Genome-wide multi-omics profiling of the 8p11-p12 amplicon in breast carcinoma
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Toshima Z. Parris1, Elisabeth Werner Rönnerman1,2, Hanna Engqvist1, Jana Biermann1, Katarina Truvé3, Szilárd Nemes4, Eva Forssell-Aronsson5, Giovanni Solinas6, Anikó Kovács2, Per Karlsson1,* and Khalil Helou1,*
1Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
2Sahlgrenska University Hospital, Department of Clinical Pathology and Genetics, Gothenburg, Sweden
3Bioinformatics Core Facility, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
4Swedish Hip Arthroplasty Register, Gothenburg, Sweden
5Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
6The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
*These authors contributed equally to this work
Toshima Z. Parris, email: [email protected]
Keywords: breast cancer; genomic instability; 8p11-p12 amplification; genomic profiling; molecular subtype
Received: February 21, 2018 Accepted: April 20, 2018 Published: May 08, 2018
Genomic instability contributes to the neoplastic phenotype by deregulating key cancer-related genes, which in turn can have a detrimental effect on patient outcome. DNA amplification of the 8p11-p12 genomic region has clinical and biological implications in multiple malignancies, including breast carcinoma where the amplicon has been associated with tumor progression and poor prognosis. However, oncogenes driving increased cancer-related death and recurrent genetic features associated with the 8p11-p12 amplicon remain to be identified. In this study, DNA copy number and transcriptome profiling data for 229 primary invasive breast carcinomas (corresponding to 185 patients) were evaluated in conjunction with clinicopathological features to identify putative oncogenes in 8p11-p12 amplified samples. Illumina paired-end whole transcriptome sequencing and whole-genome SNP genotyping were subsequently performed on 23 samples showing high-level regional 8p11-p12 amplification to characterize recurrent genetic variants (SNPs and indels), expressed gene fusions, gene expression profiles and allelic imbalances. We now show previously undescribed chromothripsis-like patterns spanning the 8p11-p12 genomic region and allele-specific DNA amplification events. In addition, recurrent amplification-specific genetic features were identified, including genetic variants in the HIST1H1E and UQCRHL genes and fusion transcripts containing MALAT1 non-coding RNA, which is known to be a prognostic indicator for breast cancer and stimulated by estrogen. In summary, these findings highlight novel candidate targets for improved treatment of 8p11-p12 amplified breast carcinomas.
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