The mutational characterization of adenoid cystic carcinoma
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ABSTRACT: Adenoid cystic carcinoma (ACC) typically emanate from the major and minor salivary glands of the head and neck. ACCs have high rates of perineural invasion, locoregional recurrence, and distant metastasis. Here we report sequencing of 60 tumor/normal pairs and find substantial mutational diversity. On pathway analysis, a significant percentage of mutations involved chromatin remodeling, DNA damage, protein kinase A signaling, and FGF/IGF/PI3K signaling. Whole genome sequencing and FISH confirmed the MYB-NFIB translocation as the main structural variant in ACC. Evaluation of potential driver mutations KDM6A and PIK3CA reveal that specific, observed alterations impart functional consequences. Collectively, our data delineate the ACC mutational landscape and establish a molecular foundation for investigating new therapies for this disease.
SECONDARY ACCESSION(S): PRJNA197421PRJNA197420
REPOSITORIES: dbGaP
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Project description:Adenoid cystic carcinoma (ACC) is one of the most common malignancies that arise in the salivary glands, with an incidence of 4.5 per 1,000,000. It can also arise in glandular tissue closely related to salivary glands in the lacrimal gland, nasal passages and tracheobronchial tree, as well as in glands of the breast and vulva. At all of these sites, it is characterized by a distinctive histology of basaloid epithelial cells arranged in cribriform or tubular patterns, usually demonstrating abundant hyaline extracellular matrix secretion and some degree of myoepithelial differentiation. ACC is generally a slow-growing tumor characterized by a protracted clinical course, usually well over 5 years in duration, marked by regional recurrence, distant metastasis and/or spread along peripheral nerves. A recurrent chromosomal translocation, t(6;9)(q23;p21), has been identified in ACC, and recently it has been discovered that in a majority of ACC the MYB gene on chromosome 6 is fused to the 3’ terminus of the NFIB gene on chromosome 9, creating a fusion gene product resulting in increased MYB-related transcriptional activation. Recently it has been determined that most cell lines with attribution of ACC derivation are either contaminants of other cell lines or do not have the characteristic MYB-NFIB translocation. Also, there are no animal models of this histologically and genetically defined tumor type. To address the paucity of experimental and pre-clinical models systems of ACC, we have for several years been establishing xenograft tumor lines from clinical samples of ACC. We describe our experience with these models and their characterization here. Analysis of 12 xenografts of human adenoid cystic carcinoma (ACC) along with 10 samples of ACC directly from humans. Note, that 12 of these samples are paired primary ACC & xenograft ACC from the same individual (6 pairs in total).
2011-05-03 | E-GEOD-28996 | biostudies-arrayexpress
Project description:Adenoid cystic carcinoma (ACC) is one of the most common malignancies that arise in the salivary glands, with an incidence of 4.5 per 1,000,000. It can also arise in glandular tissue closely related to salivary glands in the lacrimal gland, nasal passages and tracheobronchial tree, as well as in glands of the breast and vulva. At all of these sites, it is characterized by a distinctive histology of basaloid epithelial cells arranged in cribriform or tubular patterns, usually demonstrating abundant hyaline extracellular matrix secretion and some degree of myoepithelial differentiation. ACC is generally a slow-growing tumor characterized by a protracted clinical course, usually well over 5 years in duration, marked by regional recurrence, distant metastasis and/or spread along peripheral nerves. A recurrent chromosomal translocation, t(6;9)(q23;p21), has been identified in ACC, and recently it has been discovered that in a majority of ACC the MYB gene on chromosome 6 is fused to the 3’ terminus of the NFIB gene on chromosome 9, creating a fusion gene product resulting in increased MYB-related transcriptional activation. Recently it has been determined that most cell lines with attribution of ACC derivation are either contaminants of other cell lines or do not have the characteristic MYB-NFIB translocation. Also, there are no animal models of this histologically and genetically defined tumor type. To address the paucity of experimental and pre-clinical models systems of ACC, we have for several years been establishing xenograft tumor lines from clinical samples of ACC. We describe our experience with these models and their characterization here.
2011-05-03 | GSE28996 | GEO
Project description: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.
2015-03-13 | GSE59702 | GEO
Project description: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.
2015-03-13 | GSE59701 | GEO
Project description: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.
