Mapping of candidate tumor suppressor genes on chromosome 12 in adenoid cystic carcinoma

Rutherford, Susan; Frierson, Henry F.; Moskaluk, Christopher A.

doi:10.1038/labinvest.3700314

Cited by 30 publications

(27 citation statements)

References 31 publications

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“…7,8 Yet, the resolution of these techniques was limited, and loss-of-heterozygoty (LOH) studies have subsequently been performed to map deletions at 6q and 12q. 9,10 Consistent with previous cytogenomic analyses, a recent study using concurrent LOH and copy number analysis by SNP genotyping arrays has concluded that ACCs are characterized by limited number of chromosomal aberrations with the most frequent area of deletion present on 9p. 11 Array CGH has been developed to increase the spatial resolution for the detection of chromosomal copy number alterations (CNAs).…”

supporting

confidence: 60%

“…Notably, we report MCRs of deletions on 6q and on 12q, which overlap with previously identified regions of common allelic losses that were mapped by LOH studies, an observation that further supports the validity of our methodology. 9,10 Using oligonucleotide CGH array, at least five probes are required for a reliable call for loss or gain. 14,15 In this study, we made a definite call only using at least 10 probes.…”

Section: Discussionmentioning

confidence: 99%

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High-resolution array comparative genomic hybridization analysis of human bronchial and salivary adenoid cystic carcinoma

Bernheim

Toujani

Saulnier

et al. 2008

Laboratory Investigation

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Adenoid cystic carcinoma (ACC) is a rare but distinctive tumor. Oligonucleotide array comparative genomic hybridization has been applied for cataloging genomic copy number alterations (CNAs) in 17 frozen salivary or bronchial tumors. Only four whole chromosome CNAs were found, and most cases had 2-4 segmental CNAs. No high level amplification was observed. There were recurrent gains at 7p15.2, 17q21-25, and 22q11-13, and recurrent losses at 1p35, 6q22-25, 8q12-13, 9p21, 12q12-13, and 17p11-13. The minimal region of gain at 7p15.2 contained the HOXA cluster. The minimal common regions of deletions contained the CDKN2A/CDKN2B, TP53, and LIMA1 tumor suppressor genes. The recurrent deletion at 8q12.3-13.1 contained no straightforward tumor suppressor gene, but the MIRN124A2 microRNA gene, whose product regulates MMP2 and CDK6. Among unique CNAs, gains harbored CCND1, KIT/PDGFRA/KDR, MDM2, and JAK2. The CNAs involving CCND1, MDM2, KIT, CDKN2A/2B, and TP53 were validated by FISH and/or multiplex ligation-dependent probe amplification. Although most tumors overexpressed cyclin D1 compared with surrounding glands, the only case to overexpress MDM2 had the corresponding CNA. In conclusion, our report suggests that ACC is characterized by a relatively low level of structural complexity. Array CGH and immunohistochemical data implicate MDM2 as the oncogene targeted at 12q15. The gain at 4q12 warrants further exploration as it contains a cluster of receptor kinase genes (KIT/PDGFRA/KDR), whose products can be responsive to specific therapies.

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supporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

High-resolution array comparative genomic hybridization analysis of human bronchial and salivary adenoid cystic carcinoma

Bernheim

Toujani

Saulnier

et al. 2008

Laboratory Investigation

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“…The combined genetic and genomic efforts fail to identify putative tumor suppressor gene(s) from 12q12-q13. However, downregulation of several genes from this region has been reported (17). In contrast to chromosomal losses, gains were infrequent.…”

Section: Discussionmentioning

confidence: 93%

Deletion of 1p32-p36 Is the Most Frequent Genetic Change and Poor Prognostic Marker in Adenoid Cystic Carcinoma of the Salivary Glands

