Abstract P3-14-01: Molecular definition of the transition of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC).
Authors: Colavito S , Stepansky A , Madan A , Harris LN , Hicks J , Bossuyt V , Rimm D , Lannin D , Stern DF 
Published: August 2014

Background: Ductal carcinoma in situ (DCIS) is thought to be a precursor lesion to invasive ductal carcinoma and sometimes occurs in combination with invasive disease. However, the majority of DCIS lesions do not progress to invasive disease. To date no molecular markers have been identified that associate with the potential for development to invasive disease. Our work has sought to identify molecular markers that can be used to determine the likelihood of DCIS being associated with invasive disease. Identification of such markers could be of direct therapeutic benefit, since patients with a high likelihood of associated or subsequent invasive disease could be managed more aggressively.

Methods: We have compiled matched pairs, consisting of patients that have recurred with DCIS, compared to those who have DCIS plus invasive disease. Laser-capture microdissection was used to isolate in situ and invasive components of the latter, and in situ components of the former. We analyzed these samples by parallel cDNA-mediated Annealing, Selection, Extension, and Ligation (DASL) analysis of transcription, and DNA copy number analysis by resequencing. In addition, exome capture deep re-sequencing has been conducted on multiple cored in situ versus invasive components of DCIS from the same tumor sample.

Results: Gene expression analysis revealed candidate genes that were specific to DCIS and others that were expressed only in the adjacent invasive component of the tissue. These genes are currently being evaluated to identify interesting candidates. Additionally, we characterized the gene expression signatures from tumors that recurred as DCIS only, to the DCIS component of those tumors that recurred with adjacent invasive disease. We identified genes that were differentially expressed between these data sets.

The DNA copy number analysis of laser-captured samples indicated a single dominant clone in each DCIS. In contrast to previously reported observations, the profiles of invasive versus non-invasive lesions differ significantly from one another. Observations of non-invasive versus invasive components of adjacent disease in two of the pairs indicate that the profile of the invasive lesions differ from that of the non-invasive component, however the profiles share many individual features.

Discussion: Our data identify differences between in situ and neighboring invasive tumor that may mark features associated with progression. Integration of the copy number and transcription profiling datasets will reveal the extent to which genomic alterations drive changes in gene expression. Identification of markers that distinguish indolent and aggressive subsets of DCIS that can be used to predict an association with invasive disease has the potential for near term clinical utility and may identify therapeutic targets for aggressive DCIS.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-14-01.