GENETIC ABERRATIONS IN HYPODIPLOID BREAST-CANCER - FREQUENT LOSS OF CHROMOSOME-4 AND AMPLIFICATION OF CYCLIN D1 ONCOGENE

The evolution of somatic genetic aberrations in breast cancer has rema ined poorly understood. The most common chromosomal abnormality is hyp erdiploidy, which is thought to arise via a transient hypodiploid stat e. However, hypodiploidy persists in 1 to 2% of breast tumors, which a re characterized by a poor prognosis. Vile studied the genetic aberrat ions in 15 flow cytometrically hypodiploid breast cancers by comparati ve genomic hybridization (CGH) and fluorescence in situ hybridization (FISH), Surprisingly, numerous copy number gains were detected in addi tion to the copy number losses. The number of gains per tumor was 4.3 +/- 3.2 and that of losses was 4.5 +/- 3.3 (mean +/- SD), which is sim ilar to that previously observed in hyperdiploid breast cancers. Gains at chromosomes or chromosomal regions at 11q13, Iq, 19, and 16p and l osses of 2q, 4, 6q, 9p, 15, and 18 were most commonly observed. Compar ed with unselected breast carcinomas, hypodiploid tumors showed certai n differences. Loss of chromosome 4 (53%) and gain of 11q13 (60%) were significantly more common in hypodiploid tumors. The gain at 11q13 wa s found by FISH to harbor amplification of the Cyclin D1 oncogene, whi ch is therefore three to four times more common in hypodiploid than in unselected breast cancers (15 to 20%). Structural chromosomal aberrat ions (such as Cyclin D1 amplification) were present both in diploid an d hypodiploid tumor cell populations, as assessed by FISH and CGH afte r flow cytometric sorting. Together these results indicate that hypodi ploid tumors form a distinct genetic entity of invasive breast cancer, although they probably share a common genetic evolution pathway where structural chromosomal aberrations precede gross DNA ploidy changes.