Abstract
BackgroundGenomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor genes whose absence or overexpression may give rise to cellular growth advantage. So far, it has not been easy to identify the driver genes underlying gains and losses. A powerful approach to identify these driver genes could be a cross-species comparison of array comparative genomic hybridization (aCGH) data from cognate mouse and human tumors. Orthologous regions of mouse and human tumors that are commonly gained or lost might represent essential genomic regions selected for gain or loss during tumor development.MethodsTo identify genomic regions that are associated with BRCA1- and BRCA2-mutated breast cancers we compared aCGH data from 130 mouse Brca1Δ/Δ;p53Δ/Δ, Brca2Δ/Δ;p53Δ/Δ and p53Δ/Δ mammary tumor groups with 103 human BRCA1-mutated, BRCA2-mutated and non-hereditary breast cancers.ResultsOur genome-wide cross-species analysis yielded a complete collection of loci and genes that are commonly gained or lost in mouse and human breast cancer. Principal common CNAs were the well known MYC-associated gain and RB1/INTS6-associated loss that occurred in all mouse and human tumor groups, and the AURKA-associated gain occurred in BRCA2-related tumors from both species. However, there were also important differences between tumor profiles of both species, such as the prominent gain on chromosome 10 in mouse Brca2Δ/Δ;p53Δ/Δ tumors and the PIK3CA associated 3q gain in human BRCA1-mutated tumors, which occurred in tumors from one species but not in tumors from the other species. This disparity in recurrent aberrations in mouse and human tumors might be due to differences in tumor cell type or genomic organization between both species.ConclusionsThe selection of the oncogenome during mouse and human breast tumor development is markedly different, apart from the MYC gain and RB1-associated loss. These differences should be kept in mind when using mouse models for preclinical studies.
Highlights
Genomic gains and losses are a result of genomic instability in many types of cancers
We found that the average number of copy number alterations (CNAs) was significantly higher in the Brca1Δ/Δ;p53Δ/Δ tumor group compared with the p53Δ/Δ tumor group between thresholds of 0.04 - 0.54, and significantly higher in the Brca2Δ/Δ;p53Δ/Δ
We find that amplification of the MYC locus and the loss of the RB/ INTS6 locus is evolutionarily conserved in mouse and human mammary tumor development, and that Aurora kinase A (AURKA) amplification is conserved in mouse and human BRCA2mutated tumors
Summary
Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor genes whose absence or overexpression may give rise to cellular growth advantage. Analysis of the recurrent regions of chromosomal instability in BRCA1 or BRCA2 mutated breast tumors may point to loci and/or genes involved in development and progression of BRCA-associated hereditary breast cancer. To gain insight into the specific effects of BRCA1 or BRCA2 loss on genomic instability, we used aCGH profiles of genetically defined mouse models for BRCA1- and BRCA2associated breast cancer as biological data filters to mine the human breast cancer genome [10,11]. It is well known that human basal-like and luminal human breast tumors have different aCGH profiles [16]; the comparison of aCGH profiles of mouse Brca1Δ/Δ;p53Δ/Δ carcinomas with basal-like human BRCA1-mutated tumors may give results relevant for basal-like breast tumors as well as for BRCA1-loss
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