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01.12.2017 | Research | Ausgabe 1/2017 Open Access

Journal of Translational Medicine 1/2017

Comprehensive molecular biomarker identification in breast cancer brain metastases

Zeitschrift:
Journal of Translational Medicine > Ausgabe 1/2017
Autoren:
Hans-Juergen Schulten, Mohammed Bangash, Sajjad Karim, Ashraf Dallol, Deema Hussein, Adnan Merdad, Fatma K. Al-Thoubaity, Jaudah Al-Maghrabi, Awatif Jamal, Fahad Al-Ghamdi, Hani Choudhry, Saleh S. Baeesa, Adeel G. Chaudhary, Mohammed H. Al-Qahtani
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12967-017-1370-x) contains supplementary material, which is available to authorized users.

Abstract

Background

Breast cancer brain metastases (BCBM) develop in about 20–30% of breast cancer (BC) patients. BCBM are associated with dismal prognosis not at least due to lack of valuable molecular therapeutic targets. The aim of the study was to identify new molecular biomarkers and targets in BCBM by using complementary state-of-the-art techniques.

Methods

We compared array expression profiles of three BCBM with 16 non-brain metastatic BC and 16 primary brain tumors (prBT) using a false discovery rate (FDR) p < 0.05 and fold change (FC) > 2. Biofunctional analysis was conducted on the differentially expressed probe sets. High-density arrays were employed to detect copy number variations (CNVs) and whole exome sequencing (WES) with paired-end reads of 150 bp was utilized to detect gene mutations in the three BCBM.

Results

The top 370 probe sets that were differentially expressed between BCBM and both BC and prBT were in the majority comparably overexpressed in BCBM and included, e.g. the coding genes BCL3, BNIP3, BNIP3P1, BRIP1, CASP14, CDC25A, DMBT1, IDH2, E2F1, MYCN, RAD51, RAD54L, and VDR. A number of small nucleolar RNAs (snoRNAs) were comparably overexpressed in BCBM and included SNORA1, SNORA2A, SNORA9, SNORA10, SNORA22, SNORA24, SNORA30, SNORA37, SNORA38, SNORA52, SNORA71A, SNORA71B, SNORA71C, SNORD13P2, SNORD15A, SNORD34, SNORD35A, SNORD41, SNORD53, and SCARNA22. The top canonical pathway was entitled, role of BRCA1 in DNA damage response. Network analysis revealed key nodes as Akt, ERK1/2, NFkB, and Ras in a predicted activation stage. Downregulated genes in a data set that was shared between BCBM and prBT comprised, e.g. BC cell line invasion markers JUN, MMP3, TFF1, and HAS2. Important cancer genes affected by CNVs included TP53, BRCA1, BRCA2, ERBB2, IDH1, and IDH2. WES detected numerous mutations, some of which affecting BC associated genes as CDH1, HEPACAM, and LOXHD1.

Conclusions

Using complementary molecular genetic techniques, this study identified shared and unshared molecular events in three highly aberrant BCBM emphasizing the challenge to detect new molecular biomarkers and targets with translational implications. Among new findings with the capacity to gain clinical relevance is the detection of overexpressed snoRNAs known to regulate some critical cellular functions as ribosome biogenesis.
Zusatzmaterial
Additional file 1. Probe sets differentially expressed in breast cancer brain metastases (BCBM) compared to breast cancer (BC) and primary brain tumors (prBT).
Additional file 2. Exon expression levels for a number of cancer associated genes. A, BRCA1; B, BRCA2; C, ERBB2; D, TP53; E, ER1 (ESR1); F, PR (PGR); G, SNORD116-4; H, MKI67; I, VDR; and J, BCL3. Comparably low expression of a number of exon probes can be presumbably attributed to splicing events of transcripts; asterisks mark examples. BCL3 is upregulated on the gene expression level (Additional file 1). Notably, 5` located exons of ERBB2 are lower expressed than 3` located exons in prBT and expression levels of the two probes covering the SNORD116-4 transcript diverge in BCBM and prBT compared to BC. Exon probes are displayed from 5` (left) to 3` (right) of the transcripts. Blue and red colors in heat maps refer to lower and higher expression, respectively.
Literatur
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