Research IndicatorsGraph generated 11 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 11 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
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 "CRTC3"
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: CRTC3 (cancer-related)
Ishibashi K, Ito Y, Masaki A, et al.Warthin-like Mucoepidermoid Carcinoma: A Combined Study of Fluorescence In Situ Hybridization and Whole-slide Imaging.
Am J Surg Pathol. 2015; 39(11):1479-87 [PubMed
] Related Publications
There has been some debate as to whether a subset of metaplastic Warthin tumors (mWTs) harbor the mucoepidermoid carcinoma (MEC)-associated CRTC1-MAML2 fusion. We analyzed 15 tumors originally diagnosed as mWT (mWT-like tumors), 2 of which had concurrent MECs. We looked for the CRTC1/3-MAML2 fusion transcripts and performed immunohistochemistry for p63 and fluorescence in situ hybridization (FISH) for the MAML2 split. To localize MAML2 split-positive cells at the cellular level, whole tumor tissue sections were digitalized (whole-slide imaging [WSI]). The CRTC1-MAML2, but not CRTC3-MAML2 was detected in 5/15 mWT-like tumors. FISH-WSI results showed that all epithelial cells harbored the MAML2 split in fusion-positive mWT-like tumors and were totally negative in fusion-negative mWT-like tumors. A review of the hematoxylin and eosin-stained slides showed that morphology of the "metaplastic" epithelium was virtually indistinguishable between fusion-positive and fusion-negative tumors. However, oncocytic bilayered tumor epithelium, characteristic to typical WT, was always found somewhere in the fusion-negative tumors but not in the fusion-positive tumors. This distinguishing histologic finding enabled 5 pathologists to easily differentiate the 2 tumor groups with 100% accuracy. The age and sex distribution of fusion-positive mWT-like tumor cases was similar to that of fusion-positive MEC cases and significantly different from those of fusion-negative mWT-like tumor and typical WT cases. In addition, only fusion-positive mWT-like tumors possessed concurrent low-grade MECs. In conclusion, a subset of mWT-like tumors were positive for the CRTC1-MAML2 fusion and had many features that are more in accord with MEC than with WT. The term Warthin-like MEC should be considered for fusion-positive mWT-like tumors.
Prieto-Granada CN, Inagaki H, Mueller JThymic Mucoepidermoid Carcinoma: Report of a Case With CTRC1/3-MALM2 Molecular Studies.
Int J Surg Pathol. 2015; 23(4):277-83 [PubMed
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Thymic mucoepidermoid carcinoma (TMEC) is a vanishingly rare entity that usually presents as low to intermediate grade MEC and carries a better prognosis when compared with other poorly differentiated thymic carcinomas. The recently described fusions, t(11;19)(q21;p13) CREB (cAMP response element-binding protein)-regulated transcription coactivator 1 and MAML2, mastermind-like gene 2 (CRTC1-MAML2) and t(11:15)(q21;q26) CRTC3-MAML2 characterize a considerable proportion of MEC examples arising from a variety of anatomical sites. Recent data point out that the aberrant proteins produced by this fusion drive oncogenesis by disrupting the cAMP/CREB and NOTCH1 pathways. To date, only 2 TMEC cases have been reported to have MAML2 rearrangements, a feature that was found to be absent in TMEC mimics. These findings led the authors to recommend this test as a diagnostic tool in the differential diagnosis for thymic carcinoma. Herein, we present a case of TMEC arising in a 58-year-old woman, which was predominantly cystic with intracystic papillary formations composed of a mixture of mucinous cells and intermediate/epidermoid eosinophilic cells. This case was negative for CTCR1-MAML2 and CTCR3-MAML2 fusion transcripts by reverse transcriptase polymerase chain reaction and lacked a MAML2 rearrangement by fluorescence in situ hybridization. We report a CTCR1/3-MAML2 fusion and MAML2 rearrangement-negative TMEC, indicating that a different molecular pathway must be involved in the generation of these tumors. The possibility of fusion-negative TMEC should be taken into consideration in the differential diagnosis of a thymic carcinoma.
Skálová A, Vanecek T, Simpson RH, et al.CRTC1-MAML2 and CRTC3-MAML2 fusions were not detected in metaplastic Warthin tumor and metaplastic pleomorphic adenoma of salivary glands.
