Methylation Profiling of Benign and Malignant Breast Lesions and Its Application to Cytopathology

• Published in: Modern pathology 2003-11, Vol.16 (11), p.1095-1101
• Main Authors: Pu, Robert T, Laitala, Lauren E, Alli, Patricia M, Fackler, Mary Jo, Sukumar, Saraswati, Clark, Douglas P
• Format: Article
• Language: English
• Subjects: Biopsy; Biopsy, Needle; Breast cancer; Breast Diseases - genetics; Breast Diseases - pathology; Breast lesions; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Carcinoma - genetics; Carcinoma - pathology; Carcinoma in Situ - genetics; Carcinoma in Situ - pathology; Cellular biology; Cyclin D2; DNA Fingerprinting; DNA Methylation; Female; Fine needle aspiration biopsy; Gene Frequency; Genes; Humans; Laboratory Medicine; Medicine; Medicine & Public Health; Methylation profile; Middle Aged; MSP; Neoplasm Invasiveness; original-article; Pathology; Polymerase Chain Reaction; Promoter Regions, Genetic - genetics; RARβ2; RASSF1A; Surgical and cytopathology specimens
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1097/01.MP.0000095782.79895.E2

Methylation of tumor suppressor genes has been implicated in breast cancer development. However, methylation profiles of different breast lesions, subtypes of carcinoma in particular, have not been examined in detail. In this study, we use methylation-specific PCR (MSP) to generate gene methylation profiles of different breast lesions and to test the clinical utility of such profiles. We examined the methylation status of three genes, RARβ2, RASSF1A, and cyclin D2, on 102 samples of breast tissue, from benign (n = 36), to in situ carcinoma (n = 21), to invasive carcinoma (n = 45). We found that almost all cases of invasive carcinoma (96%) contained at least one methylated gene from our panel, whereas gene methylation was less common among benign lesions (42%) and in situ carcinoma (76%). Of the three genes, cyclin D2 methylation was most specific for malignancy because only 1 of 35 benign cases was methylated at this gene (1 case was not informative). The major histologic subtypes of invasive carcinoma show similar methylation profiles in the genes examined. We next performed MSP analysis on archival breast fine-needle aspiration (FNA) biopsy samples and corresponding surgical biopsy specimens and found a high concordance between the two types of specimens. We then analyzed 17 breast FNA biopsy samples with an indeterminate diagnosis. In this setting, MSP had a high specificity (100%) and modest sensitivity (67%) for identifying malignancy.