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Breast cancer research: BCR 05/2010; 12 Suppl 1:O6. · 5.24 Impact Factor
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ABSTRACT: Breast cancer is a heterogeneous disease, encompassing multiple entities associated with distinct biological features and clinical behaviours. Microarray-based expression profiling analysis has been used to unravel the molecular underpinning of several characteristics of breast cancer, including its proclivity to disseminate to distant sites and the molecular basis of histological grade. Furthermore, a breast cancer molecular classification based on transcriptional analysis has been proposed. However, microarray studies have primarily analysed invasive ductal carcinomas of no special type. Histological special types of breast cancer, which account for up to 25% of all invasive breast cancers, have not been systematically studied. Despite the limited interest, in recent years it has become apparent that the histopathological characteristics of these cancers may be underpinned by distinct arrays of genetic changes, providing direct evidence for genotypic–phenotypic correlations between morphological patterns and molecular changes in breast cancer (eg t(12;15) in secretory carcinoma of the breast). Here we review the molecular characteristics of special types of breast cancer, with special emphasis on their microarray-based expression profiles and their impact on our understanding of breast cancer. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology 11/2008; 216(4):394 - 398. · 6.32 Impact Factor
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ABSTRACT: The ESR1 gene maps 6q25 and encodes for oestrogen receptor alpha, which has been shown to play a pivotal role in the development of breast and endometrial cancer. It has recently been reported that oestrogen receptor alpha expression may be driven in some cases by ESR1 gene amplification and that this phenomenon may be an early event in breast and endometrial carcinogenesis. Although copy number gains of 6q have been reported by several groups, their prevalence, association with oestrogen receptor alpha expression, and clinical implications have been a matter of controversy. Here we discuss the key issues regarding the methods employed in the identification of ESR1 amplification, and briefly review the current literature and recent controversies on the subject of ESR1 amplification in endometrial and breast cancers.
The Journal of Pathology 09/2008; 216(3):271-4. · 6.32 Impact Factor
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ABSTRACT: Breast cancer is a heterogeneous disease, encompassing multiple entities associated with distinct biological features and clinical behaviours. Microarray-based expression profiling analysis has been used to unravel the molecular underpinning of several characteristics of breast cancer, including its proclivity to disseminate to distant sites and the molecular basis of histological grade. Furthermore, a breast cancer molecular classification based on transcriptional analysis has been proposed. However, microarray studies have primarily analysed invasive ductal carcinomas of no special type. Histological special types of breast cancer, which account for up to 25% of all invasive breast cancers, have not been systematically studied. Despite the limited interest, in recent years it has become apparent that the histopathological characteristics of these cancers may be underpinned by distinct arrays of genetic changes, providing direct evidence for genotypic-phenotypic correlations between morphological patterns and molecular changes in breast cancer (eg t(12;15) in secretory carcinoma of the breast). Here we review the molecular characteristics of special types of breast cancer, with special emphasis on their microarray-based expression profiles and their impact on our understanding of breast cancer.
The Journal of Pathology 08/2008; 216(4):394-8. · 6.32 Impact Factor
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C Marchiò,
M Iravani,
R Natrajan,
M B Lambros,
K Savage,
N Tamber,
K Fenwick,
A Mackay,
R Senetta,
S Di Palma,
F C Schmitt,
G Bussolati,
L O Ellis,
A Ashworth,
A Sapino, J S Reis-Filho
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ABSTRACT: Pure invasive micropapillary carcinoma (MPC) is a special histological type that accounts for 0.7-3% of all breast cancers. MPC has a distinctive growth pattern and a more aggressive clinical behaviour than invasive ductal carcinomas of no special type (IDC-NSTs). To define the molecular characteristics of MPCs, we profiled a series of 12 MPCs and 24 grade and oestrogen receptor (ER)-matched IDC-NSTs using high-resolution microarray comparative genomic hybridization (aCGH). In addition, we generated a tissue microarray containing a series of 24 MPCs and performed immunohistochemical analysis with ER, PR, Ki-67, HER2, CK5/6, CK14, CK17, EGFR, topoisomerase-IIalpha, cyclin D1, caveolin-1, E-cadherin, and beta-catenin antibodies. In situ hybridization probes were employed to evaluate the prevalence of amplification of HER2, TOP2A, EGFR, CCND1, MYC, ESR1, and FGFR1 genes. aCGH analysis demonstrated that MPCs significantly differed from IDC-NSTs at the genomic level. Gains of 1q, 2q, 4p, 6p, 6q23.2-q27, 7p, 7q, 8p, 8q, 9p, 10p, 11q, 12p, 12q, 16p, 17p, 17q, 19p, 20p, 20q, and 21q, and losses of 1p, 2p, 6q11.1-q16.3, 6q21-q22.1, 9p, 11p, 15q, and 19q were more prevalent in MPCs. High-level gains/amplifications of 8p12-p11, 8q12, 8q13, 8q21, 8q23, 8q24, 17q21, 17q23, and 20q13 were significantly associated with MPCs. A comparison between 24 MPCs and a series of 48 grade and ER-matched IDC-NSTs revealed that high cyclin D1 expression, high proliferation rates, and MYC (8q24) amplification were significantly associated with MPCs. Our results demonstrate that MPCs have distinct histological features and molecular genetic profiles supporting the contention that they constitute a distinct pathological entity.
