Quantitative hypermethylation of a small panel of genes augments the diagnostic accuracy in fine-needle aspirate washings of breast lesions

Carmen Jeronimo, Paula Monteiro, Rui Henrique, Mário Dinis-Ribeiro, Isabel Costa, Vera L. Costa, Luísa Filipe, André L. Carvalho, Mohammad Hoque, Irene Pais, Conceição Leal, Manuel R. Teixeira, David Sidransky

Research output: Contribution to journalArticle

Abstract

Purpose: We hypothesized that comprehensive breast cancer methylation profiling might provide biomarkers for diagnostic assessment of suspicious breast lesions using fine needle aspiration biopsy (FNA). Experimental design: Twenty-three gene promoters were surveyed by quantitative methylation-specific PCR in bisulfite-modified DNA from 66 breast carcinomas (BCa), 31 fibroadenomas (FB) and 12 normal breast (NT) samples to define a set of genes differentially methylated in malignant and non-malignant tissues. This set was tested in 78 FNA washings obtained pre-operatively (66 malignant, 12 benign), with histopathological diagnosis. Receiver operator characteristic (ROC) curve analysis identified a gene panel which might distinguish cancer from non-cancerous lesions. Finally, this panel was validated in an independent series of FNA washings (45 cases) in which cytomorphology did not reach definitive diagnosis. Results: In tissue samples, 14-3-3-σ, DAPK, CCND2, RASSF1A, CALCA, APC, HIN1, RARβ2, TIG1, and GSTP1 methylation levels differed significantly among BCa, FB, and NT. ROC curve analysis identified a panel of four gene loci (CCND2, RASSF1A, APC, and HIN1) that discriminated BCa from benign lesions in a set of 78 FNA washings from histologically characterized breast lesions. When this panel was tested in the validation dataset of 45 FNA washings, breast cancer was identified with perfect specificity (100%) when 3 of 4 gene loci tested positive, providing estimated added information of 91% over cytomorphologic evaluation alone. Conclusions: Our data provide evidence that multigene methylation analysis augments diagnostic accuracy of cytological assessment of suspicious breast lesions, and might be a valuable ancillary tool for breast cancer diagnosis.

Original languageEnglish (US)
Pages (from-to)27-34
Number of pages8
JournalBreast Cancer Research and Treatment
Volume109
Issue number1
DOIs
StatePublished - May 2008

Fingerprint

Needles
Fine Needle Biopsy
Breast
Breast Neoplasms
Methylation
Genes
Fibroadenoma
Research Design
Biomarkers
Polymerase Chain Reaction
DNA
Neoplasms

Keywords

  • Breast cancer
  • Cancer biomarkers
  • Epigenetic profile
  • Fine needle aspiration biopsy
  • Quantitative methylation-specific PCR

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Quantitative hypermethylation of a small panel of genes augments the diagnostic accuracy in fine-needle aspirate washings of breast lesions. / Jeronimo, Carmen; Monteiro, Paula; Henrique, Rui; Dinis-Ribeiro, Mário; Costa, Isabel; Costa, Vera L.; Filipe, Luísa; Carvalho, André L.; Hoque, Mohammad; Pais, Irene; Leal, Conceição; Teixeira, Manuel R.; Sidransky, David.

In: Breast Cancer Research and Treatment, Vol. 109, No. 1, 05.2008, p. 27-34.

Research output: Contribution to journalArticle

Jeronimo, C, Monteiro, P, Henrique, R, Dinis-Ribeiro, M, Costa, I, Costa, VL, Filipe, L, Carvalho, AL, Hoque, M, Pais, I, Leal, C, Teixeira, MR & Sidransky, D 2008, 'Quantitative hypermethylation of a small panel of genes augments the diagnostic accuracy in fine-needle aspirate washings of breast lesions', Breast Cancer Research and Treatment, vol. 109, no. 1, pp. 27-34. https://doi.org/10.1007/s10549-007-9620-x
Jeronimo, Carmen ; Monteiro, Paula ; Henrique, Rui ; Dinis-Ribeiro, Mário ; Costa, Isabel ; Costa, Vera L. ; Filipe, Luísa ; Carvalho, André L. ; Hoque, Mohammad ; Pais, Irene ; Leal, Conceição ; Teixeira, Manuel R. ; Sidransky, David. / Quantitative hypermethylation of a small panel of genes augments the diagnostic accuracy in fine-needle aspirate washings of breast lesions. In: Breast Cancer Research and Treatment. 2008 ; Vol. 109, No. 1. pp. 27-34.
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abstract = "Purpose: We hypothesized that comprehensive breast cancer methylation profiling might provide biomarkers for diagnostic assessment of suspicious breast lesions using fine needle aspiration biopsy (FNA). Experimental design: Twenty-three gene promoters were surveyed by quantitative methylation-specific PCR in bisulfite-modified DNA from 66 breast carcinomas (BCa), 31 fibroadenomas (FB) and 12 normal breast (NT) samples to define a set of genes differentially methylated in malignant and non-malignant tissues. This set was tested in 78 FNA washings obtained pre-operatively (66 malignant, 12 benign), with histopathological diagnosis. Receiver operator characteristic (ROC) curve analysis identified a gene panel which might distinguish cancer from non-cancerous lesions. Finally, this panel was validated in an independent series of FNA washings (45 cases) in which cytomorphology did not reach definitive diagnosis. Results: In tissue samples, 14-3-3-σ, DAPK, CCND2, RASSF1A, CALCA, APC, HIN1, RARβ2, TIG1, and GSTP1 methylation levels differed significantly among BCa, FB, and NT. ROC curve analysis identified a panel of four gene loci (CCND2, RASSF1A, APC, and HIN1) that discriminated BCa from benign lesions in a set of 78 FNA washings from histologically characterized breast lesions. When this panel was tested in the validation dataset of 45 FNA washings, breast cancer was identified with perfect specificity (100{\%}) when 3 of 4 gene loci tested positive, providing estimated added information of 91{\%} over cytomorphologic evaluation alone. Conclusions: Our data provide evidence that multigene methylation analysis augments diagnostic accuracy of cytological assessment of suspicious breast lesions, and might be a valuable ancillary tool for breast cancer diagnosis.",
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T1 - Quantitative hypermethylation of a small panel of genes augments the diagnostic accuracy in fine-needle aspirate washings of breast lesions

