Frequent loss Xq25 on the inactive X chromosome in primary breast carcinomas is associated with tumor grade and axillary lymph node metastasis

Abstract

We previously applied arbitrarily primed polymerase chain reaction DNA fingerprinting to identify molecular genetic alterations in primary breast carcinomas. One of the most frequently observed fingerprint alterations was a reduction in the intensity of the MCG1-B2 band in 32% of tumors, indicating recurrent loss of X-chromosome segments. This article reports a mapping analysis of those chromosomal deletions. The subchromosomal origin of MCG1-B2 was determined to be the Xq25 chromosomal region. Loss of heterozygosity (LOH) analysis was carried out on 72 infiltrating ductal carcinomas with a panel of seven microsatellite markers spanning Xq25. The smallest common region of the X-chromosome deletions was mapped to between markers DXS8059 and DXS8009, with the highest LOH frequency of 52.4% at the DXS8098 locus. The LOH at DXS8098 was associated with larger tumor size (> 3 cm) (P = 0.048, Fisher exact test), higher histologic grade (P = 0.036, Fisher exact test), and axillary lymph node metastasis (P = 0.020, Fisher exact test). These results suggest that the Xq25 region harbors a putative tumor suppressor gene whose inactivation in breast cancer is associated with tumor progression and metastasis. LOH at this region, therefore, potentially could be used as a prognostic marker for disease development. One of the two X chromosomes is transcriptionally silent in women. The loss of the Xq25 region detected in this study occurred preferentially on the inactive X chromosome. This suggests that the putative tumor suppressor gene may escape X inactivation.