Detection of monoclonal microsatellite alterations in atypical breast hyperplasia.

Rosenberg, Carol L.; Morenas, Antonio de las; Huang, Kui; Cupples, L. Adrienne; Faller, Douglas V.; Larson, Pamela S.

doi:10.1172/jci118890

Cited by 29 publications

(19 citation statements)

References 26 publications

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“…The LOH/AI changes in AH have been shown to involve all informative markers on a chromosome arm, consistent with the pattern found in breast cancer, and in contrast to normal breast tissue and ductal hyperplasia where AI involved only single markers [32]. Atypical hyperplasia lesions are considered to be monoclonal microsatellite alterations involving both length variation and allele loss [33], and which may involve multiple genes such as Myc, EGFR, CDH13, BRCA1, p53 (Table 4). Amari et al [34] studied 23 synchronous lesions of ADH, DCIS, and invasive carcinoma.…”

Section: Structural Chromosomal Changes In Atypical Hyperplasiasupporting

confidence: 61%

“…The causes of aneuploidy in AH are not clear; however, alterations in multiple genes known to contribute to aneuploidy have been observed in AH (Tables 4, 5, 6). 1q32-42/D1S549 MSI/LOH AH-25.0% [33] 1q32-qter CGH ADH-high-level amplification [7] 2p11.2 CGH ALH-gains, 50% [84] 2q35/D2S362 LOH ADH noncancerous breast-none ADH cancerous breast-6%…”

Section: Numerical Chromosomal Changes In Atypical Hyperplasiamentioning

confidence: 99%

“…Comedo-9% [85] 3p rhoA, cdc25A CGH ADH-gains [83] 3p24/D3S1298 MSI/LOH AH-8.3% [33] 3p22ter CGH ADH gain, 67% Gain, 60% [83] 3q11-q21 CGH ADH loss, 11.1% [35] 5p CGH Gain Gain Gain [7] 5p14 CGH ADH-high-level amplification [7] 5q32-33. 100.0% 100.0% [88] 7p22-qter CGH ADH-high-level amplification [7] 7q35ter CGH ADH-gain, 33.3% Gain, 40% [83] 8p NRG1 (just distal to region) CGH ADH-loss Loss Loss [7] 8p/D8S339 LOH ADH with cancer-C 25% C35% [34] 8p12-pter CGH ADH-Loss, 11.1% [35] 8q CGH ADH-high-level amplification [7] 8q21-qter CGH ADH-gain, 11.1% [35] 8q24 MYC ADH-gain, 66.0% Gain, 60% Gain, 80% [83] 8q24 Comedo-13% [85] 13q32-q34 CGH ADH-high-level amplification [7] 14q11.2-q12 CGH ADH-high-level amplification [7] 14q24/D14S62 LOH ADH noncancerous breast-none ADH cancerous breast-12%…”

Section: Numerical Chromosomal Changes In Atypical Hyperplasiamentioning

confidence: 99%

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Molecular profile of atypical hyperplasia of the breast

Danforth

2017

Breast Cancer Res Treat

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Purpose Atypical ductal and atypical lobular hyperplasia (AH) of the breast are important proliferative lesions which are associated with a significantly increased risk for breast cancer. The breast cancer which develops in association with AH may occur synchronously, representing local progression, or metachronously at a later date in either the ipsilateral or contralateral breast. These high-risk characteristics of AH suggest they contain significant genomic changes. Methods To define the genomic changes in AH, a comprehensive review of the literature was conducted to identify the numerical chromosomal and structural chromosomal changes, DNA methylation, and gene expression abnormalities in atypical ductal and atypical lobular hyperplasia. Results AHs are characterized by advanced genomic changes including aneuploidy, loss of heterozygosity, gross chromosomal rearrangements such as amplifications and large-scale deletions, DNA methylation of tumor suppressor and other genes, and gene expression differences between AH and surrounding normal breast tissue including significant estrogen receptor expression. Many of these changes are shared by an associated synchronous breast cancer, consistent with an important precursor role for AH. At the same time, many of the genomic changes of AHs are also shared by common sporadic breast cancer, consistent with a high risk for future development of metachronous breast cancer. Conclusions This molecular profile should help clarify the genomic characteristics and malignant predisposition of AH, and aid in the identification of new targets for the prevention of breast cancer

