Genome instability, gene expression and prognosis in breast cancer

Abstract: Aneuploid cancers are regarded as being more malignant than tumors of other ploidy categories, and they are characterized by increased genomic instability. Our investigations resulted in the characterization of an aneuploid subtype of breast carcinoma that proved to be genomically stable. In image cytometric DNA histograms this subtype possessed a low percentage (<8.8%) of nonmodal DNA values as measured by the stemline scatter index (SSI), which is defined as sum of the percentage of cells in the S-phase region, the G2 exceeding rate and the coefficient of variation of the tumor stemline. The cut point of SSI - 8.8% (p=0.03) enabled us to also subdivide diploid and tetraploid tumors into genomically stable and unstable variants. One possible reason for aneuploidy or genomic instability in general is impaired distribution of chromosomes at mitosis, caused by numerical or structural centrosome aberrations. Cyclin A and E seem to be involved in centrosome duplication. We measured significant upregulation of cyclin A and E mRNA levels in genomically unstable diploid (Dgu) and aneuploid (Agu) breast cancer ploidy subtypes, as well as cyclin A protein overexpression. Furthermore, we assessed a high percentage of cells with centrosomal aberrations in Agu breast tumors but not in the genomically stable aneuploid (Ags) and diploid (Dgs) subtypes. In a follow-up study comprising 890 patients with primary breast adenocarcinoma, and an average follow-up period of 8.9 years, we measured significantly better overall and distant metastasis free survival for patients with gs breast carcinomas as compared to patients with gu tumors. Furthermore we identified proteins significantly differentially expressed between stable and unstable breast carcinomas as well as between benign breast lesions and all subtypes of breast carcinomas.