High-Throughput Copy Number Analysis of 17q23 in 3520 Tissue Specimens by Fluorescence in Situ Hybridization to Tissue Microarrays

Andersen, Claus Lindbjerg; Monni, Outi; Wagner, Urs; Kononen, Juha; Bärlund, Maarit; Bucher, Christoph; Haas, Philippe; Nocito, Antonio; Bissig, Heidi; Sauter, Guido; Kallioniemi, Anne

doi:10.1016/s0002-9440(10)64158-2

Cited by 62 publications

(44 citation statements)

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“…Our FISH analyses on TMA showed an overall success rate of 73% with most of the failures due to missing or unrepresentative samples or poor hybridization quality. This result is in good concordance with previous TMA studies, 23,24 even though our samples were exclusively breast tumors that are difficult to evaluate due to the melting of the fat during the hybridization procedure. 17 In addition, many of the samples were derived from very old archival tissue with variable fixation that is also known to hamper the FISH analysis.…”

Section: Discussionsupporting

confidence: 92%

Frequent amplification and overexpression of CCND1 in male breast cancer

Bärlund

Kuukasjärvi

Syrjäkoski

et al. 2004

Intl Journal of Cancer

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Genetic events underlying the pathogenesis of breast cancer have been studied extensively and several clinically significant markers have been identified. For example, amplification and overexpression of the ERBB2 oncogene is associated with poor prognosis in breast cancer and ERBB2 serves as a target for antibody-based therapy. Current knowledge on the pathogenesis of male breast cancer (MBC) is limited. The purpose of our study was to investigate the potential relevance of a series of genes known to be amplified in female breast cancer (FBC) in a the development and pathogenesis of MBC. To this end, we applied fluorescence in situ hybridization and immunohistochemistry to the analysis of 128 breast tumors from males. Amplification of ERBB2, MYC, PPM1D and ZNF217 was detected rarely (1-2% of tumors) indicating a considerably lower amplification frequency than in FBC. CCND1 amplification was observed in 12% of cases, being in good concordance with findings from FBC. In addition, CCND1 overexpression was detected in 63% of tumors and was associated with ER positivity (p < 0.0001). Our results indicate distinct differences in the genetic basis of MBC and FBC and suggest that marked differences exist in the pathogenesis of these diseases. The lack of ERBB2 involvement was especially unexpected and implies that ERBB2-targeted therapies are unlikely to be beneficial in MBC. Furthermore, the high frequency of hormone receptor positivity and the association between ER positivity and CCND1 overexpression supports the notion that hormonal regulation is likely to be essential for the development of MBC. © 2004 Wiley-Liss, Inc. Key words: male breast cancer; gene amplification; CCND1; tissue microarrayMale breast cancer (MBC) is a rare disease, representing Ͻ1% of all breast cancers and Ͻ1% of all cancers in men. 1,2 All histological types of breast cancer have been identified in men, with infiltrating ductal carcinoma representing about 80% of cases. Similarly to FBC, hormonal, genetic, and environmental factors are involved in the etiology of MBC. 3 Conditions associated with increased estrogen or decreased androgen levels, such as Klinefelter syndrome and testicular disorders, predispose to MBC. 1 Particularly, the Klinefelter syndrome, characterized by 47,XXY karyotype, is associated with a 50-fold increase in breast cancer risk. 4 The genetic factor most clearly associated with MBC is BRCA2 germline mutation and its frequency in men with breast cancer varies considerably (4 -40%) depending on the population investigated. 3,5 Germline BRCA1 mutations are also found in male breast cancer patients. 5 The possible role and clinical utility of oncogene alterations have been widely investigated in FBC. The most extensively studied is the ERBB2 oncogene that belongs to the epidermal growth factor receptor family. ERBB2 is amplified and overexpressed in 10 -34% of FBC and has been shown to have prognostic and predictive value. 6 Targeted therapy against ERBB2 is currently undergoing clinical trials and shows potential benefit...

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Section: Discussionsupporting

confidence: 92%

Frequent amplification and overexpression of CCND1 in male breast cancer

Bärlund

Kuukasjärvi

Syrjäkoski

et al. 2004

Intl Journal of Cancer

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“…Other genes from the microarray and located on 17q but further apart from ERBB2 were not found in the signature except for ITGA2B/CD41, ITGB3/CD61, PECAM1/CD31 and MAP2K6. Overexpression of these genes may not be due to increased ERBB2 gene copy number per se, but may be triggered by intense ERBB2 signalling; it might also be due to the presence of other telomeric, 17q-associated amplicons (Andersen et al, 2002;Hyman et al, 2002). ITGA2, whose gene is not on 17q, was also overexpressed in ERBB2 þ tumours.…”

Section: Content Of the Erbb2 Gesmentioning

confidence: 99%

Identification and validation of an ERBB2 gene expression signature in breast cancers

Borie²,

et al. 2004

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“…After that, numerous studies have reported increased copy numbers of 17q23 in tumours of brain, lung, ovary, pancreas, bladder, testis, and liver (Muleris et al, 1994;Ried et al, 1994;Korn et al, 1996;SolinasToldo et al, 1996;Brinkschmidt et al, 1997;Marchio et al, 1997;Richter et al, 1997;Schwendel et al, 1997;Sonoda et al, 1997;Weber et al, 1997;Vandesompele et al, 1998;Clark et al, 2002;Willis et al, 2003). We recently performed an extensive survey on the distribution and frequency of the 17q23 copy number increases in 3520 tumours representing 166 different tumour types (Andersen et al, 2002). The results confirmed previous data and indicated that increased 17q23 copy number occurs most commonly in brain, lung, breast, ovarian, urinary bladder, and soft tissue tumours, although high-level amplification was observed exclusively in breast cancer.…”

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confidence: 99%

High-level amplification at 17q23 leads to coordinated overexpression of multiple adjacent genes in breast cancer

et al. 2007

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Increased copy numbers of 17q23 chromosomal region have been shown to occur in different tumour types and to be associated with tumour progression and with poor prognosis. Several genes have earlier been proposed as potential oncogenes at this region largely on the grounds of cell lines studies. In this study, we performed a systematic gene expression survey on 26 primary breast tumours with known 17q23 amplification status by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The 17q23 amplicon is restricted to an B5 MB region in breast cancer and contains 29 known genes. Our survey revealed a statistically significant (Po0.01) difference between the high level and no amplification groups in a set of eleven genes whereas no difference between the moderate and the non-amplified tumour groups were observed. Interestingly, these 11 genes were located adjacent to one another within a 1.56 Mb core region in which all except one of the genes were overexpressed. These data suggest that only high-level amplification at the 17q23 amplicon core leads to elevated gene expression in breast cancer. Moreover, our results highlight the fact that 17q23 amplicon carries multiple candidate genes and that this may be a more common event in gene amplification than previously thought.

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High-Throughput Copy Number Analysis of 17q23 in 3520 Tissue Specimens by Fluorescence in Situ Hybridization to Tissue Microarrays

Cited by 62 publications

References 24 publications

Frequent amplification and overexpression of CCND1 in male breast cancer

Frequent amplification and overexpression of CCND1 in male breast cancer

Identification and validation of an ERBB2 gene expression signature in breast cancers

High-level amplification at 17q23 leads to coordinated overexpression of multiple adjacent genes in breast cancer

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