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Identification of copy number alterations associated with the progression of DCIS to invasive ductal carcinoma

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Abstract

Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive ductal carcinoma (IDC). Annotation of the genetic differences between the two lesions may assist in the identification of genes that promote the invasive phenotype. Synchronous DCIS and IDC cells were microdissected from FFPE tissue and analysed by molecular inversion probe (MIP) copy number arrays. Matched IDC and DCIS showed highly similar copy number profiles (average of 83% of the genome shared) indicating a common clonal origin although there is evidence that the DCIS continues to evolve in parallel with the co-existing IDC. Four chromosomal regions of loss (3q, 6q, 8p and 11q) and four regions of gain (5q, 16p, 19q and 20) were recurrently affected in IDC but not in DCIS. CCND1 and MYC showed increased amplitude of gain in IDC. One region of loss (17p11.2) was specific to DCIS. IDC-specific regions include genes with previous links to breast cancer progression and potential therapeutic targets such as AXL, SPHK1 and PLAUR.

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Acknowledgments

The authors would like to dedicate this publication to the memory of Clint Johnson, who carried out many of the experiments as part of his PhD candidature. He was a fine scholar, talented scientist-in-training, and is sadly missed by his colleagues. His PhD candidature was supported by an Australian Postgraduate Award. This study was also supported by the Victorian Breast Cancer Research Consortium and the Australian National Health and Medical Research Council (NHMRC, No. 509050).

Conflicts of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. VBCRC Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett St, East Melbourne, Victoria, VIC, 8006, Australia

    Clint E. Johnson, Kylie L. Gorringe, Ella R. Thompson, Samantha E. Boyle & Ian G. Campbell

  2. Department of Pathology, University of Melbourne, Melbourne, VIC, Australia

    Clint E. Johnson, Kylie L. Gorringe & Ian G. Campbell

  3. Department of Anatomical Pathology, St Vincent’s Hospital, Fitzroy, VIC, Australia

    Ken Opeskin & Prue Hill

  4. Affymetrix Inc., Santa Clara, CA, USA

    Yuker Wang

  5. The Breast Service, Suite 12, The Royal Women’s Hospital, 3052, Parkville, Australia

    G. Bruce Mann

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  1. Clint E. Johnson
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  2. Kylie L. Gorringe
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  3. Ella R. Thompson
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  4. Ken Opeskin
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  5. Samantha E. Boyle
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  6. Yuker Wang
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  7. Prue Hill
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  8. G. Bruce Mann
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  9. Ian G. Campbell
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Corresponding authors

Correspondence to G. Bruce Mann or Ian G. Campbell.

Additional information

Clint E. Johnson, Kylie L. Gorringe and Ella R. Thompson contributed equally to this study.

G. Bruce Mann and Ian G. Campbell contributed equally to this study.

Clint E. Johnson—Deceased.

Electronic supplementary material

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Supplementary Table 1 List of samples with clinical characteristics (XLS 27 kb)

Supplementary Table 2 Peak regions of CNA in DCIS (XLS 44 kb)

Supplementary Table 3 DCIS and IDC-specific regions (XLS 36 kb)

10549_2011_1835_MOESM4_ESM.pdf

Supplementary Fig. 1 Examples of regions where the IDC showed increased amplitude of gain compared to the DCIS, which refined the minimal region of IDC-specific change for the chromosome Supplementary Fig. 2 Frequency plots for chromosomes 11 and 8 showing the combination of IDC-specific gain with increased amplitude gain in the IDC to define new regions on each chromosome that identified known oncogenes. Also shown are copy number traces for 3 cases where we had obtained parallel Agilent 180K aCGH data (y-axis = log2 CN from -1 to 1, line is average of 10 probes for cases 780 and 650 and 20 probes for case 695), in each case confirming the increase in CN observed by MIP array (y-axis = total CN, line is average of 20 probes). DCIS – red, IDC – blue. Supplementary Fig. 3 Top: frequency plot of chr 17 DCIS-specific losses. Middle: heatmap of gains (red) and losses (blue) of 5 samples with DCIS-specific deletions (pink box, minimal overlap). Lower: “B” allele plots i.e. SNP alleles with the minimum intensity. DCIS (red) and IDC (green). Dashed line, LOH threshold. The first four cases show DCIS LOH only; case 416 has LOH of both, but IDC shows copy number neutral LOH. (PDF 2479 kb)

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Johnson, C.E., Gorringe, K.L., Thompson, E.R. et al. Identification of copy number alterations associated with the progression of DCIS to invasive ductal carcinoma. Breast Cancer Res Treat 133, 889–898 (2012). https://doi.org/10.1007/s10549-011-1835-1

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