The Journal of Pathology 08/2008; 215(4):398-410. · 6.32 Impact Factor
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P T Simpson, J S Reis-Filho,
M B K Lambros,
C Jones,
D Steele,
A Mackay,
M Iravani,
K Fenwick,
T Dexter,
A Jones,
L Reid,
L Da Silva,
S J Shin,
D Hardisson,
A Ashworth,
F C Schmitt,
J Palacios,
S R Lakhani
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ABSTRACT: Pleomorphic lobular carcinomas (PLC) of the breast display histological features associated with classic invasive lobular carcinoma (ILC), yet they also exhibit more conspicuous nuclear atypia and pleomorphism, and an aggressive clinical behaviour. From a breast cancer progression perspective, it is unclear whether PLC is a variant of ILC or is a high-grade invasive ductal carcinoma (IDC) that has lost E-cadherin. The molecular features of 26 PLC were studied using immunohistochemistry [oestrogen receptor (ER), progesterone receptor (PR), HER2, p53 and E-cadherin], 0.9 Mb resolution, microarray-based comparative genomic hybridization (aCGH), fluorescent (FISH) and chromogenic (CISH) in situ hybridization and loss of heterozygosity. Comparative analysis was performed with aCGH data from PLC with classic ILC (16 cases) and high grade IDC (35 cases). PLCs were frequently ER- and PR-positive, E-cadherin-negative and occasionally HER2- and p53-positive. Recurrent copy number changes identified by aCGH included gains on 1q, 8q, 11q, 12q, 16p and 17q and losses on 8p, 11q, 13q, 16q and Xq. Highly recurrent 1q+ (100% of cases), 16p+ (93%), 11q- (53%) and 16q- (93%) and evidence of the der(1;16)/der(16)t(1;16) rearrangement, as detected by FISH, suggested that PLC had a 'lobular genotype'. Focal amplifications were evident at 8p12-p11, 8q24, 11q13.1-q14.1, 12q14, 17q12 and 20q13. Loss of BRCA2 was detected in 40% of PLC by LOH. Comparative analysis of aCGH data suggested the molecular features of PLC (ER/PR-positive, E-cadherin-negative, 1q+, 11q(-), 16p+ and 16q(-)) were more closely related to those of ILC than IDC, implicating an overlapping developmental pathway for these lobular tumour types. Molecular alterations found in PLC that are more typical of high-grade IDC than ILC (p53 and HER2 positivity, 8q+, 17q24-q25+, 13q(-) and amplification of 8q24, 12q14, 17q12 and 20q13) are likely to drive the high-grade and more aggressive biology of PLC.
The Journal of Pathology 08/2008; 215(3):231-44. · 6.32 Impact Factor
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C Marchiò,
R Natrajan,
K K Shiu,
M B K Lambros,
S M Rodriguez-Pinilla,
D S P Tan,
C J Lord,
D Hungermann,
K Fenwick,
N Tamber,
A Mackay,
J Palacios,
A Sapino,
H Buerger,
A Ashworth, J S Reis-Filho
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ABSTRACT: Expression profiling studies have suggested that HER2-amplified breast cancers constitute a heterogeneous group that may be subdivided according to their ER status: HER2-amplified ER-positive breast carcinomas that fall into the luminal B cluster; and HER2-amplified ER-negative cancers which form a distinct molecular subgroup, known as the erbB2 or HER2 subgroup. ER-negative breast cancer differs significantly from ER-positive disease in the pattern, type, and complexity of genetic aberrations. Here we have compared the genomic profiles of ER-positive and ER-negative HER2-amplified cancers using tiling path microarray-based comparative genomic hybridization (aCGH). Validation of the differentially amplified regions was performed in an independent series of 70 HER2-amplified breast cancers. Although HER2-amplified cancers had remarkably complex patterns of molecular genetic aberrations, ER-positive and ER-negative HER2-amplified breast carcinomas shared most molecular genetic features as defined by aCGH. Genome-wide Fisher's exact test analysis revealed that less than 1.5% of the genome was significantly differentially gained or lost in ER-positive versus ER-negative HER2-amplified cancers. However, two regions of amplification were significantly associated with ER-positive carcinomas, one of which mapped to 17q21.2 and encompassed GJC1, IGFBP4, TNS4, and TOP2A. Chromogenic in situ hybridization analysis of an independent validation series confirmed the association between ER status and TOP2A amplification. In conclusion, although hormone receptor status does not determine the overall genetic profile of HER2-amplified breast cancers, specific genetic aberrations may be characteristic of subgroups of HER2 breast cancers.
