Loss of Heterozygosity in Normal Tissue Adjacent to Breast Carcinomas

Abstract

Loss of heterozygosity (LOH) was detected in morphologically normal lobules adjacent to breast cancers. The most frequent aberration was at chromosome 3p22-25; of ten cases with this LOH in the carcinoma, six displayed the same LOH in adjacent normal lobules. This suggests that in a subset of sporadic breast cancers, a tumor suppresser gene at 3p22-25 may be important in initiation or early progression of tumorigenesis. Among sixteen breast cancers with LOH at 17p13.1 and five breast cancers with LOH at 11p15.5, one case each displayed the same LOH in adjacent normal lobules. Thus the molecular heterogeneity that characterizes invasive breast cancers may occur at the earliest detectable stages of progression.The mature breast contains lobules, clusters of closed glandular spaces that produce milk during lactation. These lobules are connected to the nipple-areolar complex by a system of branching ducts that are surrounded by varying amounts of fat and connective tissue. Breast cancer is thought to develop within a terminal ductal-lobular unit (TDLU), which includes the lobule and its most proximal ducts (1).Breast cancer evolves by clonal selection of cells that acquire multiple molecular changes. One model suggests that breast cancer, like colon cancer (2), develops through a defined progression of morphologically distinguishable stages beginning with benign hyperplasia, which progresses to atypical hyperplasia, then to in situ carcinoma, and finally to invasive cancer (1). This sequential progression may not be the only way that breast cancers develop, however. Many small invasive cancers do not have atypical components, which suggests that they may have developed directly from morphologically normal epithelium. If this were true, one might expect to find evidence of a "field effect" in which at least some of the genetic aberrations found in invasive cancers are also present in the morphologically normal epithelium.To test this hypothesis, we carefully microdissected hematoxylin-eosin-stained sections of breast cancers so as to isolate morphologically discrete regions (Fig. 1A). DNA was prepared from malignant areas of the section and from adjacent normal TDLUs. As a control for each case, DNA was also prepared from normal breast skin (usually from a separate section) that had been similarly microdissected.We studied LOH at chromosome 3p24, 11p15.5, 13q13, and 17p13.1 because these loci show LOH in a high percentage (ϳ30 to 60%) of invasive ductal breast cancers (3, 4). For the carcinomatous regions, the frequency of LOH at 3p24 (48%) and 11p15.5 (29%) was similar to that previously reported (4). The frequency of LOH in the invasive components was higher than the literature values for 13q13 (64% here versus ϳ40%) and for 17p13.1 (80% here versus ϳ60%). These discrepancies may be due to random variation because our sample size was small.In 8 of 30 cases we detected LOH in the adjacent morphologically normal TDLUs (Table 1). In all eight cases, the same allele was missing in the adjacent carcinoma (Fig. 2, A an...

Loss of heterozygosity at chromosome 9p in ductal carcinoma in situ and invasive carcinoma of the breast

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Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma

“…In surgically resected samples, extensive areas of normal epithelium were frequently present, and the relatively large microdissected foci may have contained more than one clonal or subclonal populations. Allelic losses have also been described in histologically normal epithelium adjacent to or near breast and gallbladder carcinomas (Deng et al, 1996;Wistuba et al, 1995).…”

“…Losses at other 3p regions (3p12, 3p14.2, 3p14 ± 21) and the TP53 gene were present mainly in histologically advanced lesions (dysplasia and CIS). Of interest, 3p deletions have been described as early events during the multistage pathogenesis of several other epithelial cancers including head and neck, cervix and breast (Deng et al, 1996;Wistuba et al, 1997b). In contrast, deletions at chromosome 5q and 13q (near the APC and at RB genes) were mainly associated with invasive carcinomas, and were relatively rare in precursor lesions.…”

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

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