Philipp Lachenmann: DELPHI Rationale


Walter Hohlweg Prize 1998

PD Dr. Rita Schmutzler

Department of Gynecology and Obstetrics, Bonn University Clinic

Genetic alterations in the aromatase gene associate with metastatic progression of primary breast carcinomas

Loss of heterozygosity indicates the existence of a putative tumor associated gene in the region concerned. In a preliminary study we found an association of LOH15q with brain metastases of primary breast carcinomas. These results strongly suggest the existence of a gene involved in metastatic tumor progression on chromosomal arm 15q.

We therefore analysed 240 primary breast carcinomas, 20 brain metastases and 10 local recurrencies of primary breast carcinomas. Ten microsatellite markers spanning the chromosomal region 15q12-21 were used. While only 28% of primary breast carcinomas showed LOH15q this alteration could be demonstrated in 70% of brain metastases and recurrencies. Importantly, analysis of LOH in several other chromosomal regions did not demonstrate such an increase in LOH frequencies indicating that LOH15q is a specific event associated with tumor progression rather than an alteration accumulated by chance. Highest LOH frequencies could be detected with an intragenic marker of the CYP19 gene which encodes for the aromatase enzyme.

Under the hypothesis that CYP19 may act as an oncogene in breast cancer progression we subsequently analyzed CYP19 for amplification by the use of differential PCR. We could detect CYP19 amplifications in 3 of 24 metastases and recurrencies and in 2 of 44 primary breast carcinomas (chi2-test, p=0.05). These results suggest that genetic alterations in the CYP19 gene are involved in the progression of breast carcinomas. Alternatively, a gene closely linked to CYP19 may be the target of allelic loss on 15q12.



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