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Original Article |
1 Clinical Breast Care Project, Windber Research Institute, 620 Seventh Street, Windber, Pennsylvania 15963
2 Invitrogen Bioinformatics, 1600 Faraday Avenue, PO Box 6482, Carlsbad, California 92008
3 Clinical Breast Care Project, Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Washington, DC 20307
Correspondence: Address correspondence and reprint requests to: Rachel E. Ellsworth, PhD; E-mail: r.ellsworth{at}wriwindber.org.
Background: Breast cancer development has been characterized as a nonobligatory sequence of histological changes from normal epithelium through invasive malignancy. Although genetic alterations are thought to accumulate stochastically during tumorigenesis, little is known about the timing of critical mutations. This study examined allelic imbalance (AI) in tissue samples representing a continuum of breast cancer development to examine the evolution of genomic instability.
Methods: Laser-microdissected DNA samples were collected from histologically normal breast specimens (n = 25), atypical ductal hyperplasia (ADH, n = 16), ductal carcinoma-in-situ (DCIS, n = 37), and stage I to III invasive carcinomas (n = 72). Fifty-two microsatellite markers representing 26 chromosomal regions commonly deleted in breast cancer were used to assess patterns of AI.
Results: AI frequencies were <5% in histologically normal and ADH specimens, 20% in DCIS lesions, and approximately 25% in invasive tumors. Mann-Whitney tests showed (1) that levels of AI in ADH samples did not differ significantly from those in histologically normal tissues and (2) that AI frequencies in DCIS lesions were not significantly different from those in invasive carcinomas. ADH and DCIS samples, however, differed significantly (P < .0001).
Conclusions: DCIS lesions contain levels of genomic instability that are characteristic of advanced invasive tumors, and this suggests that the biology of a developing carcinoma may already be predetermined by the in situ stage. Observations that levels of AI in ADH lesions are similar to those in disease-free tissues provide a genomic rationale for why prevention strategies at the ADH level are successful and why cases with ADH involving surgical margins do not require further resection.
Key Words: Allelic imbalance • Atypical ductal hyperplasia • Ductal carcinoma-in-situ • Breast cancer • Tumor progression
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