Loss of heterozygosity in ductal lavage for breast tumor and the contralateral breast

Yonekura, Y; Yamamoto, Daigo; Okugawa, Homa; Kamiyama, Yasuo

doi:10.3892/or.13.4.739

Cited by 6 publications

(7 citation statements)

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“…As a consequence, LOH analysis would be highly susceptible to preferential allele amplification, a well-recognized hazard when undertaking PCR using low genome copy numbers (10). Whether or not this prejudiced the reporting of LOH in previous DL studies (8,9) is not known. In this study, DL samples obtained from women with germline BRCA1 or BRCA2 mutations were assessed for LOH at 17q.21 (in BRCA1 carriers) and at 13q.12 (in BRCA2 carriers) with the inclusion of specific controls to address the reliability of the LOH assay and to correlate the frequency of LOH with DNA yield.…”

Section: Introductionmentioning

confidence: 83%

“…Two previous studies suggest that the assessment for LOH is possible in cells obtained via DL (8,9), however, neither study addressed possible confounding factors which may have adversely influenced the reliability of genotyping. DL fluid contains a variety of different cell types including foam cells, macrophages, lymphocytes, and only a small proportion of these may be of epithelial origin (4,5), which are the most likely source of genetically aberrant premalignant cells.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies did not quantitate the DNA recovered from DL samples and were not able to assess the extent to which preferential allele amplification influenced the accuracy of genotyping (8,9). In our study, we used a real-time quantitative PCR assay to accurately determine DNA yield in all DL samples.…”

Section: Discussionmentioning

confidence: 99%

“…Isaacs et al (8) reported LOH in 58% of DL samples taken from breasts unaffected with cancers in BRCA1 carriers. Yonekura et al (9) reported a rate of 74% to 93% LOH in DL samples from breasts affected with cancer, 60% to 84% in the contralateral, unaffected breast, and up to 67% in women with benign breast disease. Although these data seem promising, on theoretical grounds, the identification of LOH in the context of the high levels of contamination of DL fluid with nonepithelial cells (up to 100%; refs.…”

Section: Introductionmentioning

confidence: 99%

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Loss of Heterozygosity Analysis in Ductal Lavage Samples from BRCA1 and BRCA2 Carriers: A Cautionary Tale

Antill

2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Loss of heterozygosity (LOH) in breast ductal lavage (DL) fluid has been reported to be a potential biomarker of malignant change. Interpretation of LOH is reliant on sufficient quality and quantity of DNA. We investigated LOH of the BRCA1/2 loci in DL samples from BRCA1/2 mutation carriers, while also assessing the effect of DNA quantity. Methods: DNA yield was estimated using quantitative realtime PCR. Allelic status of DL DNA was determined using fluorescently tagged microsatellite markers with the subject's lymphocytic DNA serving as a control. Samples were scored as consistently heterozygous or as demonstrating LOH if the same result was observed in replicate experiments. Additionally, samples were scored as ''discordant LOH'' if they initially showed LOH, but in replicate experiments either showed heterozygosity or LOH of the opposite allele.

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Section: Introductionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Loss of Heterozygosity Analysis in Ductal Lavage Samples from BRCA1 and BRCA2 Carriers: A Cautionary Tale

Antill

2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Markers D9S916, D9S974, and D9S942 were found informative in 20 of 33 (61%), 25 of 33 (76%), and 18 of 33 (55%) samples, respectively. The average ratios at all three microsatellite loci were compared with the cutoff value of 0.70 (loss of 30% or greater) to define LOH (36,37). LOH of INK4a/ARF was present in only one microsatellite marker for 1 of 23 (4.3%) atypical RPFNA samples: 0 at D9S916, 1 at D9S974, and 0 at D9S942.…”

Section: Resultsmentioning

confidence: 99%

Morphologically Normal-Appearing Mammary Epithelial Cells Obtained from High-Risk Women Exhibit Methylation Silencing of INK4a/ARF

