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The Accumulation of Specific Amplifications Characterizes Two Different Genomic Pathways of Evolution of Familial Breast Tumors

Authors' Affiliations: ¹ Human Genetics Group; Human Cancer Genetics Programme; ² Cytogenetics Unit, Biotechnology Programme; and ³ Laboratory of Breast and Gynecological Cancer, Molecular Pathology Programme, Spanish National Cancer Center, Madrid, Spain; and ⁴ Department of Genetics, Hospital Santa Creu i Sant Pau, Barcelona, Spain

Requests for reprints: Javier Benítez, Human Genetics Department, Spanish National Cancer Centre CNIO, Calle Melchor Fernandez Almagro 3, Madrid 28029, Spain. Phone: 34-91-224-6965; Fax: 34-91-224-6923; E-mail: jbenitez{at}cnio.es.

Purpose and Methods: High-level DNA amplifications are recurrently found in breast cancer, and some of them are associated with poor patient prognosis. To determine their frequency and co-occurrence in familial breast cancer, we have analyzed 80 tumors previously characterized for BRCA1 and BRCA2 germ-line mutations (26 BRCA1, 18 BRCA2, and 36 non-BRCA1/2) using high-resolution comparative genomic hybridization.

Results: Twenty-one regions were identified as recurrently amplified, such as 8q21-23 (26.25%), 17q22-25 (13.75%), 13q21-31 (12.50%), and 8q24 (11.25%), many of which were altered in each familial breast cancer group. These amplifications defined an amplifier phenotype that is correlated with a higher genomic instability. Based on these amplifications, two different genomic pathways have been established in association with 8q21-23 and/or 17q22-25 and with 13q21-31 amplification. These pathways are associated with specific genomic regions of amplification, carry specific immunohistochemical characteristics coincident with high and low aggressiveness, and have a trend to be associated with BRCA1 and BRCA2/X, respectively.

Conclusion: In summary, our data suggest the existence of two different patterns of evolution, probably common to familial and sporadic breast tumors.

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