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10.1245/s10434-007-9459-8
Annals of Surgical Oncology 14:3070-3077 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Correlation of Levels and Patterns of Genomic Instability With Histological Grading of DCIS

Rachel E. Ellsworth, PhD1,4, Darrell L. Ellsworth, PhD1, Brad Love, PhD2, Heather L. Patney, BS1, Laurel R. Hoffman, BS1, Jennifer Kane, HT (ASCP)1, Jeffrey A. Hooke, MD3 and Craig D. Shriver, MD3

1 Clinical Breast Care Project, Windber Research Institute, 620 Seventh Street, Windber, PA 15963, USA
2 Invitrogen Informatics, 1600 Faraday Avenue, PO Box 6482, Carlsbad, CA 92008, USA
3 Clinical Breast Care Project, Walter Reed Army Medical Center, 6900 Georgia Ave, NW, Washington, DC 20307, USA
4 Henry M. Jackson Foundation for the Advancement of Military Medicine, 1401 Rockville Pike, Suite 600, Rockville, MD 20852, USA

Correspondence: Address correspondence and reprint requests to: Rachel E. Ellsworth, PhD; E-mail: r.ellsworth{at}wriwindber.org

Background: Histological grading of ductal carcinoma-in-situ (DCIS) lesions separates DCIS into three subgroups (well-, moderately, or poorly differentiated). It is unclear, however, whether breast disease progresses along a histological continuum or whether each grade represents a separate disease. In this study, levels and patterns of allelic imbalance (AI) were examined in DCIS lesions to develop molecular models that can distinguish pathological classifications of DCIS.

Methods: Laser microdissected DNA samples were collected from DCIS lesions characterized by a single pathologist including well- (n = 18), moderately (n = 35), and poorly differentiated (n = 47) lesions. A panel of 52 microsatellite markers representing 26 chromosomal regions commonly altered in breast cancer was used to assess patterns of AI.

Results: The overall frequency of AI increased significantly (P < .001) with increasing grade (well differentiated, 12%; moderately differentiated, 17%; poorly differentiated, 26%). Levels of AI were not significantly different between well- and moderately differentiated grades of disease but were significantly higher (P < .0001) in poorly differentiated compared with well- or moderately differentiated disease. No statistically significant differences in patterns of AI were detected between well- and moderately differentiated disease; however, AI occurred significantly more frequently (P < .05) in high-grade lesions at chromosomes 6q25–q27, 8q24, 9p21, 13q14, and 17p13.1, and significantly more frequently in low-grade lesions at chromosome 16q22.3–q24.3.

Conclusions: The inability to discriminate DCIS at the genetic level suggests that grades 1 and 2 DCIS may represent a single, non–high-grade form of DCIS, whereas poorly differentiated DCIS seems to be a genetically more advanced disease that may represent a discrete disease entity, characterized by a unique spectrum of genetic alterations.

Key Words: Allelic imbalance • Ductal carcinoma-in-situ • Genomic instability • Histological grade • Tumor classification






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