Identification and refinement of two regions on chromosomal arm 15q involved in breast cancer progression

Loss of heterozygosity constitutes a major mechanism of genetic abberations in breast cancer, and strongly indicates the involvement of tumor-suppressor genes in the affected chromosomal regions. Ascertainment and refinement of such deleted regions by highly polymorphic microsatellite markers is a prerequisite for the identification of candidate genes and the isolation of novel genes. Prelimary results from our group indicate the existence of genes located on chromosomal arm 15q that may be involved in breast cancer progression to metastatic stage (Wick et al, Oncogene 1996). In this study a panel of 210 primary breast carcinomas, 28 metastases and 17 local recurrencies from primary breast carcinomas were analyzed for loss of heterozygosity by the use of 16 highly polymorphic markers spanning the chromosomal region 15q11-21. After PCR amplification, microsatellite markers were separated by PAGE. LOH15q was seen in 30 out of 45 (67%) metastases and recurrences, but only in 50 out of 210 (24%) primary tumors (P < 0.01). We identified two subregions defined by microsatellite markers D15S514 (15q15) and CYP19 (15q21.1). LOH15q21.1 was most frequently detected in progressive tumor stages. Importantly, analysis of LOH in several other chromosomal regions (ie BRCA1 and BRCA2, TP53, RB1, ATM) did not demonstrate a general increase in LOH frequencies, indicating that LOH15q is a specific event associated with tumor progression. We are currently analyzing candidate genes located in the regions of interest.