Transcriptional consequences of genomic structural aberrations in breast cancer.

Koichiro Inaki
Axel M Hillmer
Leena Ukil
Fei Yao
Xing Yi Woo
Leah A Vardy
Kelson Folkvard Braaten Zawack
Charlie Wah Heng Lee
Pramila Nuwantha Ariyaratne
Yang Sun Chan
Kartiki Vasant Desai
Jonas Bergh
Per Hall
Thomas Choudary Putti
Wai Loon Ong
Atif Shahab
Valere Cacheux-Rataboul
Radha Krishna Murthy Karuturi
Wing-Kin Sung
Xiaoan Ruan
Guillaume Bourque
Yijun Ruan
Edison T Liu


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.