Abstract S6-2: Characterization of different foci of multifocal breast cancer using genomic, transcriptomic and epigenomic data
Authors: Desmedt C , Nik-Zainal S , Fumagalli D , Rothé F , Singhal S , Majjaj S , Brown D , Dedeurwaerder S , Defrance M , Maetens M , Adnet P-Y , Vincent D , Salgado R , Fuks F , Piccart M , Larsimont D , Campbell P , Sotiriou C 
Published: August 2014

Abstract
Background: A significant proportion of breast cancer (BC) patients (pts) develop multiple synchronous unilateral breast tumors, also referred to as multifocal BC (MBC), which represent a diagnostic and therapeutic challenge. Here, we aimed first to better define the incidence of MBCs and then to compare different foci from ductal MBCs in a global analysis using genomic, transcriptomic and epigenomic data.
Methods: The incidence of MBCs was sought via a systematic query of all pathology reports between 2000 and 2010 within the Institut Bordet. The biological characterization of MBCs focused on 5 ductal MBCs for which the foci did not differ in terms of grade, hormonal receptors and HER2 status, since this is the case for the majority of MBCs. It involved the identification of somatic rearrangements (Rs), transcriptomic and epigenomic profiling in 2 foci from each pt, via low-coverage whole genome sequencing, HG133 Plus 2.0 Chips and Infinium Methylation 450K arrays respectively. Genomic Rs were validated using an orthogonal sequencing platform.
Results: MBC is a frequent finding since it concerns 24% (1410/5811) of primary BCs. When investigating the genomics of the 5 MBCs, we observed that the number of Rs varied in each pt, with 3 pts having few (&lt;10) Rs whilst the other 2 pts showed &gt; 100Rs with a particular tandem-duplication phenotype. All pts had Rs common to both foci, suggesting a shared genetic background. Strikingly, in 4 pts, we observed a branched evolutionary pattern since private Rs were present in each focus. In contrast, we observed a linear evolutionary pattern in the remaining pt, since private Rs were only found in 1 of the 2 foci.
Two pts were genetically very similar with ≥75% common Rs. Although the transcriptomic profiles looked very similar between the 2 foci, significant epigenomic differences were observed in 1 of the 2 pts investigated. Two other pts had 50% common Rs. In one pt there were only minor differences in transcriptomic and methylation patterns between the 2 foci. Contrastingly, in the second pt, DNA methylation patterns were dramatically discordant between the foci, suggesting that genomic, transcriptomic and epigenomic patterns are not necessarily correlated. Only in 1 pt of the 5 investigated, the 2 foci were extremely different, with only 14% of common Rs. These genetic differences were associated with dramatic differences in methylation and transcriptomic profiles. Interestingly, for 4 pts some of the identified rearrangements were found in parts of tumor-adjacent histologically normal breast tissue.
Conclusions: Today, the College of American Pathologists recommends analysing more than 1 focus from MBC if they differ in histology and grading (Lester 2009). Here, we demonstrated for the first time that different lesions from MBC, which concerns ¼ of the ductal BC population, can differ at the (epi)genetic and transcriptomic level even when the foci present similar histology, grading, hormonal and HER2 status. Since the number of genetic alterations with potential clinical utility is rapidly growing due to increasing numbers of targeted therapies, these findings suggest that interrogating only the largest lesion might not be sufficient for adequate management of MBCs.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S6-2.