The Journal of Pathology 07/2008; 216(4):399-407. · 6.32 Impact Factor
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C Marchiò,
M Iravani,
R Natrajan,
MB Lambros,
K Savage,
N Tamber,
K Fenwick,
A Mackay,
R Senetta,
S Di Palma,
FC Schmitt,
G Bussolati,
IO Ellis,
A Ashworth,
A Sapino, JS Reis-Filho
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[hide abstract]
ABSTRACT: Pure invasive micropapillary carcinoma (MPC) is a special histological type that accounts for 0.7–3% of all breast cancers. MPC has a distinctive growth pattern and a more aggressive clinical behaviour than invasive ductal carcinomas of no special type (IDC-NSTs). To define the molecular characteristics of MPCs, we profiled a series of 12 MPCs and 24 grade and oestrogen receptor (ER)-matched IDC-NSTs using high-resolution microarray comparative genomic hybridization (aCGH). In addition, we generated a tissue microarray containing a series of 24 MPCs and performed immunohistochemical analysis with ER, PR, Ki-67, HER2, CK5/6, CK14, CK17, EGFR, topoisomerase-IIα, cyclin D1, caveolin-1, E-cadherin, and β-catenin antibodies. In situ hybridization probes were employed to evaluate the prevalence of amplification of HER2, TOP2A, EGFR, CCND1, MYC, ESR1, and FGFR1 genes. aCGH analysis demonstrated that MPCs significantly differed from IDC-NSTs at the genomic level. Gains of 1q, 2q, 4p, 6p, 6q23.2–q27, 7p, 7q, 8p, 8q, 9p, 10p, 11q, 12p, 12q, 16p, 17p, 17q, 19p, 20p, 20q, and 21q, and losses of 1p, 2p, 6q11.1–q16.3, 6q21–q22.1, 9p, 11p, 15q, and 19q were more prevalent in MPCs. High-level gains/amplifications of 8p12–p11, 8q12, 8q13, 8q21, 8q23, 8q24, 17q21, 17q23, and 20q13 were significantly associated with MPCs. A comparison between 24 MPCs and a series of 48 grade and ER-matched IDC-NSTs revealed that high cyclin D1 expression, high proliferation rates, and MYC (8q24) amplification were significantly associated with MPCs. Our results demonstrate that MPCs have distinct histological features and molecular genetic profiles supporting the contention that they constitute a distinct pathological entity. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology 04/2008; 215(4):398 - 410. · 6.32 Impact Factor
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R Natrajan,
RD Williams,
SN Hing,
A Mackay, JS Reis-Filho,
K Fenwick,
M Iravani,
H Valgeirsson,
A Grigoriadis,
CF Langford,
O Dovey,
SG Gregory,
BL Weber,
A Ashworth,
PE Grundy,
K Pritchard-Jones,
C Jones
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ABSTRACT: Despite the excellent survival of Wilms tumour patients treated with multimodality therapy, approximately 15% will suffer from tumour relapse, where response rates are markedly reduced. We have carried out microarray-based comparative genomic hybridisation on a series of 76 Wilms tumour samples, enriched for cases which recurred, to identify changes in DNA copy number associated with clinical outcome. Using 1Mb-spaced genome-wide BAC arrays, the most significantly different genomic changes between favourable histology tumours that did (n = 37), and did not (n = 39), subsequently relapse were gains on 1q, and novel deletions at 12q24 and 18q21. Further relapse-associated loci included losses at 1q32.1, 2q36.3-2q37.1, and gain at 13q31. 1q gains correlated strongly with loss of 1p and/or 16q. In 3 of 11 cases with concurrent 1p−/1q+, a breakpoint was identified at 1p13. Multiple low-level sub-megabase gains along the length of 1q were identified using chromosome 1 tiling-path arrays. One such recurrent region at 1q22-q23.1 included candidate genes RAB25, NES, CRABP2, HDGF and NTRK1, which were screened for mRNA expression using quantitative RT-PCR. These data provide a high-resolution catalogue of genomic copy number changes in relapsing favourable histology Wilms tumours. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology 07/2006; 210(1):49 - 58. · 6.32 Impact Factor
