Genomic differences between pure ductal carcinoma in situ and synchronous ductal carcinoma in situ with invasive breast cancer

// Shinn Young Kim 1, 3, * , Seung-Hyun Jung 1, 3, * , Min Sung Kim 2 , In-Pyo Baek 1, 3 , Sung Hak Lee 4 , Tae-Min Kim 5 , Yeun-Jun Chung 1, 3 , Sug Hyung Lee 2 1 Department of Microbiology, The Catholic University of Korea, Seoul 2 Department of Pathology, The Catholic University of Korea, Seoul 3 Department of Integrated Research Center for Genome Polymorphism, The Catholic University of Korea, Seoul 4 Department of Hospital Pathology, The Catholic University of Korea, Seoul 5 Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul * These authors have contributed equally to this work Correspondence to: Yeun-Jun Chung, e-mail: yejun@catholic.ac.kr Sug Hyung Lee, e-mail: suhulee@catholic.ac.kr Keywords: breast cancer, ductal carcinoma in situ , genomic difference, whole exome, copy number alteration Received: December 22, 2014 Accepted: January 17, 2015 Published: March 26, 2015 ABSTRACT Although ductal carcinoma in situ (DCIS) precedes invasive ductal carcinoma (IDC), the related genomic alterations remain unknown. To identify the genomic landscape of DCIS and better understand the mechanisms behind progression to IDC, we performed whole-exome sequencing and copy number profiling for six cases of pure DCIS and five pairs of synchronous DCIS and IDC. Pure DCIS harbored well-known mutations (e.g., TP53, PIK3CA and AKT1 ), copy number alterations (CNAs) and chromothripses, but had significantly fewer driver genes and co-occurrence of mutation/CNAs than synchronous DCIS-IDC. We found neither recurrent nor significantly mutated genes with synchronous DCIS-IDC compared to pure DCIS, indicating that there may not be a single determinant for pure DCIS progression to IDC. Of note, synchronous DCIS genomes were closer to IDC than pure DCIS. Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations. Our results indicate that although pure DCIS has already acquired some drivers, more changes are needed to progress to IDC. In addition, IDC-associated DCIS is more aggressive than pure DCIS at genomic level and should really be considered IDC. Finally, the data suggest that PR-negativity could be used to predict aggressive breast cancer genotypes.