Bean

Bryson

Pilié

et al. 2007

Clinical Cancer Research

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Purpose: p16(INK4a) has been appreciated as a key regulator of cell cycle progression and senescence. Cultured human mammary epithelial cells that lack p16(INK4a) activity have been shown to exhibit premalignant phenotypes, such as telomeric dysfunction, centrosomal dysfunction, a sustained stress response, and, most recently, a dysregulation of chromatin remodeling and DNA methylation.These data suggest that cells that lack p16(INK4a) activity would be at high risk for breast cancer development and may exhibit an increased frequency of DNA methylation events in early cancer. Experimental Design: To test this hypothesis, the frequencies of INK4a/ARF promoter hypermethylation, as well as four additional selected loci, were tested in the initial random periareolar fine needle aspiration samples from 86 asymptomatic women at high risk for development of breast cancer, stratified using the Masood cytology index. Results: INK4a/ARF promoter hypermethylation was observed throughout all early stages of intraepithelial neoplasia and, importantly, in morphologically normal-appearing mammary epithelial cells; 29 of 86 subjects showed INK4a/ARF promoter hypermethylation in at least one breast. Importantly, INK4a/ARF promoter hypermethylation was not associated with atypia, and the frequency of hypermethylation did not increase with increasing Masood cytology score. The frequency of INK4a/ARF promoter hypermethylation was associated with the combined frequency of promoter hypermethylation of retinoic acid receptor-h2, estrogen receptor-a, and breast cancer-associated 1genes (P = 0.001). Conclusions: Because INK4a/ARF promoter hypermethylation does not increase with age but increases with the frequency of other methylation events, we predict that INK4a/ARF promoter hypermethylation may serve as a marker of global methylation dysregulation. p16(INK4a) acts to block cell cycle progression by binding to cyclin-dependent kinase-4 (CDK4) and CDK6 and inhibiting the catalytic activity of the CDK4-CDK6/cyclin D complex required for retinoblastoma protein phosphorylation (1, 2). p16(INK4a) blocks progression beyond the G 1 -S restriction point by disrupting the formation of an E2F-DB active transcriptional complexes, thereby preventing the transcription of cell cycle progression genes (3). Loss or inactivation of p16(INK4a) function has been observed in numerous tumor types (4 -6), and p16(INK4a) has been implicated to play an important role in the control of replicative senescence in fibroblasts and human mammary epithelial cells (7,8).Loss of p16(INK4a) function has been identified to be the result of both genetic and epigenetic events. Multiple mechanisms exist, including point mutation, loss of heterozygosity (LOH), small homozygous deletion (<200 kb), and promoter hypermethylation. LOH at the INK4a/ARF locus (9p21) has been reported in a number of neoplasias, including breast

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Nutritional predictors for cellular nipple aspirate fluid: Nutrition and Breast Health Study

Kato

Ren

Visscher

et al. 2005

Breast Cancer Res Treat

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The presence of epithelial cells in breast nipple aspirate fluid (NAF), irrespective of abnormality, has been associated with increased risk of breast cancer in previous studies. We sought to investigate whether the presence of epithelial cells in NAF is associated with nutritional parameters among 71 healthy premenopausal women who participated in the Nutrition and Breast Health Study and provided any samples of NAF during the study. Total of 142 samples which were obtained over a 1-year period of intervention with low-fat and/or high vegetable-fruit diets were available for cytological evaluation. The odds ratios (ORs) and 95% confidence intervals (CIs) for the detection of epithelial cells in NAF were estimated by fitting generalized estimating equations models by quartile level of nutritional parameters. The probability of yielding epithelial cell-positive NAF progressively increased with increasing total fat intake (p=0.001). The OR for the highest quartile level of fat intake, compared with lowest, was 7.22 (95% CI 1.14-45.82). On the other hand, there were a marginally significant inverse association with total fiber intake as well as an weak inverse association with the number of servings of fruit and vegetables. Furthermore, the probability of detecting epithelial cells in NAF decreased with increasing plasma levels of lutein and alpha-carotene (p-values for linear trend; 0.001 and 0.049, respectively). The ORs for the highest versus lowest quartile levels are 0.17 (95% CI 0.04-0.65) and 0.19 (95% CI 0.04-0.91), respectively. These results are generally in support of roles of nutritional factors in breast cancer and thus further studies are warranted.

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Loss of heterozygosity in ductal lavage for breast tumor and the contralateral breast

Cited by 6 publications

References 0 publications

Loss of Heterozygosity Analysis in Ductal Lavage Samples from BRCA1 and BRCA2 Carriers: A Cautionary Tale

Loss of Heterozygosity Analysis in Ductal Lavage Samples from BRCA1 and BRCA2 Carriers: A Cautionary Tale

Morphologically Normal-Appearing Mammary Epithelial Cells Obtained from High-Risk Women Exhibit Methylation Silencing of INK4a/ARF

Nutritional predictors for cellular nipple aspirate fluid: Nutrition and Breast Health Study

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