© 1998 by Oxford University Press
Journal Of The National Cancer Institute, Vol 90, 697-703, Copyright © 1998 by Oxford University Press
P O'Connell, V Pekkel, SA Fuqua, CK Osborne, GM Clark and DC Allred
BACKGROUND: Usual ductal hyperplasia (UDH), atypical ductal hyperplasia
(ADH), and ductal carcinoma in situ (DCIS) are risk factors for invasive
breast cancer (IBC), suggesting that these lesions may be direct precursors
of IBC. To identify genetic changes that may be important in the early
development of precursor lesions and their progression to malignant or
invasive disease, we examined 399 putative precursors (211 UDH, 51 ADH, 81
non-comedo DCIS, and 56 comedo DCIS) for loss of heterozygosity (LOH) at 15
polymorphic genetic loci known to exhibit high rates of loss in IBC. We
also assessed the sharing of LOH by putative precursors and synchronous
cancers. METHODS: The polymerase chain reaction was used to analyze DNA
from microdissected archival specimens. RESULTS AND CONCLUSIONS: In
hyperplasias from noncancerous breasts (i.e., without DCIS and/or IBC in
analyses of hyperplasias), LOH at any given locus was rare (range, 0%-15%),
although 37% of UDH and 42% of ADH lesions showed loss for at least one
locus, suggesting that the development of hyperplasias can involve many
different tumor suppressor genes. In DCIS from noncancerous breasts (i.e.,
without IBC in analyses of DCIS), LOH was common, with 70% of noncomedo
lesions and 79% of comedo lesions showing at least one loss. In DCIS,
substantial rates of loss (up to 37%) were observed at loci on chromosomes
16q, 17p, and 17q, suggesting that inactivated tumor suppressor genes in
these regions may be important in the development of noninvasive breast
cancer. When DCIS lesions from cancerous and noncancerous breasts were
compared, substantially more LOH was observed in the cancerous breasts at a
few loci (on chromosomes 2p, 11p, and 17q), suggesting that genetic
alterations in these regions may be important in the progression to
invasive disease. Among specimens harvested from cancerous breasts, 37% of
UDH, 45% of ADH, 77% of noncomedo DCIS, and 80% of comedo DCIS lesions
shared LOH with synchronous cancers at one locus or more, supporting the
idea that the putative precursors and the cancers are genetically related.
ARTICLES
Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci
Department of Pathology, University of Texas Health Science Center at San Antonio 78248, USA.
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