Genetic Heterogeneity in Ductal Carcinoma of the Breast

Abstract

SUMMARY:Genetic heterogeneity in breast cancer has been observed both by cytogenetic and loss of heterozygosity (LOH) analyses; however, the frequency with which genetically heterogeneous clones arise is unknown. In this study, a panel of 115 breast carcinomas was analyzed to determine the extent of clonal divergence in tumor foci at progressive stages of tumor evolution. Intraductal, infiltrating, and metastatic tumor components were microdissected from each tumor and tested for LOH at 20 microsatellite markers on seven chromosomal arms. Of these cases, 24 (21%) demonstrated genetically divergent clones during tumor progression. Clonal divergence, inferred from discordant LOH patterns, was observed most commonly between intraductal and infiltrating tumor (18 cases), but was also demonstrated between infiltrating and metastatic tumor (11 cases). Discordant LOH was observed with markers on one chromosomal arm in 16 cases, on two in 7 cases, and on four in 1 case, and was observed most commonly with markers on 17p, 17q, and 16q. More detailed microdissection of four cases provided evidence for a specific chronology of genetic alterations occurring during the progression of each tumor. The results indicate that the different tumor components observed microscopically in breast cancer specimens often represent genetically divergent clones. (Lab Invest 2000, 80:291-301).E lucidation of the sequence of genetic events responsible for progression of breast cancer from in situ to infiltrating and metastatic carcinoma is an important goal of efforts to understand the biological basis of this common malignancy. Progression is believed to occur through the accumulation of genetic changes via a process of clonal evolution and clonal selection (Brenner and Aldaz, 1997;Nowell, 1976). Surgically resected breast carcinoma specimens provide a unique resource for analyzing the genetic changes that occur during progression, because specimens typically contain foci of tumor in various stages of progression, including in situ carcinoma, invasive tumor, and lymph node metastases. Morphologically normal epithelial constituents of the breast are usually represented in such specimens, and foci of benign proliferative epithelial lesions may also be present.Detailed studies of colon cancer have shown that adenomatous epithelium adjacent to carcinoma typically has some but not all of the genetic lesions present in the fully developed malignancy, consistent with direct progression from adenoma to carcinoma (Boland et al, 1995;Fearon and Vogelstein, 1990;Vogelstein et al, 1988). By analogy, it might be expected that a similar analysis of breast tumors in different stages of progression would likewise show the accumulation of genetic changes with progression. However, genetic analysis of breast cancer specimens has suggested that the individual foci of tumor identifiable by microscopic examination may not show the precursor-product relationship often observed in colon cancer. Cytogenetic studies in particular have revealed sufficient genetic...

Ductal carcinoma in situ of the breast with different histopathological grades and corresponding new breast tumour events: Analysis of loss of heterozygosity

“…We detected MSI in only four of the 30 DCIS samples, at five markers on chromosomes 3, 8, 11, and 16. The low frequency of MSI in the present material is consistent with the proportion of MSI found in DCIS and invasive breast cancer in other studies [8,29,30].…”

Diagnostic and Prognostic Utility of Molecular Markers in Synchronous Bilateral Breast Carcinoma

“…The use of multiple targets helps described intratumoral heterogeneity. 52 Given that carcinogenesis is a multistep process of irreversible mutation acquisition causally associated with enhanced neoplastic phenotype, mutations acquired early are expected to be clonally expanded in metastasis derived from that cancer. Therefore, the initial molecular lesions detected in the primary tumor will be retained in the corresponding asynchronous distant metastases, with a noticeable accumulation of additional genetic events.…”

Evaluation of pathways for progression of heterogeneous breast tumors

“…Although these observations are consistent with DCIS being a progenitor of IDC, they do not exclude the possibility that DCIS and IDC may have a common progenitor and progress in separate lineages. Observations that have been interpreted specifically as consistent with independent progression of DCIS and IDC have included measurements of nuclear morphometry (Mommers et al, 2001a;Mariuzzi et al, 2002) and microsatellite markers (Fujii et al, 1996;Lichy et al, 2000).…”