AU - Jeronimo, Carmen

AU - Monteiro, Paula

AU - Henrique, Rui

AU - Dinis-Ribeiro, Mário

AU - Costa, Isabel

AU - Costa, Vera L.

AU - Filipe, Luísa

AU - Carvalho, André L.

AU - Hoque, Mohammad

AU - Pais, Irene

AU - Leal, Conceição

AU - Teixeira, Manuel R.

AU - Sidransky, David

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N2 - Purpose: We hypothesized that comprehensive breast cancer methylation profiling might provide biomarkers for diagnostic assessment of suspicious breast lesions using fine needle aspiration biopsy (FNA). Experimental design: Twenty-three gene promoters were surveyed by quantitative methylation-specific PCR in bisulfite-modified DNA from 66 breast carcinomas (BCa), 31 fibroadenomas (FB) and 12 normal breast (NT) samples to define a set of genes differentially methylated in malignant and non-malignant tissues. This set was tested in 78 FNA washings obtained pre-operatively (66 malignant, 12 benign), with histopathological diagnosis. Receiver operator characteristic (ROC) curve analysis identified a gene panel which might distinguish cancer from non-cancerous lesions. Finally, this panel was validated in an independent series of FNA washings (45 cases) in which cytomorphology did not reach definitive diagnosis. Results: In tissue samples, 14-3-3-σ, DAPK, CCND2, RASSF1A, CALCA, APC, HIN1, RARβ2, TIG1, and GSTP1 methylation levels differed significantly among BCa, FB, and NT. ROC curve analysis identified a panel of four gene loci (CCND2, RASSF1A, APC, and HIN1) that discriminated BCa from benign lesions in a set of 78 FNA washings from histologically characterized breast lesions. When this panel was tested in the validation dataset of 45 FNA washings, breast cancer was identified with perfect specificity (100%) when 3 of 4 gene loci tested positive, providing estimated added information of 91% over cytomorphologic evaluation alone. Conclusions: Our data provide evidence that multigene methylation analysis augments diagnostic accuracy of cytological assessment of suspicious breast lesions, and might be a valuable ancillary tool for breast cancer diagnosis.

AB - Purpose: We hypothesized that comprehensive breast cancer methylation profiling might provide biomarkers for diagnostic assessment of suspicious breast lesions using fine needle aspiration biopsy (FNA). Experimental design: Twenty-three gene promoters were surveyed by quantitative methylation-specific PCR in bisulfite-modified DNA from 66 breast carcinomas (BCa), 31 fibroadenomas (FB) and 12 normal breast (NT) samples to define a set of genes differentially methylated in malignant and non-malignant tissues. This set was tested in 78 FNA washings obtained pre-operatively (66 malignant, 12 benign), with histopathological diagnosis. Receiver operator characteristic (ROC) curve analysis identified a gene panel which might distinguish cancer from non-cancerous lesions. Finally, this panel was validated in an independent series of FNA washings (45 cases) in which cytomorphology did not reach definitive diagnosis. Results: In tissue samples, 14-3-3-σ, DAPK, CCND2, RASSF1A, CALCA, APC, HIN1, RARβ2, TIG1, and GSTP1 methylation levels differed significantly among BCa, FB, and NT. ROC curve analysis identified a panel of four gene loci (CCND2, RASSF1A, APC, and HIN1) that discriminated BCa from benign lesions in a set of 78 FNA washings from histologically characterized breast lesions. When this panel was tested in the validation dataset of 45 FNA washings, breast cancer was identified with perfect specificity (100%) when 3 of 4 gene loci tested positive, providing estimated added information of 91% over cytomorphologic evaluation alone. Conclusions: Our data provide evidence that multigene methylation analysis augments diagnostic accuracy of cytological assessment of suspicious breast lesions, and might be a valuable ancillary tool for breast cancer diagnosis.

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KW - Quantitative methylation-specific PCR

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