Increasing chromosome 1 copy number parallels histological progression in breast carcinogenesis

Cummings, Margaret C.; Aubele, Michaela; Mattis, A.; Purdie, David M.; Hutzler, Peter; Höfler, Heinz; Werner, Martin

doi:10.1054/bjoc.1999.1064

Cited by 20 publications

(18 citation statements)

References 14 publications

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“…Based on a small number of LOH events, these results warrant further examination in a larger study. However, they are consistent with data suggesting that genes important early in breast tumorigenesis may be located on 1q and 16q, 14,19 whereas genes acting later may be on 17p (for instance, p53 20 -22 ) or 11q. 22,23 We did not examine abnormalities of specific genes, but microsatellites were selected to be in the vicinity of several genes implicated in breast carcinogenesis, ie, p53 (on 17p13) CCND1 (cyclin D1 on 11q13), or ATM (on 11q23).…”

Section: Discussionsupporting

confidence: 90%

“…Consistent with this, a recent study posits aneuploidy as a late event in breast carcinogenesis, 36 and only rare cytogenetic abnormalities have been reported in normal-appearing tissue adjacent to cancers. 19,37 In summary, the current data indicate that clonal, genetically abnormal ducts/TDLUs are scattered throughout normal-appearing epithelium of cancerous breasts. These clones are distinct from the co-existing cancer, and could be a consequence either of normal development or of pathological events.…”

Section: Discussionmentioning

confidence: 61%

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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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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 61%

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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“…These data suggesting the existence at 1q of several regions of gains were thus concordant with LOH studies, indicating the occurrence of at least four regions of allelic imbalance in breast tumours (Kerangueven et al, 1997). Because gains at 1q were observed both in low-and high-grade breast tumours, its implication in early stages of disease development has been shown (Tirkkonen et al, 1998;Cummings et al, 2000). Recent data using BAC-based array-CGH on independent sets of breast tumours have confirmed the frequent nature of gains on chromosome 1, as well as the existence of multiple cores of amplification (Stange et al, 2006).…”

mentioning

confidence: 99%

Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q

et al. 2006

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Chromosome 1 is involved in quantitative anomalies in 50 -60% of breast tumours. However, the structure of these anomalies and the identity of the affected genes remain to be determined. To characterise these anomalies and define their consequences on gene expression, we undertook a study combining array-CGH analysis and expression profiling using specialised arrays. Array-CGH data showed that 1p was predominantly involved in losses and 1q almost exclusively in gains. Noticeably, high magnitude amplification was infrequent. In an attempt to fine map regions of copy number changes, we defined 19 shortest regions of overlap (SROs) for gains (one at 1p and 18 at 1q) and of 20 SROs for losses (all at 1p). These SROs, whose sizes ranged from 170 kb to 3.2 Mb, represented the smallest genomic intervals possible based on the resolution of our array. The elevated incidence of gains at 1q, added to the wellestablished concordance between DNA copy increase and augmented RNA expression, made us focus on gene expression changes at this chromosomal arm. To identify candidate oncogenes, we studied the RNA expression profiles of 307 genes located at 1q using a home-made built cDNA array. We identified 30 candidate genes showing significant overexpression correlated to copy number increase. In order to substantiate their involvement, RNA expression levels of these candidate genes were measured by quantitative (Q)-RT -PCR in a panel of 25 breast cancer cell lines previously typed by array-CGH. Q -PCR showed that 11 genes were significantly overexpressed in the presence of a genomic gain in these cell lines, and 20 overexpressed when compared to normal breast.

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“…6 Breast cancer progression is characterized by the accumulation of numeric changes on many chromosomes, particularly early or frequent increases in the copy numbers of chromosomes 1,8,11, and 17. [7][8][9][10][11][12][13][14][15][16] Fluorescence in situ hybridization (FISH) evaluation of chromosomal aberrations in ductal lavage specimens may be more sensitive and specific than conventional cytologic evaluation for categorization of breast lesions. [17][18][19] To determine the utility of FISH in categorizing breast epithelial changes, we used this technique to evaluate numeric changes in chromosomes 1,8,11, and 17 in breast FNA specimens from 27 women at high risk for breast cancer.…”

mentioning

confidence: 99%

Correlation of cytologic findings and chromosomal instability detected by fluorescence in situ hybridization in breast fine-needle aspiration specimens from women at high risk for breast cancer

et al. 2006

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Cytologic evaluation of ductal lavage or random periareolar fine-needle aspiration (FNA) specimens has been proposed to improve risk stratification of women at high risk for breast cancer. However, cytologic assessment of morphologic changes is subjective. To assess the utility of fluorescence in situ hybridization (FISH) in the categorization of breast lesions, we prospectively evaluated 32 random periareolar FNA specimens from 27 women at high risk for breast cancer. Cytologic specimens were prepared using the thin preparation technique, and diagnoses were made on the basis of previously published criteria. Specimens were also evaluated by FISH for chromosomes 1, 8, 11, and 17. Monosomy was defined as the loss of one signal or both signals in 420% of cells, and polysomy was defined as the presence of Z3 signals in 46% of cells. Cytologic smears from seven invasive ductal carcinomas and nine benign breast specimens from women at low risk for breast cancer were included for comparison. In the high-risk group, cytologic findings were nonproliferative epithelium (NPE) in 16 cases and hyperplasia in 16 cases. Chromosomal aberrations were detected in 11 (69%) of 16 NPE cases, 14 (89%) of 16 hyperplasia cases, seven (100%) of seven carcinoma cases, and none of the low-risk cases. Highrisk cases had significantly more monosomy of chromosomes 1, 11, and 17 and polysomy of chromosome 8 compared to low-risk cases and significantly less polysomy of chromosomes 1, 8, 11, and 17 compared to patients with cancer. There were no significant differences in monosomy or polysomy of individual chromosomes or a combination of chromosomes between the NPE and hyperplasia groups. This study shows that aberrations of chromosome number are common in high-risk women irrespective of cytologic findings. Studies evaluating the association between specific patterns of chromosomal polysomy and progression to malignancy may be warranted.

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Increasing chromosome 1 copy number parallels histological progression in breast carcinogenesis

Cited by 20 publications

References 14 publications

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

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

Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q

Correlation of cytologic findings and chromosomal instability detected by fluorescence in situ hybridization in breast fine-needle aspiration specimens from women at high risk for breast cancer

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