Am J Surg Pathol. 2013; 37(11):1743-50 [PubMed
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The recurrent translocations t(11;19) and t(11;15) resulting in CRTC1-MAML2 or CRTC3-MAML2 fusion oncogenes, respectively, are identified in a large proportion of mucoepidermoid carcinomas (MECs) of the salivary gland and have impact on prognosis. However, there are conflicting data on the specificity of this translocation, in particular, on its putative occurrence in Warthin tumor (WT) of the parotid gland as reported in few previous cases. It was speculated that extensive squamous metaplasia could explain the presence of t(11;19) translocation in a subset of WTs. We evaluated 76 salivary gland tumors, including 16 cases of metaplastic WT and 8 cases of pleomorphic adenoma (PA) with squamous and/or mucinous metaplasia, extensive enough morphologically to mimic MEC. Detection of CRTC1-MAML2 and CRTC3-MAML2 fusion transcripts and MAML2 gene break was performed using nested reverse transcription-polymerase chain reaction and fluorescence in situ hybridization (FISH), respectively. None of 16 analyzed metaplastic WTs showed positivity for fusion transcripts CRTC1-MAML2 or CRTC3-MAML2, and none showed rearrangement of the MAML2 gene by FISH. Similarly, we did not detect these transcripts or break of MAML2 gene in any case of PA with extensive squamous/mucinous metaplasia. For comparison, 40 cases of low-grade MEC were also evaluated. CRTC1-MAML2 and CRTC3-MAML2 fusion transcripts were detected in 17 and 5 cases, respectively. The FISH method using break-apart probe demonstrated the MAML2 gene rearrangement in 25 cases of low-grade MEC. In contrast to low-grade MEC, neither metaplastic WTs nor metaplastic PAs harbored translocations t(11;19) and anticipated t(11;15) resulting in CRTC1-MAML2 and CRTC3-MAML2 fusion transcripts, respectively, and/or MAML2 gene rearrangement.
Ham S, Meachem SJ, Choong CS, et al.Overexpression of aromatase associated with loss of heterozygosity of the STK11 gene accounts for prepubertal gynecomastia in boys with Peutz-Jeghers syndrome.
J Clin Endocrinol Metab. 2013; 98(12):E1979-87 [PubMed
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CONTEXT: Peutz-Jeghers syndrome (PJS) is an autosomal-dominant disorder that arises as a consequence of mutations in the STK11 gene that encodes LKB1. PJS males often have estrogen excess manifesting as gynecomastia and advanced bone age. We and others have previously described an increase in testicular aromatase expression in PJS patients. However, the underlying mechanism has not yet been explored.
OBJECTIVE: The aim of this study was to characterize the role of LKB1 in regulating the expression of aromatase in boys with PJS via signaling pathways involving AMP-activated protein kinase (AMPK) and cyclic AMP-responsive element binding protein-regulated transcription coactivators (CRTCs).
PATIENTS: We studied testicular biopsies from two boys with STK11 mutations: a 13-year-old boy and an unrelated 4-year-old boy with prepubertal gynecomastia and advanced bone age, as well as breast tissue from the 13-year-old boy.
RESULTS: Loss of heterozygosity of STK11, measured by the absence of LKB1 immunofluorescence, was observed in Sertoli cells of abnormal cords of testis samples from affected individuals. This was associated with loss of p21 expression and decreased phosphorylation of AMPK, known downstream targets of LKB1, as well as the increased expression of aromatase. Similar results of low LKB1 expression in cells expressing aromatase were observed in the mammary epithelium from one of these individuals. Nuclear expression of the CRTC proteins, potent stimulators of aromatase and known to be inhibited by AMPK, was significantly correlated with aromatase.
CONCLUSIONS: Loss of heterozygosity of the STK11 gene leads to an increase in aromatase expression associated with an increase in CRTC nuclear localization, thereby providing a mechanism whereby PJS results in increased endogenous estrogens in affected males.
Noda H, Okumura Y, Nakayama T, et al.Clinicopathological significance of MAML2 gene split in mucoepidermoid carcinoma.
