Abstract
Ductal carcinoma in situ (DCIS) is a non-invasive type of breast cancer with highly variable potential of becoming invasive and affecting mortality. Currently, many patients with DCIS are overtreated due to the lack of specific biomarkers that distinguish low risk lesions from those with a higher risk of progression. In this study, we analyzed 57 pure DCIS and 313 invasive breast cancers (IBC) from different patients. Three levels of genomic data were obtained; gene expression, DNA methylation, and DNA copy number. We performed subtype stratified analyses and identified key differences between DCIS and IBC that suggest subtype specific progression. Prominent differences were found in tumors of the basal-like subtype: Basal-like DCIS were less proliferative and showed a higher degree of differentiation than basal-like IBC. Also, core basal tumors (characterized by high correlation to the basal-like centroid) were not identified amongst DCIS as opposed to IBC. At the copy number level, basal-like DCIS exhibited fewer copy number aberrations compared with basal-like IBC. An intriguing finding through analysis of the methylome was hypermethylation of multiple protocadherin genes in basal-like IBC compared with basal-like DCIS and normal tissue, possibly caused by long range epigenetic silencing. This points to silencing of cell adhesion-related genes specifically in IBC of the basal-like subtype. Our work confirms that subtype stratification is essential when studying progression from DCIS to IBC, and we provide evidence that basal-like DCIS show less aggressive characteristics and question the assumption that basal-like DCIS is a direct precursor of basal-like invasive breast cancer.
Highlights
Ductal carcinoma in situ (DCIS) is a non-invasive, non-obligate precursor to invasive breast cancer (IBC) with low risk of progression[1]
All sample information correlation coefficients to the subtype centroids compared with including clinical and molecular parameters is presented in Table 1 IBC; this was evident for the basal-like subtype (Table 2)
We have explored differences between DCIS and IBC in a subtype specific manner using gene expression, copy number and DNA-methylation data derived from fresh frozen tumor material
Summary
Ductal carcinoma in situ (DCIS) is a non-invasive, non-obligate precursor to invasive breast cancer (IBC) with low risk of progression[1]. As breast cancer screening has become widespread, more DCIS lesions are being detected[2,3,4]. Autopsy studies and studies on DCIS from non-treated patients show that many lesions, if left alone, will never progress to invasive disease[5,6,7,8,9]. There is currently no robust method to distinguish DCIS with invasive potential from those that may be left untreated. DCIS is a heterogeneous disease and may at time of diagnosis vary from indolent lesions to tumors on the verge of becoming invasive. As a consequence of this uncertainty, treatment for DCIS is often extensive, resulting in substantial overtreatment[12,13,14,15]
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