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| Status |
Public on Dec 21, 2018 |
| Title |
Genomic, transcriptomic and epigenomic characterization of multifocal breast cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
Methylation profiling by array
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| Summary |
A significant proportion of breast cancer patients develop multiple synchronous unilateral breast tumors, also referred to as multifocal tumors, which represent a diagnostic and therapeutic challenge. Multifocality has been associated with a possible adverse patient outcome, propensity for axillary nodal involvement, and increased risk of local recurrence following breast conserving surgery when compared to unifocal tumors. Previous studies indicate that most lesions from multifocal tumors are concordant with regard to the currently used pathological parameters (histological subtype and grade, hormonal receptors and HER2 status). However, to our knowledge, no study has yet provided a detailed molecular analysis of multifocal breast cancer. Here, we aimed to better define the incidence of multifocal breast cancer using a systematic analysis of pathology reports of primary breast cancers and to compare different foci from 5 multifocal breast cancers in a global analysis using genomic, transcriptomic and epigenomic data. We demonstrate that multifocality is a frequent finding since it concerns 22% (945/4340) of breast cancer patients with primary ductal breast cancer. We find that different lesions from multifocal breast cancer can differ at the (epi)genomic and transcriptomic level even when the foci present similar histology, grading, hormonal and HER2 status despite having a common genetic background. Since the number of (epi)genetic alterations with potential clinical utility is rapidly growing due to increasing numbers of targeted therapies, these findings suggest that it might be necessary to interrogate the different lesions of multifocal breast cancers for adequate treatment management of these tumors.
The biological characterization of multifocal breast cancer here is focused on 5 cancers for which the foci did not differ in terms of histological grade, hormonal receptors and HER2 status. The characterization of multifocal tumors involved the identification of somatic rearrangements in 2 foci from each patient via low-coverage whole genome sequencing. Putative rearrangements were amplified by polymerase chain reaction (PCR) and capillary sequenced in tumor and matching blood-derived germline DNA to validate the somatic rearrangements. For all patients, the presence of a number of validated rearrangements was assessed in different paraffin blocks of tumor-adjacent histologically normal tissue by nested PCR. We also performed transcriptomic and epigenomic profiling in 4 and 5 patients respectively using the HG-U133 Plus 2.0 Chips and Infinium Methylation 450K arrays (RNA was not available for patient E).
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| Overall design |
To investigate the incidence of multifocality in primary breast cancer patients, we systematically queried pathological reports from patients diagnosed between 2000 and 2010 at the Institut Jules Bordet through the Belgian National Cancer Registry. Five patients with multifocal ductal breast cancer, for which a frozen sample of at least 2 lesions with similar ER, HER2 and histological grade was available, were studied. The cellular composition and the immuno-histochemistry staining of ER, PgR, HER2 and Ki67 were centrally reviewed by the same pathologist. All patients gave their written consent for this research project. The molecular characterization of the multifocal tumors involved the identification of somatic rearrangements, transcriptomic and epigenomic profiling in 2 foci from each patient, via low-coverage whole genome sequencing, HG-U133 Plus 2.0 Chips and Infinium Methylation 450K arrays respectively. Genomic rearrangements were validated using an orthogonal sequencing platform. The project has been approved by the ethics committee of the Institut Jules Bordet.
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| Contributor(s) |
Desmedt C, Nik-Zainal S, Fumagalli D, Rothé F, Majjaj S, Brown D, Dedeurwaerder S, Defrance M, Calonne E, Maetens M, Adnet P, Paesmans M, O'Meara S, Michiels S, Vincent D, Salgado R, Fuks F, Piccart M, Larsimont D, Stratton M, Campbell P, Sotiriou C |
| Citation missing |
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| Submission date |
Jul 18, 2012 |
| Last update date |
Mar 25, 2019 |
| Contact name |
David Brown |
| E-mail(s) |
david.brown@bordet.be
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| Phone |
+3225413743
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| Organization name |
Institut Jules Bordet
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| Lab |
J.-C. Heuson Breast Cancer Translational Research Laboratory
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| Street address |
Boulevard de Waterloo 127
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| City |
Brussels |
| ZIP/Postal code |
1000 |
| Country |
Belgium |
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| Platforms (2) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
| GPL13534 |
Illumina HumanMethylation450 BeadChip (HumanMethylation450_15017482) |
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| Samples (38)
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| Relations |
| BioProject |
PRJNA170906 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE39451_Matrix_signal.txt.gz |
46.9 Mb |
(ftp)(http) |
TXT |
| GSE39451_RAW.tar |
265.7 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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