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A non-BRCA1/2 hereditary breast cancer sub-group defined by aCGH profiling of genetically related patients

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Abstract

Germline mutations in BRCA1 and BRCA2 explain approximately 25% of all familial breast cancers. Despite intense efforts to find additional high-risk breast cancer genes (BRCAx) using linkage analysis, none have been reported thus far. Here we explore the hypothesis that BRCAx breast tumors from genetically related patients share a somatic genetic etiology that might be revealed by array comparative genomic hybridization (aCGH) profiling. As BRCA1 and BRCA2 tumors can be identified on the basis of specific genomic profiles, the same may be true for a subset of BRCAx families. Analyses used aCGH to compare 58 non-BRCA1/2 familial breast tumors (designated BRCAx) to sporadic (non-familiar) controls, BRCA1 and BRCA2 tumors. The selection criteria for BRCAx families included at least three cases of breast cancer diagnosed before the age of 60 in the family, and the absence of ovarian or male breast cancer. Hierarchical cluster analysis was performed to determine sub-groups within the BRCAx tumor class and family heterogeneity. Analysis of aCGH profiles of BRCAx tumors indicated that they constitute a heterogeneous class, but are distinct from both sporadic and BRCA1/2 tumors. The BRCAx class could be divided into sub-groups. One subgroup was characterized by a gain of chromosome 22. Tumors from family members were classified within the same sub-group in agreement with the hypothesis that tumors from the same family would harbor a similar genetic background. This approach provides a method to target a sub-group of BRCAx families for further linkage analysis studies.

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Acknowledgments

This study was supported by the Dutch Cancer Society/Koningin Wilhelmina Fonds, Grant NKB_NKI2007-3749.

Conflict of interest

The authors declare to have no competing interests.

Author information

Author notes

  1. E. H. van Beers

    Present address: Skyline-Diagnostics Research, Dr Molewaterplein 50, Suite Ee 1971, 3015 GE, Rotterdam, The Netherlands

  2. S. A. Joosse

    Present address: Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

Authors and Affiliations

  1. Department of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    M. A. Didraga, E. H. van Beers, S. A. Joosse, K. I. M. Brandwijk & P. M. Nederlof

  2. Department of Clinical Genetics, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands

    R. A. Oldenburg

  3. Department of Bioinformatics and Statistics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    L. F. A. Wessels

  4. Family Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    F. B. L. Hogervorst & S. Verhoef

  5. Department of Pathology and Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    M. J. Ligtenberg & N. Hoogerbrugge

  6. Department of Human Genetics and Department of Pathology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands

    P. Devilee

  7. Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    P. M. Nederlof

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  1. M. A. Didraga
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Corresponding author

Correspondence to P. M. Nederlof.

Additional information

MA Didraga and EH van Beers contributed equally to this work.

Electronic supplementary material

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10549_2011_1357_MOESM1_ESM.pdf

Supplementary Table 1 Chromosomal locations of significantly differential frequencies of gains and losses in pair wise comparisons between BRCAx and sporadic control, BRCA1- and BRCA2-mutated breast tumors, respectively (PDF 178 kb)

10549_2011_1357_MOESM2_ESM.pdf

Supplementary Table 2 Frequency of BAC clones per chromosome contributing to the 22 gain/22 loss classifier (PDF 129 kb)

10549_2011_1357_MOESM3_ESM.pdf

Supplementary Fig. 1 Heatmap diagrams (derived from log2 ratios) per chromosome comparing BRCAx tumors with BRCA1, BRCA2, and sporadic control tumors. Chromosomes 8, 17, 21, and 22 are presented in Fig. 2. Samples are sorted vertically. This vertical sorting is performed individually per panel (class), based on sample-to-sample complete Pearson correlation clustering of DNA copy number state (CGH level). Horizontal axes are not plotted to genomic scale but jump from BAC to BAC clone at the library density of approximately 1 MB resolution. Color scales were set to saturate at -1 and 1 for relative DNA copy numbers (red–black-green). Gains are represented in green and losses in red (PDF 621 kb)

10549_2011_1357_MOESM4_ESM.pdf

Supplementary Fig. 2 Test probability scores for the training sets of the ‘22 gain’ (blue) and ‘22 loss’ (pink) associated tumor samples (PDF 130 kb)

10549_2011_1357_MOESM5_ESM.pdf

Supplementary Fig. 3 Classification results for all 58 BRCAx tumors. Classification is made based on probability scores of the training sets from Supplementary Fig 2. Samples predicted as 22 gain-like are plotted in blue and the ones predicted as 22 loss-like are plotted in pink (PDF 122 kb)

10549_2011_1357_MOESM6_ESM.pdf

Supplementary Fig. 4 Classification results for all 49 sporadic control tumors. Classification is made based on probability scores of the training sets from Supplementary Fig. 2. Samples predicted as 22 gain-like are plotted in blue and the ones predicted as 22 loss-like are plotted in pink (PDF 121 kb)

10549_2011_1357_MOESM7_ESM.pdf

Supplementary Fig. 5 Heatmap diagram representation of hierarchical cluster analysis (complete Pearson correlation) for the BRCAx tumors from cluster 1, 2 and 5 as defined in Fig. 5. In total 207 BACs were included in the cluster analysis selected by PAM analysis of cluster 1 and 2 compared to cluster 5. Gains are represented in green and losses in red. The BAC names and chromosome numbers are indicated on the right, the sample number and cluster number above. (PDF 224 kb)

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Didraga, M.A., van Beers, E.H., Joosse, S.A. et al. A non-BRCA1/2 hereditary breast cancer sub-group defined by aCGH profiling of genetically related patients. Breast Cancer Res Treat 130, 425–436 (2011). https://doi.org/10.1007/s10549-011-1357-x

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