2015-03-13 | GSE59700 | GEO
Project description:Mutations in PIK3CA, the gene encoding the p110α subunit of PI3K, induce transformation of mammary epithelial cells (MEC). Studies suggest the transforming action of mutant PIK3CA requires binding to activated receptor tyrosine kinases or adaptors. We examined in transgenic mice if ErbB3, a powerful activator of PI3K, is required for mutant PIK3CA-mediated MEC transformation. ErbB3 loss delayed PIK3CAH1047R-dependent mammary gland hyperplasia, but tumor latency, gene expression and markers of PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with other tyrosine phosphorylated adaptors, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Combined inhibition of ErbB RTKs and PI3K with lapatinib and the p110α inhibitor BYL719, respectively, reduced PIK3CAH1047R-dependent tumor growth and PI3K signaling more potently than the p110α inhibitor alone. In human breast cancer cells harboring PIK3CAH1047R, the combination with BYL719 and an ErbB3 inhibitor synergistically inhibited tumor growth and P-Akt. These data suggest that basal tumor growth and PI3K signaling do not depend on ErbB RTKs in PIK3CAH1047R-expressing tumors. However, upon inhibition of p110α, these receptors limit the action of PI3K inhibitors potentially explaining the more potent effect of the combination against PI3K-mutant cancers. reference x sample
2013-06-20 | E-GEOD-43037 | biostudies-arrayexpress
Project description:PI3K/AKT pathway plays one of pivotal roles in breast cancer development and maintenance. PIK3CA, coding PIK3 catalytic subunit, is the oncogene which shows the high frequency of gain-of-function mutations leading to the PI3K/AKT pathway activation in breast cancer. In particular in the ERα-positive breast tumors PIK3CA mutations have been observed in 30% to 40%. However, genes expressed in connection to the pathway activation in breast tumorigenesis remain largely unknown. To identify downstream relevant target genes (and signaling pathways) turned on by the aberrant PI3K/AKT signal in breast tumors, we analyzed gene expression by pangenomic oligonucleotide microarray in a series of 43 ERα-positive tumors with and without PIK3CA mutations. 43 ERα-positive breast tumors including 14 tumors with PIK3CA mutations and 29 tumors without PIK3CA mutattions were used as screening set for microarray.
2011-01-10 | E-GEOD-22035 | biostudies-arrayexpress
Project description:Mutations in PIK3CA, the gene encoding the p110α subunit of PI3K, induce transformation of mammary epithelial cells (MEC). Studies suggest the transforming action of mutant PIK3CA requires binding to activated receptor tyrosine kinases or adaptors. We examined in transgenic mice if ErbB3, a powerful activator of PI3K, is required for mutant PIK3CA-mediated MEC transformation. ErbB3 loss delayed PIK3CAH1047R-dependent mammary gland hyperplasia, but tumor latency, gene expression and markers of PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with other tyrosine phosphorylated adaptors, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Combined inhibition of ErbB RTKs and PI3K with lapatinib and the p110α inhibitor BYL719, respectively, reduced PIK3CAH1047R-dependent tumor growth and PI3K signaling more potently than the p110α inhibitor alone. In human breast cancer cells harboring PIK3CAH1047R, the combination with BYL719 and an ErbB3 inhibitor synergistically inhibited tumor growth and P-Akt. These data suggest that basal tumor growth and PI3K signaling do not depend on ErbB RTKs in PIK3CAH1047R-expressing tumors. However, upon inhibition of p110α, these receptors limit the action of PI3K inhibitors potentially explaining the more potent effect of the combination against PI3K-mutant cancers.
2013-06-20 | GSE43037 | GEO
Project description:Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy amongst head and neck tumors that is poorly understood on a molecular level. We sought to perform a comprehensive approach for novel oncogene candidate screening under the control of promoter methylation in order to learn more about the molecular basis of this unusual disease. We performed global demethylation of normal salivary gland cell strains using 5-aza-deoxycytidine (5-Aza dC) and trichostatin (TSA). Expression arrays were performed, and the profiles of treated and untreated cells compared. We then used expression microarray analysis of primary ACC and normal salivary gland samples to generate ACC-specific expression profiling. Next, we integrated the two profiles to identify a subset of genes for further validation of decreased methylation in the promoter region in ACC vs normals. Finally, only genes that showed decreased methylation in ACC compared to normal were further validated for mRNA, protein, and promoter methylation levels in a larger ACC cohort.
2013-10-01 | E-GEOD-25746 | biostudies-arrayexpress
Project description:PI3K/AKT pathway plays one of pivotal roles in breast cancer development and maintenance. PIK3CA, coding PIK3 catalytic subunit, is the oncogene which shows the high frequency of gain-of-function mutations leading to the PI3K/AKT pathway activation in breast cancer. In particular in the ERα-positive breast tumors PIK3CA mutations have been observed in 30% to 40%. However, genes expressed in connection to the pathway activation in breast tumorigenesis remain largely unknown. To identify downstream relevant target genes (and signaling pathways) turned on by the aberrant PI3K/AKT signal in breast tumors, we analyzed gene expression by pangenomic oligonucleotide microarray in a series of 43 ERα-positive tumors with and without PIK3CA mutations.
2011-01-10 | GSE22035 | GEO