Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q

Abstract

Chromosome 1 is involved in quantitative anomalies in 50 -60% of breast tumours. However, the structure of these anomalies and the identity of the affected genes remain to be determined. To characterise these anomalies and define their consequences on gene expression, we undertook a study combining array-CGH analysis and expression profiling using specialised arrays. Array-CGH data showed that 1p was predominantly involved in losses and 1q almost exclusively in gains. Noticeably, high magnitude amplification was infrequent. In an attempt to fine map regions of copy number changes, we defined 19 shortest regions of overlap (SROs) for gains (one at 1p and 18 at 1q) and of 20 SROs for losses (all at 1p). These SROs, whose sizes ranged from 170 kb to 3.2 Mb, represented the smallest genomic intervals possible based on the resolution of our array. The elevated incidence of gains at 1q, added to the wellestablished concordance between DNA copy increase and augmented RNA expression, made us focus on gene expression changes at this chromosomal arm. To identify candidate oncogenes, we studied the RNA expression profiles of 307 genes located at 1q using a home-made built cDNA array. We identified 30 candidate genes showing significant overexpression correlated to copy number increase. In order to substantiate their involvement, RNA expression levels of these candidate genes were measured by quantitative (Q)-RT -PCR in a panel of 25 breast cancer cell lines previously typed by array-CGH. Q -PCR showed that 11 genes were significantly overexpressed in the presence of a genomic gain in these cell lines, and 20 overexpressed when compared to normal breast.

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

“…While amplification events at the gene-dense 1q locus occur in 50% or more of breast tumors, 40 “driver” genes with immune regulatory functions have not been proposed. In our analysis, amplified immune genes were identified by the significant enrichment of immune-related ontology terms.…”

Prognostic Significance of TRIM24/TIF-1α Gene Expression in Breast Cancer

“…The TRIM24/TIF-1␣ gene region is covered by two bacterial artificial chromosome clones and the 7q34 genomic region represented by eight different clones. DNA labeling and hybridization were performed as previously described 18 with slight modifications: 600 ng of DNA were labeled with BioPrime Total Genomic Labeling System (Invitrogen SARL, Cergy Pontoise, France). Arrays were scanned using the Axon 4000B scanner (Molecular Devices, CA) and images were analyzed using Genepix 6.0.…”

Lobular and ductal carcinomas of the breast have distinct genomic and expression profiles

“…IntegraChip V2 is composed of 3172 BAC clones including 2862 sequenced clones with a median gap of 1 clone/0.8 Mb. DNA labeling, hybridization, were performed as previously described (Orsetti et al, 2006). Image processing and analysis are detailed in Supplementary information.…”