Transcriptional consequences of genomic structural aberrations in breast cancer

• Published in: Genome research Vol. 21; no. 5; pp. 676 - 687
• Main Authors: Inaki, Koichiro, Hillmer, Axel M, Ukil, Leena, Yao, Fei, Woo, Xing Yi, Vardy, Leah A, Zawack, Kelson Folkvard Braaten, Lee, Charlie Wah Heng, Ariyaratne, Pramila Nuwantha, Chan, Yang Sun, Desai, Kartiki Vasant, Bergh, Jonas, Hall, Per, Putti, Thomas Choudary, Ong, Wai Loon, Shahab, Atif, Cacheux-Rataboul, Valere, Karuturi, Radha Krishna Murthy, Sung, Wing-Kin, Ruan, Xiaoan, Bourque, Guillaume, Ruan, Yijun, Liu, Edison T
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01-05-2011
• Subjects: Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Line, Tumor; Chromosome Mapping; Chromosomes, Human, Pair 17 - genetics; Female; Gene Dosage; Gene Expression Profiling; Gene Rearrangement; Genome, Human - genetics; Genomic Instability; High-Throughput Nucleotide Sequencing; Humans; Medicin och hälsovetenskap; Membrane Proteins - genetics; Membrane Proteins - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Ribosomal Protein S6 Kinases - genetics; Ribosomal Protein S6 Kinases - metabolism; Sequence Analysis, DNA; Transcription, Genetic
• ISSN: 1088-9051; 1549-5469; 1549-5469
• DOI: 10.1101/gr.113225.110

Using a long-span, paired-end deep sequencing strategy, we have comprehensively identified cancer genome rearrangements in eight breast cancer genomes. Herein, we show that 40%-54% of these structural genomic rearrangements result in different forms of fusion transcripts and that 44% are potentially translated. We find that single segmental tandem duplication spanning several genes is a major source of the fusion gene transcripts in both cell lines and primary tumors involving adjacent genes placed in the reverse-order position by the duplication event. Certain other structural mutations, however, tend to attenuate gene expression. From these candidate gene fusions, we have found a fusion transcript (RPS6KB1-VMP1) recurrently expressed in ∼30% of breast cancers associated with potential clinical consequences. This gene fusion is caused by tandem duplication on 17q23 and appears to be an indicator of local genomic instability altering the expression of oncogenic components such as MIR21 and RPS6KB1.