Cancer Sci. 2013; 104(1):85-92 [PubMed
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CRTC1-MAML2 and CRTC3-MAML2 fusions have been associated with favorable clinicopathological features of mucoepidermoid carcinomas. However, the significance of the MAML2 gene split has not been fully clarified. In the present study, 95 mucoepidermoid carcinomas (paraffin-embedded materials) were analyzed for CRTC1-MAML2 and CRTC3-MAML2 fusions by RT-PCR and for the MAML2 gene split by FISH. Quantitative RT-PCR for the CRTC1-MAML2 transcript was performed in selected cases. MLL gene involvement, which has been reported in some leukemia cases, was examined by FISH in fusion partner-unknown cases. CRTC1-MAML2 and CRTC3-MAML2 fusions were detected in 37 and 6 cases, respectively. The MAML2 gene split was detected in 62 cases, which included all CRTC1/3-MAML2 fusion-positive cases. The level of CRTC1-MAML2 transcript expression was highly variable, and its clinicopathological impact was unclear. The MLL gene split was not detected. Mucoepidermoid carcinomas negative for CRTC1/3-MAML2 and positive for the MAML2 gene split (n = 19) showed favorable clinicopathological tumor features similar to those positive for CRTC1/3-MAML2 fusions. Compared with negative cases (n = 33), mucoepidermoid carcinomas positive for the MAML2 split (n = 62) were associated with lower patient age, a mild female predilection, a smaller tumor size, less frequent nodal metastasis, a lower clinical stage, a lower histological grade, and longer overall and disease-free survival. The MAML2 gene split emerged as an independent prognostic factor for both overall and disease-free survival in multivariate prognostic analysis. The presence of the MAML2 gene split defines a distinct mucoepidermoid carcinoma subset that is associated clinicopathologically with favorable tumor features.
Nakayama T, Miyabe S, Okabe M, et al.Clinicopathological significance of the CRTC3-MAML2 fusion transcript in mucoepidermoid carcinoma.
Mod Pathol. 2009; 22(12):1575-81 [PubMed
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Mucoepidermoid carcinoma is the most common primary malignancy of the salivary gland. We and others showed that CRTC1-MAML2 gene fusion was associated with favorable clinicopathological tumor features. Recently, a novel gene fusion, CRTC3-MAML2, was reported as a rare gene alteration in a case of mucoepidermoid carcinoma. However, its frequency and clinicopathological significance remains unclear. In all, 101 cases of mucoepidermoid carcinoma and 89 cases of non-mucoepidermoid carcinoma of the salivary gland were analyzed, and RNA was extracted from formalin-fixed, paraffin-embedded specimens. In the CRTC family, there have been three genes, CRTC1, CRTC2, and CRTC3. We developed reverse transcription-polymerase chain reaction (RT-PCR) assays for CRTC1-MAML2, CRTC2-MAML2, and CRTC3-MAML2 fusions. Clinicopathological data of the patients were obtained from their clinical records. Of 101 cases of mucoepidermoid carcinoma, 34 (34%) and 6 (6%) were positive for CRTC1-MAML2 and CRTC3-MAML2 fusion transcripts. However, in the 89 cases of non-mucoepidermoid carcinoma, neither transcript was noted. In the former cases, CRTC1-MAML2 and CRTC3-MAML2 fusions were mutually exclusive. The other fusion, CRTC2-MAML2, was not detected. We confirmed that the clinicopathological features of CRTC1-MAML2-positive mucoepidermoid carcinomas indicated an indolent course. CRTC3-MAML2-positive mucoepidermoid carcinomas also had clinicopathologically favorable features; all cases showed a less advanced clinical stage, negative nodal metastasis, no high-grade tumor histology, and no recurrence or tumor-related death after surgical resection of the tumor. It is interesting to note that patients with CRTC3-MAML2-positive tumors (mean 36 years of age) were significantly younger that those with the CRTC1-MAML2 fusion (55 years) and those with fusion-negative tumors (58 years). In conclusion, CRTC3-MAML2 fusion, which is mutually exclusive with CRTC1-MAML2 fusion and specific to mucoepidermoid carcinoma, may be detected more frequently than previously expected. Mucoepidermoid carcinomas possessing CRTC3-MAML2 fusion may be associated with favorable clinicopathological features and patients may be younger than those with CRTC1-MAML2 fusion or those with no detectable gene fusion.
Fehr A, Röser K, Heidorn K, et al.A new type of MAML2 fusion in mucoepidermoid carcinoma.
Genes Chromosomes Cancer. 2008; 47(3):203-6 [PubMed
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The present study reports for the first time a CRTC3-MAML2 fusion gene in a mucoepidermoid carcinoma, as determined by RT-PCR and sequencing. We screened a total of 67 formalin-fixed, paraffin-embedded mucoepidermoid carcinomas for the presence of chimeric genes. In one of these samples, a CRTC3-MAML2 fusion gene was detected. Thus, this report demonstrates the existence of a fusion of MAML2 with CREB regulated transcriptional coactivator CRTC3 additional to the already known fusion of MAML2 and CRTC1. Both gene fusions seem to result in an identical tumor phenotype and the fusion genes CRTC1-MAML2 and CRTC3-MAML2 may play a similar role in the development of mucoepidermoid carcinomas.