CNA) in ACC, PA, Ca-ex-PA and MEC. The incidence of biopsied lacrimal gland lesions was 1.3/1,000,000/year, and ~50% were neoplastic lesions. Of these, 55% were malignant tumours with epithelial tumours as the most frequent. The overall incidence was increasing, and this was caused by an increase in biopsied non-neoplastic lesions. We found that 10/14 ACCs either expressed the MYB-NFIB fusion gene and/or had rearrangements of MYB. All ACCs expressed the MYB protein. ACC was characterized by recurrent copy number losses involving 6q, 12q and 17q and gains involving 19q, 8q and 11q. ArrayCGH revealed an apparently normal genomic profile in 11/19 PAs. The remaining 8 PAs had recurrent copy number losses involving 1p, 6q, 8q and 13q and gain involving 9p. PA expressed PLAG1 in all tumours whereas only 2/29 tumours expressed HMGA2. Ca-ex-PA was characterized by recurrent copy number gain involving 22q. PLAG1 was expressed in 3/5 Ca-ex-PA whereas none of these tumours expressed HMGA2. MEC expressed the CRTC1-MAML2, and this fusion was found to be tumour-specific for lacrimal gland MEC. In conclusion, lacrimal gland lesions that require pathological evaluation are rare in the Danish population, and the incidence rate of biopsied benign lesions is increasing. Epithelial tumours of the lacrimal gland are molecularly very similar to their salivary gland counterparts in the expression of the tumour-specific fusion genes and in their genomic imbalances as demonstrated by arrayCGH. MYB-NFIB is a useful biomarker for ACC and MYB, and its downstream target genes may be potential therapeutic targets for these tumours.
Stenman G, Persson F, Andersson MKDiagnostic and therapeutic implications of new molecular biomarkers in salivary gland cancers.
Oral Oncol. 2014; 50(8):683-90 [PubMed
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Salivary gland carcinomas (SGCs) are uncommon tumors, constituting approximately 5% of all cancers of the head and neck. They are a heterogeneous group of diseases that pose significant diagnostic and therapeutic challenges. The treatment of patients with SGCs is mainly restricted to surgery and/or radiation therapy and there is only limited data available on the role of conventional systemic and targeted therapies in the management of patients with advanced disease. There is thus a great need to develop new molecular biomarkers to improve the diagnosis, prognostication, and therapeutic options for these patients. In this review, we will discuss the most recent developments in this field, with focus on pathognomonic gene fusions and other driver mutations of clinical significance. Comprehensive cytogenetic and molecular genetic analyses of SGCs have revealed a translocation-generated network of fusion oncogenes. The molecular targets of these fusions are transcription factors, transcriptional coactivators, and tyrosine kinase receptors. Prominent examples of clinically significant fusions are the MYB-NFIB fusion in adenoid cystic carcinoma and the CRTC1-MAML2 fusion in mucoepidermoid carcinoma. The fusions are key events in the molecular pathogenesis of these tumor types and contribute as new diagnostic, prognostic, and therapeutic biomarkers. Moreover, next-generation sequencing analysis of SGCs have revealed new druggable driver mutations, pinpointing alternative therapeutic options for subsets of patients. Continued molecular characterization of these fusions and their down-stream targets will ultimately lead to the identification of novel driver genes in SGCs and will form the basis for development of new therapeutic strategies for these patients.
Costa AF, Altemani A, García-Inclán C, et al.Analysis of MYB oncogene in transformed adenoid cystic carcinomas reveals distinct pathways of tumor progression.
Lab Invest. 2014; 94(6):692-702 [PubMed
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Adenoid cystic carcinomas can occasionally undergo dedifferentiation, a phenomenon also referred to as high-grade transformation. However, cases of adenoid cystic carcinomas have been described showing transformation to adenocarcinomas that are not poorly differentiated, indicating that high-grade transformation may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form, which may encompass a wide spectrum of carcinomas in terms of aggressiveness. The aim of this study was to gain more insight in the biology of this pathological phenomenon by means of genetic profiling of both histological components. Using microarray comparative genomic hybridization, we compared the genome-wide DNA copy-number changes of the conventional and transformed area of eight adenoid cystic carcinomas with high-grade transformation, comprising four with transformation into moderately differentiated adenocarcinomas and four into poorly differentiated carcinomas. In general, the poorly differentiated carcinoma cases showed a higher total number of copy-number changes than the moderately differentiated adenocarcinoma cases, and this correlated with a worse clinical course. Special attention was given to chromosomal translocation and protein expression of MYB, recently being considered to be an early and major oncogenic event in adenoid cystic carcinomas. Our data showed that the process of high-grade transformation is not always accompanied by an accumulation of genetic alterations; both conventional and transformed components harbored unique genetic alterations, which indicate a parallel progression. Our data further demonstrated that the MYB/NFIB translocation is not necessarily an early event or fundamental for the progression to adenoid cystic carcinoma with high-grade transformation.
von Holstein SL, Fehr A, Persson M, et al.Lacrimal gland pleomorphic adenoma and carcinoma ex pleomorphic adenoma: genomic profiles, gene fusions, and clinical characteristics.
