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Improved Grading of Breast Adenocarcinomas Based on Genomic Instability

¹ Division of Cellular and Molecular Analysis, Department of Oncology and Pathology, Karolinska Institute and Hospital, Stockholm, Sweden; ² Department of Molecular Medicine, Karolinska Institute, Rolf Luft’s Center for Diabetes Research, Karolinska Hospital, Stockholm, Sweden; ³ Department of Surgery, Medical University of Luebeck, Luebeck, Germany; ⁴ Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden; ⁵ Astrid Lindgren Children’s Hospital, Karolinska Hospital, Stockholm, Sweden; and ⁶ Department of Oncology and Pathology, Unit of Tumor Pathology, Karolinska Institute and Hospital, Stockholm, Sweden

Numerous investigations have shown that in primary breast adenocarcinomas DNA aneuploidy in contrast to DNA diploidy indicates high malignancy potential. On the basis of the study of 104 breast carcinomas, we describe a subtype of aneuploidy, which demonstrates a low degree of malignancy. 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 clinically low and high malignant variants. One possible reason for aneuploidy is impaired distribution of chromosomes at mitosis caused by numerical or structural centrosome aberrations. Cyclins A and E seem to be involved in centrosome duplication. Real-time quantitative PCR measurements of cyclin A and E transcript levels and immunohistochemical determination of cyclin A protein expression showed statistically significantly increased values in the tumors with a high SSI (>8.8%), compared with those with a low SSI. A pilot study demonstrated centrosomal aberrations in an average of 9.6% of the measured cells in four aneuploid carcinomas with high SSI values and in an average of 2.5% of the cells in three aneuploid and three diploid tumors with low SSI. Our data indicate that the SSI, most likely reflecting the degree of genomic instability, allows additional classifying of the known aneuploid, diploid, and tetraploid categories of primary breast adenocarcinomas into low and high malignant subtypes.

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