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Section: Structural Chromosomal Changes In Atypical Hyperplasiasupporting

confidence: 61%

Section: Numerical Chromosomal Changes In Atypical Hyperplasiamentioning

confidence: 99%

Section: Numerical Chromosomal Changes In Atypical Hyperplasiamentioning

confidence: 99%

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Molecular profile of atypical hyperplasia of the breast

Danforth

2017

Breast Cancer Res Treat

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“…Cytogenetic analysis of tumor specimens grown for short periods of time in culture has provided evidence for the presence of apparently unrelated clones in half of the tumors analyzed Pandis et al, 1993;Teixeira et al, 1994;. Clonal chromosome aberrations have also been reported in benign lesions including fibroadenoma, atypical hyperplasia, and intraductal papilloma (Dietrich et al, 1995;Kasami et al, 1997;Petersson et al, 1997;Rosenberg et al, 1996) as well as in benign epithelium in patients from breast cancer families (Petersson et al, 1996) or at no increased risk of breast cancer (Larson et al, 1998). Our results, in agreement with these studies, support the idea that formation of genetically divergent clones can occur in benign breast epithelium showing no morphologic abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Genetic Heterogeneity in Ductal Carcinoma of the Breast

Lichy

Dalbègue

Zavar

et al. 2000

Laboratory Investigation

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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...

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“…DNA was extracted using standard techniques that we have described previously. 5,9 DNA for control reactions was quantitated fluorimetrically (PicoGreen dsDNA Quantitation Kit; Molecular Probes, Eugene, OR).…”

Section: Microdissection and Dna Extraction And Quantitationmentioning

confidence: 99%

Loss of Heterozygosity or Allele Imbalance in Histologically Normal Breast Epithelium Is Distinct from Loss of Heterozygosity or Allele Imbalance in Co-Existing Carcinomas

Larson

Morenas

Bennett

et al. 2002

The American Journal of Pathology

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To better understand early steps in human breast carcinogenesis, we examined allele imbalance or loss of heterozygosity (LOH), in co-existing normal-appearing breast epithelium and cancers. We microdissected a total of 173 histologically normal ducts or terminal ductolobular units (TDLUs) and malignant epithelial samples from 18 breast cancer cases, and examined their DNA for LOH at 21 microsatellite markers on 10 chromosome arms. Fourteen of 109 (13%) normal ducts/TDLUs, from 8 of 18 (44%) cases, contained LOH. The location of these 14 ducts/TDLUs appeared unrelated to distance from the cancer. LOH in normal-appearing epithelium involved only single markers, whereas LOH in cancers commonly encompassed all informative markers on a chromosome arm. In only 1 of 14 (7%) ducts/TDLUs with LOH, was the same LOH seen in the co-existing cancer. Global differences in LOH per arm in normal-appearing tissue were not demonstrated, but less LOH was seen at 11q and 17p than at 1q (P ‫؍‬ 0.002), 16q (P ‫؍‬ 0.01), and possibly 17q (P ‫؍‬ 0.06). These results indicate that in a large fraction of women with breast cancer, histologically normal breast epithelium harbors occult aberrant clones. Individual clones rarely are precursors of co-existing cancers. However, they might constitute a reservoir from which proliferative lesions or second cancers develop once additional genetic abnormalities occur, they could contribute to intratumoral genetic heterogeneity, and they are consistent with a role for genetic instability early in tumorigenesis. Breast cancers, even carcinoma in situ (CIS), the earliest recognized breast malignancy, contain numerous genetic abnormalities.

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Detection of monoclonal microsatellite alterations in atypical breast hyperplasia.

Cited by 29 publications

References 26 publications

Molecular profile of atypical hyperplasia of the breast

Molecular profile of atypical hyperplasia of the breast

Genetic Heterogeneity in Ductal Carcinoma of the Breast

Loss of Heterozygosity or Allele Imbalance in Histologically Normal Breast Epithelium Is Distinct from Loss of Heterozygosity or Allele Imbalance in Co-Existing Carcinomas

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