Rao

Roberts

Zhao

et al. 2008

Clinical Cancer Research

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Purpose: Adenoid cystic carcinoma (ACC) is a relatively uncommon salivary gland malignancy known for its protean phenotypic features and pernicious clinical behavior. Currently, no effective therapy is available for patients with advanced nonresectable, recurrent, and/or metastatic disease. The purpose of this study is to identify prognostic factors other than tumor stage that can be used to predict the outcome of the patients with ACC. Experimental Design: We used comparative genomic hybridization (CGH) to identify copy number aberrations in 53 primaryACCs. Array CGH and fluorescence in situ hybridization analysis was used to validate CGH results on selected cases.We correlated these copy number aberrations with clinicopathologic factors using Pearson's m 2 or by the two-tailed Fisher exact test. The disease-specific survival and disease-free intervals were generated by the Kaplan-Meier product limit method. Results: Chromosomal losses (n = 134) were more frequent than gains (n = 74). The most frequent genetic change was the loss of 1p32-p36 in 44% of the cases followed by 6q23-q27, and 12q12-q14. The most frequently gained chromosomal regions were 8 and 18. Of the chromosomal aberrations, loss of 1p32-p36 was the only abnormality significantly associated with patient's outcome. Conclusions: This study, for the first time, identifies loss of 1p32-p36 as a significant aberration in ACC. Molecular characterization of 1p32-36 region using the available genomic technologies may lead to the identification of new genes critical to the development of novel therapeutic targets for this disease copy number aberration.Adenoid cystic carcinoma (ACC) is an uncommon salivary gland malignancy characterized by heterogeneous phenotypic features and persistently progressive biological behavior (1 -6). Histopathologically, ACC manifests three histologic patterns, including the solid, cribriform, and tubular forms, in variable combination and dominance (7). The solid pattern is typically associated with aggressive clinical course. ACCs are known for their proclivity to perineural invasion, which significantly contribute to the intractable nature of this disease (1,8,9). Surgical resection with and without postoperative radiotherapy remains the primary treatment modality for the management of this disease. However, patients with advanced local presentation, recurrence, and/or distant metastasis have limited therapeutic options (8, 9). Therefore, elucidation of molecular events that predict the malignant risk is critical in understanding the biology, clinical behavior, and management of ACC.Previous conventional cytogenetic studies of ACC, although limited in numbers and scope, have revealed translocations involving chromosome 6q with multiple chromosomal partners (10, 11). Subsequent analysis, using comparative genomic hybridization (CGH) of these tumors have reported recurrent chromosomal gains of 16p, 17q, 19, and 22q13 and losses at 6q23-qter, 12q12-q13, 13q21-q22, and 19 (12, 13). Recently, an array CGH study of 18 p...

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“…The best characterized means of expression loss is promoter hypermethylation, which occurs in a subset of tumors and cell lines and the frequency of which seems to be dependent on the tissue of origin (4,5,(12)(13)(14)(15)(16)(17)(18)(19)(20). Further support that CHFR may mediate tumorigenesis is that its chromosomal location, 12q24, is a site for allelic imbalance and chromosome rearrangements in several types of cancer (21)(22)(23)(24)(25). In addition, Yu et al (11) published recently their description of a Chfr knockout mouse.…”

Section: Introductionmentioning

confidence: 94%

Altered Expression of the Early Mitotic Checkpoint Protein, CHFR, in Breast Cancers: Implications for Tumor Suppression

Privette¹,

González²,

Ding

et al. 2007

Cancer Research

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Mapping of candidate tumor suppressor genes on chromosome 12 in adenoid cystic carcinoma

Cited by 30 publications

References 31 publications

High-resolution array comparative genomic hybridization analysis of human bronchial and salivary adenoid cystic carcinoma

High-resolution array comparative genomic hybridization analysis of human bronchial and salivary adenoid cystic carcinoma

Deletion of 1p32-p36 Is the Most Frequent Genetic Change and Poor Prognostic Marker in Adenoid Cystic Carcinoma of the Salivary Glands

Altered Expression of the Early Mitotic Checkpoint Protein, CHFR, in Breast Cancers: Implications for Tumor Suppression

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