Mutation signature of adenoid cystic carcinoma: evidence for transcriptional and epigenetic reprogramming

Frierson, Henry F.; Moskaluk, Christopher A.

doi:10.1172/jci69070

Cited by 40 publications

(37 citation statements)

References 20 publications

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“…Several studies including small cohorts of patients with salivary gland adenoid cystic carcinomas 54,57,58 suggested that TP53 inactivation 17,54,57 and/ or amplification of 8q24.12-q24.13 encompassing MYC 57 may play a role in high-grade transformation of these lesions. Neither breast adenoid cystic carcinomas analyzed here harbored TP53 mutations and/ or MYC amplification.…”

Section: Discussionmentioning

confidence: 99%

Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer

et al. 2016

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Adenoid cystic carcinoma of the breast is a rare histologic type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes. Reverse transcription PCR and fluorescence in situ hybridization were employed to investigate the presence of the MYB-NFIB translocation. The MYB-NFIB fusion gene was detected in both adenoid cystic carcinomas and their associated high-grade triple-negative breast cancer components. Whilst the distinct components of both cases displayed similar patterns of gene copy number alterations, massively parallel sequencing analysis revealed intra-tumor genetic heterogeneity. In case 1, progression from the trabecular adenoid cystic carcinoma to the high-grade triple-negative breast cancer was found to involve clonal shifts with enrichment of mutations affecting EP300, NOTCH1, ERBB2 and FGFR1 in the high-grade triple-negative breast cancer. In case 2, a clonal KMT2C mutation was present in the cribriform adenoid cystic carcinoma, solid adenoid cystic carcinoma and high-grade triple-negative breast cancer components, whereas a mutation affecting MYB was present only in the solid and high-grade triple-negative breast cancer areas and additional three mutations targeting STAG2, KDM6A and CDK12 were restricted to the high-grade triple-negative breast cancer. In conclusion, adenoid cystic carcinomas of the breast with high-grade transformation are underpinned by MYB-NFIB fusion gene, and, akin to other forms of cancer, may be constituted by a mosaic of cancer cell clones at diagnosis. The progression from adenoid cystic carcinoma to high-grade triple-negative breast cancer of no special type may involve the selection of neoplastic clones and/ or the acquisition of additional genetic alterations.

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Section: Discussionmentioning

confidence: 99%

Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer

et al. 2016

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“…In addition, 4–12% of ACCs harbor mutations that are predicted to activate or enhance FGFR signaling independently of MYB overexpression (16;19). A role for FGFR signaling in the pathogenesis of ACC is further supported by the observation that inhibitors of the receptor kinase can suppress the growth of primary ACC xenografts (23). …”

Section: Introductionmentioning

confidence: 98%

A Phase II Study of Dovitinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma

Dillon

Petroni

Horton

et al. 2017

Clinical Cancer Research

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Purpose Genetic and preclinical studies have implicated fibroblast growth factor receptor (FGFR) signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor FGFR activity, may be active in ACC. Methods In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate (ORR) and change in tumor growth rate (TGR). Progression-free survival (PFS), overall survival (OS), metabolic response, biomarker and QOL were secondary endpoints. Results Of thirty-four evaluable patients, two (6%) had a partial response and 22 (65%) had stable disease >4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on-treatment (p<0.001). Toxicity was moderate; 63% of patients developed grade 3–4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on 18FDG-PET scans was seen in 3/15 patients but did not correlate with RECIST response. MYB gene translocation was observed and significantly correlated with over-expression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib. Conclusion Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably to those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine if FGFR signaling is a valid therapeutic target in ACC.

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“…It has been suggested that whole-chromosome copy-number changes could represent early events. 36 We found six of eight cases showing gain of whole chromosomes, such as 8,19,6,7,16,18,20,21, and 22 ( Figure 1a and b) in both components. However, a number of cases showed whole chromosome changes only in the transformed components (acc1, acc2, and acc6), which seem to suggest a late event in tumor progression.…”

Section: Discussionmentioning

confidence: 93%

“…15,[17][18][19] Frierson and Moskaluk suggested that the neoplastic transformation may be driven by a limited number of changes in transcription regulatory genes, aggravated by changes in the chromatin structure. 20 Unfortunately, to date no studies have been done on transcriptional and epigenetic reprogramming in ACC-HGT.…”

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confidence: 99%

Analysis of MYB oncogene in transformed adenoid cystic carcinomas reveals distinct pathways of tumor progression

Costa

Altemani

García‐Inclán

et al. 2014

Laboratory Investigation

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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.

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Mutation signature of adenoid cystic carcinoma: evidence for transcriptional and epigenetic reprogramming

Cited by 40 publications

References 20 publications

Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer

Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer

A Phase II Study of Dovitinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma

Analysis of MYB oncogene in transformed adenoid cystic carcinomas reveals distinct pathways of tumor progression

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