Hypermethylated genes as biomarkers of cancer in women with pathologic nipple discharge

Mary Jo Fackler, Aeisha Rivers, Wen Teo Wei, Amrit Mangat, Evangeline Taylor, Zhe Zhang, Steve Goodman, Pedram Argani, Ritu Nayar, Barbara Susnik, Saraswati Sukumar*, Seema A. Khan

*Corresponding author for this work

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Purpose: In a pilot study of women with pathologic nipple discharge (PND) undergoing ductoscopy, we tested quantitative assessment of gene promoter hypermethylation using quantitative multiplex methylation-specific PCR (QM-MSP) to enhance detection of duct carcinoma in situ (DCIS). Experimental Design: Women with PND underwent ductoscopy; ducts with significant lesions were surgically resected (36 ducts in 33 women) and those with minimal findings were not (28 ducts in 16 women). QM-MSPwas done on ductoscopy cell samples. Results were compared with cytology and tissue histology. Results: Cells from ducts with significant lesions on ductoscopy had significantly higher levels of methylation than those with minimal findings. Furthermore, cells from ducts with DCIS displayed higher levels of methylation than those with benign lesions such as papilloma (P = 0.006); or ducts with minimal findings on ductoscopy (P = 0.0001). Cumulative RASSF1A, TWIST1, and HIN1 gene methylation accurately distinguished ducts with cancerous versus benign lesions (100% sensitivity, 72% specificity, and area under the curve of 0.91 according to receiving operating characteristic analyses). QM-MSPanalysis was more informative than cytology (100% versus 29% sensitivity, respectively), for detecting DCIS. In a validation set of paraffin-embedded DCIS and papilloma samples from women presenting with PND, QM-MSP was significantly higher in DNA from DCIS than papilloma sections (P = 0.002). Conclusion: The positive predictive value of ductoscopy was more than doubled (19% versus 47%) with the addition of QM-MSP, demonstrating the benefit of targeting ducts having both high methylation and significant abnormalities on ductoscopy for surgical excision. Future large-scale studies to validate this approach are needed.

Original languageEnglish (US)
Pages (from-to)3802-3811
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number11
DOIs
StatePublished - Jun 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Fackler, M. J., Rivers, A., Wei, W. T., Mangat, A., Taylor, E., Zhang, Z., Goodman, S., Argani, P., Nayar, R., Susnik, B., Sukumar, S., & Khan, S. A. (2009). Hypermethylated genes as biomarkers of cancer in women with pathologic nipple discharge. Clinical Cancer Research, 15(11), 3802-3811. https://doi.org/10.1158/1078-0432.CCR-08-1981