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Human Cancer Biology

Ductal Carcinoma In situ and the Emergence of Diversity during Breast Cancer Evolution

D. Craig Allred, Yun Wu, Sufeng Mao, Iris D. Nagtegaal, Sangjun Lee, Charles M. Perou, Syed K. Mohsin, Peter O'Connell, Anna Tsimelzon and Dan Medina
D. Craig Allred
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Yun Wu
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Sufeng Mao
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Iris D. Nagtegaal
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Sangjun Lee
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Charles M. Perou
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Syed K. Mohsin
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Peter O'Connell
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Anna Tsimelzon
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Dan Medina
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DOI: 10.1158/1078-0432.CCR-07-1127 Published January 2008
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Abstract

Purpose: Human invasive breast cancers (IBC) show enormous histologic and biological diversity. This study comprehensively evaluated diversity in ductal carcinoma in situ (DCIS), the immediate precursors of IBCs.

Experimental Design: The extent of diversity for conventional histologic grade and standard prognostic biomarkers assessed by immunohistochemistry was evaluated in a series of pure DCIS (n = 200) compared with a contemporaneous series of IBCs (n = 200). A subset of the DCIS (n = 25) was evaluated by DNA microarrays for the presence of luminal, basal, and erbB2 intrinsic subtypes. The extent of diversity within individual cases of DCIS (n = 120) was determined by assessing multiple regions independently for histologic (nuclear) grade and several biomarkers by immunohistochemistry, which approximate microarrays in determining intrinsic subtypes.

Results: DCIS showed a broad distribution of conventional histologic grades and standard biomarkers ranging from well to poorly differentiated, nearly identical to IBCs. Microarrays showed the same intrinsic subtypes in DCIS as in IBCs. However, higher resolution analysis showed that multiple histologic grades, biomarker phenotypes, and intrinsic subtypes often coexist within the same DCIS, and these diverse regions probably compete for dominance. Diversity within cases of DCIS was highly correlated with mutated p53 (P = 0.0007).

Conclusions: These results support the hypothesis that poorly differentiated DCIS gradually evolve from well-differentiated DCIS by randomly acquiring genetic defects resulting in increasingly abnormal cellular features. This diversity is amplified by defects resulting in genetic instability (e.g., p53 mutation), and the alterations are propagated to IBC in a manner independent of progression to invasion.

  • Breast cancer
  • Premalignant lesions
  • Prevention and treatment of premalignant lesions (IENs)
  • Tumor progression, invasion, and metastasis
  • Gene expression profiling

Footnotes

  • ↵7 http://www.dchip.org

  • Grant support: Breast Cancer Research Foundation and NIH grant P50CA58183.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

    • Accepted September 17, 2007.
    • Received May 8, 2007.
    • Revision received August 16, 2007.
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Clinical Cancer Research: 14 (2)
January 2008
Volume 14, Issue 2
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Ductal Carcinoma In situ and the Emergence of Diversity during Breast Cancer Evolution
D. Craig Allred, Yun Wu, Sufeng Mao, Iris D. Nagtegaal, Sangjun Lee, Charles M. Perou, Syed K. Mohsin, Peter O'Connell, Anna Tsimelzon and Dan Medina
Clin Cancer Res January 15 2008 (14) (2) 370-378; DOI: 10.1158/1078-0432.CCR-07-1127

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Ductal Carcinoma In situ and the Emergence of Diversity during Breast Cancer Evolution
D. Craig Allred, Yun Wu, Sufeng Mao, Iris D. Nagtegaal, Sangjun Lee, Charles M. Perou, Syed K. Mohsin, Peter O'Connell, Anna Tsimelzon and Dan Medina
Clin Cancer Res January 15 2008 (14) (2) 370-378; DOI: 10.1158/1078-0432.CCR-07-1127
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Clinical Cancer Research
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