Next-generation Sequencing

A Powerful Tool for the Discovery of Molecular Markers in Breast Ductal Carcinoma In Situ

Hitchintan Kaur; Shihong Mao; Seema Shah; David H Gorski; Stephen A Krawetz; Bonnie F Sloane; Raymond R Mattingly


Expert Rev Mol Diagn. 2013;13(2):151-165. 

In This Article

Genomic Analyses & Expression Profiling of DCIS

Identifying the genetic alterations and molecular mechanisms underlying the progression from premalignant DCIS lesions to invasive carcinoma may help to establish clinical biomarkers and also lead to the identification of potential targets for therapeutic intervention. Although there have been fewer studies of DCIS[53–62] than IDC, it seems likely that the same chromosomal regions are amplified with comparable frequencies in DCIS as in IDC. Comparative genomic hybridization analyses of DCIS and IDC lesions show that low- and intermediate-grade DCIS are characterized by chromosomal loss of 16q, whereas 1q gain and 11q loss occurs at higher frequency in intermediate-grade DCIS.[63] High-grade DCIS, however, is more complex in terms of these alterations as shown by loss of 8p, 11q, 13q and 14q, gains in 1q, 5p, 8q and 17q, and amplifications of 17q12 (ErbB2/Her-2)[64] and 11q13 (cyclin D1). Molecular cytogenetic analysis by comparative genomic hybridization of several preinvasive and invasive breast cancer cell lines revealed that the most common gains are found at 8q, 1q, 7q, 3q and 7p and the most common losses at Xp, 8p, 18q and Xq.[65]

Advanced technology has facilitated interrogation of molecular events occurring at preinvasive stages of breast cancer. Several gene expression profiling studies of DCIS have been carried out using a combination of laser capture microdissection and microarrays.[55,56,59,61,62,66] Serial analysis of gene expression found that the most dramatic transcriptome changes occur at the transition from normal epithelium to DCIS rather than from DCIS to invasive cancer.[58] This conclusion is supported by the phenotypic and genomic analyses demonstrating that the molecular heterogeneity of breast ductal carcinomas is already established in in situ lesions,[61] and by studies from coexisting DCIS and IDC.[55] Higher tumor grade and the presence of necrosis have been associated with greater gene expression variability and distinct transcriptional signatures.[54,66] Hannemann et al. identified a gene expression classifier of 35 genes that differed between DCIS and IDC and a panel of 43 genes which further distinguished well and poorly differentiated DCIS.[57]