Ophthalmology. 2014; 121(5):1125-33 [PubMed
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PURPOSE: To study genetic alterations in lacrimal gland pleomorphic adenoma (PA) and carcinoma ex pleomorphic adenoma (Ca-ex-PA) with focus on copy number changes and expression patterns of the translocation target genes PLAG1, HMGA2, and CRTC1-MAML2 in relation to clinical data.
DESIGN: Experimental study.
PARTICIPANTS: A total of 36 tumors from 32 patients with lacrimal gland PA or Ca-ex-PA were included in the study.
METHODS: Genome wide, high-resolution array-based comparative genomic hybridization (arrayCGH) and immunohistochemistry were used to study the genomic profiles and expression patterns of the translocation targets PLAG1, HMGA2, and CRTC1-MAML2.
MAIN OUTCOME MEASURES: Copy number alterations (gains/losses) and protein expression of PLAG1, HMGA2, and CRTC1-MAML2.
RESULTS: Genome-wide arrayCGH analysis revealed normal genomic profiles in 10 of 17 PA samples. The average number of genomic imbalances per tumor was 3.25 (range, 1-7) in primary and recurrent PAs with alterations compared with 7.7 (range, 4-12) in Ca-ex-PAs. Five recurrent copy number alterations were identified in PAs, including losses of 1pter-p31.3, 6q22.1-q24.3, 8q24.22-q24.3, and 13q21.31-q21.33, and gain of 9p23-p22.3. Gain of 9p23-p22.3 also was seen in a Ca-ex-PA. In Ca-ex-PA, gain of 22q12.3-qter was the only recurrent alteration. Detailed analysis of the array data identified NFIB and PDGFB as the 2 major candidate target oncogenes that may be activated as a result of copy number gains involving 9p and 22q. Both genes have been implicated in the pathogenesis of PA and other types of salivary gland tumors. Immunohistochemical analysis revealed frequent overexpression of the translocation target gene PLAG1 in PAs and in 1 Ca-ex-PA. In contrast, overexpression of HMGA2 was observed in only a small subset of PAs. The CRTC1-MAML2 fusion oncoprotein was overexpressed in 2 mucoepidermoid Ca-ex-PAs.
CONCLUSIONS: Lacrimal and salivary gland PAs and Ca-ex-PAs have similar genomic profiles and frequently overexpress the PLAG1 oncoprotein. Copy number gains involving 9p23-p22.3 (NFIB) and 22q12-qter (PDGFB) may be of importance for disease progression in a subset of lacrimal gland PAs.
Widemann BC, Acosta MT, Ammoun S, et al.CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies.
Am J Med Genet A. 2014; 164A(3):563-78 [PubMed
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The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a "state-of-the-field" for NF research in 2012.
Pusztaszeri MP, Sadow PM, Ushiku A, et al.MYB immunostaining is a useful ancillary test for distinguishing adenoid cystic carcinoma from pleomorphic adenoma in fine-needle aspiration biopsy specimens.
Cancer Cytopathol. 2014; 122(4):257-65 [PubMed
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BACKGROUND: The distinction between adenoid cystic carcinoma (ACC) and pleomorphic adenoma (PA) on fine-needle aspiration biopsy (FNAB) can be challenging. Recently, a specific translocation t(6;9) involving the v-myb avian myeloblastosis viral oncogene homolog (MYB) and nuclear factor I/B (NFIB) genes was identified in ACCs, in which it contributes to MYB overexpression. The authors investigated the use of MYB immunocytochemistry in FNAB specimens as an ancillary test for the cytologic diagnosis of ACC.
METHODS: The expression of MYB was assessed in alcohol-fixed cytologic smears of histologically confirmed ACCs (n = 20) and PAs (n = 20) using immunocytochemistry. The corresponding ACCs and PAs from formalin-fixed, paraffin embedded surgical resection specimens also were stained immunohistochemically for MYB. The nuclear expression of MYB was assessed semiquantitatively using a scoring system (from 0 to 6) that combined the proportion and the intensity of staining. A score ≥4 was considered positive, and a score ≤3 was considered negative.
RESULTS: On FNAB material, 80% of ACCs (N = 16 of 20) were immunocytochemically positive for MYB. In contrast, all PAs (N = 20 of 20) were negative for MYB (P < .0001). The sensitivity of MYB on FNAB was 80%, and the specificity was 100% relative to PA. Results on corresponding histology were similar to the cytology results; however, there was often a zonal staining pattern with central areas of tumor (range, 20%-90%) that lacked immunoreactivity, thus suggesting that the immunoreactivity was maintained better in alcohol-fixed FNAB material.
CONCLUSIONS: In contrast to PAs, a majority of ACCs are immunocytochemically positive for MYB. The test is more effective using alcohol-fixed FNAB material and is potentially useful for the cytologic distinction of ACC and PA.