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6th ESACP Congress, Heidelberg, April 7-11, 1999 |
A025
One model of breast tumorigenesis postulates a sequential evolution from
normal to proliferative epithelium (hyperplasia without and with atypia) and
occasionally to neoplasia, but genetic data to support this progression are
limited. To characterize the sequence of early chromosomal alterations and
their accumulation during further progression we have carried out comparative
genomic hybridization (CGH) on different stages of breast cancer development
in the same patients. Formalin fixed, paraffin-embedded tissue sections from
5 patients were investigated. Lesions consisted of normal ducts as control
(n=5), ductal hyperplasias (DH, n=5), atypical ductal hyperplasias (ADH,
n=3), intraductal carcinomas (dCIS, n=5), and invasive ductal carcinomas
(IDC, n=5). For CGH, cell groups consisting of 300 to 500 cells of a defined
histopathological entity were laser-microdissected, the DNA was amplified
using DOP-PCR, and used for CGH analyses. Separate analysis of DH and/or ADH,
dCIS, and IDC components in the same patients revealed an increasing number
of alterations with increasing malignancy. A mean of 7.0 (±4.0) chromosomal
changes was identified in DH, 9.3 (±4.9) in ADH, 11.4 (±1.8) in dCIS, and
16.6 (±2.9) in IDC. Several consistent chromosomal changes were identified at
all histopathological entities: gains on 8q, 10q,16p,19q,20q,22q, and loss on
13q. In DH we already identified with high frequency (4/5 samples) gains on
19q,20q, and loss on 13q. Alterations additionally occuring in ADH were gains
on 1q,6p,7q,11q13,14q,15q,16q,17, and loss on 16q. The transition to dCIS was
characterized by DNA gain on 10p and losses on 5q and 9p, in IDC gain on 21q
as well as loss on 6q were additionally identified. In conclusion, several
chromosomal imbalances were identified already in DH and, therefore, can be
considered as early events in development of breast cancer. Particularly
DNA gain on 20q13, already present in DH, indicates an early involvement of
onco-genes (e.g. AIB amplification score). Most of the alterations identified
in DH persist during further malignancy development suggesting clonal origin.
The alterations additonally identified, may possibly play an important role
in transition to the more malignant stage.
ACCUMULATION OF CHROMOSOMAL IMBALANCES BY CGH DURING DEVELOPMENT AND
PROGRESSION OF BREAST CANCER
Aubele M 1, Walch A 1, Mattis A 2, Zitzelsberger H 3,4, Kremer M 2,
Höfler H 1,2, Werner M 2
1 GSF-Institute of Pathology, 2 TU München, Institute of Pathology,
3 GSF-Institute of Radiobiology, 4 LMU München, Institute of Radiobiology,
München, Germany