Clinical Relevance of Allelic Imbalances on Chromosome 10q in Brain Metastases Formation in Breast Cancer Patients

Abstract

Breast cancer is the most common malignancy in women with particularly high mortality rate in patients who develop brain metastases in course of the disease. The biology of breast cancer and its metastases has been extensively studied but is still not fully understood. The multistep process of metastases formation involves detachment from the primary tumor, migration, penetration of blood vessels, extravasation at the distant site and a successful growth at the foreign environment of the distant organ. Different hypotheses on chronology and origin of metastases have been proposed. Especially brain metastasis encounter a challenge of trespassing the blood-brain barrier. Genetic alterations leading to a loss of function in tumor suppressor genes play an important role in tumorigenesis of breast cancer. In this study we examined and compared 77 primary breast tumors and 21 brain metastases for allelic imbalances on chromosome 10q by means of PCR with fluorescence-tagged microsatellite markers and subsequent capillary electrophoresis. The goal was to detect genetic alterations in the primary tumors which are associate with metastatic spread to the brain and which could serve as a specific marker to identify breast cancer patients at high risk for brain metastases. We found a significantly higher number of AI in brain metastases than in primary tumors at virtually all examined loci at 10q. The AI accumulated around two core regions. The first core region (CR1) was found around PTEN locus (markers D10S541 and D10S 1765) and the second region (CR2) was detected around the markers D10S173 and D10S190. The AI in these loci were significantly more frequent in brain metastases than in primary tumors without relapse. Interestingly, primary tumors with later relapse to brain exhibited similar frequencies of AI at 10q like brain metastases of breast cancer. The four matched primary tumors and brain metastases showed as well similar patterns of AI. These results favor the hypothesis that a certain subset of primary tumors initially harbors AI on 10q, which are then detectable as well in their metastatic satellites. PTEN was identified as a tumor suppressor gene that is likely to be involved in formation of brain metastases of breast cancer. The locus containing PTEN carried a much higher number of AI in brain metastases than in primary tumors without relapse or relapse to other organs other than brain. According to our study this locus can be defined as a “hot spot” of AI on 10q in brain metastases. Interestingly, loss of PTEN is generally not present in epithelial tumors but is very common in primary brain tumors like glioblastoma. AI on this locus may confer the epithelial cells features supporting their survival in brain microenvironment. In conclusion, the present results show that brain metastases of breast cancer carry very complex patters of genetic alteration. Still certain regions and genes, such as PTEN, are predominantly affected and might play an important role in dissemination of breast cancer to the brain. Further studies like functional analysis of these genes are needed to determine their specific role in the metastatic cascade of breast cancer.