Abstract
BackgroundThe gene desert on human chromosomal band 8q24 harbors multiple genetic variants associated with common cancers, including breast cancer. The locus, including the gene desert and its flanking genes, MYC, PVT1 and FAM84B, is also frequently amplified in human breast cancer. We generated a megadeletion (MD) mouse model lacking 430-Kb of sequence orthologous to the breast cancer-associated region in the gene desert. The goals were to examine the effect of the deletion on mammary cancer development and on transcript level regulation of the candidate genes within the locus.MethodsThe MD allele was engineered using the MICER system in embryonic stem cells and bred onto 3 well-characterized transgenic models for breast cancer, namely MMTV-PyVT, MMTV-neu and C3(1)-TAg. Mammary tumor growth, latency, multiplicity and metastasis were compared between homozygous MD and wild type mice carrying the transgenes. A reciprocal mammary gland transplantation assay was conducted to distinguish mammary cell-autonomous from non-mammary cell-autonomous anti-cancer effects. Gene expression analysis was done using quantitative real-time PCR. Chromatin interactions were evaluated by 3C. Gene-specific patient outcome data were analysed using the METABRIC and TCGA data sets through the cBioPortal website.ResultsMice homozygous for the MD allele are viable, fertile, lactate sufficiently to nourish their pups, but maintain a 10% lower body weight mainly due to decreased adiposity. The deletion interferes with mammary tumorigenesis in mouse models for luminal and basal breast cancer. In the MMTV-PyVT model the mammary cancer-reducing effects of the allele are mammary cell-autonomous. We found organ-specific effects on transcript level regulation, with Myc and Fam84b being downregulated in mammary gland, prostate and mammary tumor samples. Through analysis using the METABRIC and TCGA datasets, we provide evidence that MYC and FAM84B are frequently co-amplified in breast cancer, but in contrast with MYC, FAM84B is frequently overexpressed in the luminal subtype, whereas MYC activity affect basal breast cancer outcomes.ConclusionDeletion of a breast cancer-associated non-protein coding region affects mammary cancer development in 3 transgenic mouse models. We propose Myc as a candidate susceptibility gene, regulated by the gene desert locus, and a potential role for Fam84b in modifying breast cancer development.
Highlights
The gene desert on human chromosomal band 8q24 harbors multiple genetic variants associated with common cancers, including breast cancer
The human ortholog of the deleted sequence contains many DNAseI HS sites, indicative of putative gene regulatory sequences (Fig. 1), including those involved in the higher-order chromatin structures mentioned in the Introduction
Breast cancer risk variants identified by Genome-Wide Association Studies (GWAS) are mostly located to non-protein coding genomic regions
Summary
The gene desert on human chromosomal band 8q24 harbors multiple genetic variants associated with common cancers, including breast cancer. Mammalian genomes harbor large sequence regions (> 500-Kb) devoid of known protein-coding genes [1, 2]. Such sequences are widely known as ‘gene deserts’. Genome-Wide Association Studies (GWAS) over the last decade showed that gene deserts frequently harbor genetic variants associated with human complex traits, including breast cancer susceptibility. The gene desert located on human chromosomal band 8q24 is exemplary in that it contains multiple cancer-associated variants identified by GWAS, including 2 breast cancer-associated variants [3,4,5]. All polymorphisms strongly correlated to the tag Single Nucleotide Polymorphisms (SNPs) are located within non-protein coding sequences (the gene desert), suggesting their involvement in long-range gene regulation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
