ISPO

Allelic loss in breast cancer

Demetrios A. Spandidos, PhD, DSc; Demetrios A. Arvanitis, BSc; Spiros Miyakis, MD, PhD; Alexis Zafiropoulos, PhD

Department of Virology, Medical School, University of Crete, Heraklion, Crete, Greece

AIM: Breast cancer represents the most frequent cancer in the female population. The involvement of chromosomal aberrations is often implicated in the development of this disease. Genomic instability is a common feature of neoplastic cells, due to rapid proliferation or elevated mutational rate. Detection of an asymmetric intensity ratio between two alleles at a microsatellite DNA locus, as compared to the profile of normal cells, is described as allelic imbalance (AI) for the tumor in question. AI may reflect the complete loss of one allele at a constitutional heterozygous locus that is masked by the presence of normal cells, by tumor heterogeneity, or by non-clonal loss. Increased DNA copy number will also reveal an AI pattern. Such alterations comprise a pathway for the full inactivation or altered expression of genes close to the affected microsatellite marker. Hence, these markers represent molecular tools for predicting the clinical behavior of tumors. Our study aimed to assess microsatellite DNA alterations in breast tumors in relation to clinical and pathological parameters. METHODS: Tumors, corresponding normal tissues, and peripheral blood samples were obtained from 82 women with sporadic breast cancer and analyzed by polymerase chain reaction (PCR), using 41 highly polymorphic microsatellite DNA markers located on 1p, 1q, 3p, 7q, 10p, 10q, 11p, 13q, 17p and 17q chromosomal arms. RESULTS: AI was most frequently found on 13q12-q13, 17p13 and 1q21-q23 at 34%, where BRCA2, TP53 and CRP genes are located respectively, followed by 17q21 at 33% and 3p25-p26 at 29%, where BRCA1 and respectively VHL have been mapped. Noteworthy, allelic imbalance towards gene amplification is apparent in 57% of breast cancer cases overexpressing Tpl2/Cot proto-oncogene on 10p11.2. Loss of heterozygosity (LOH) on 1q21-q23 correlates with the presence of extensive intaductal component (EIC) and peritumoral angiolymphatic (PALI) invasion, both independent markers of local recurrence. Moreover, estrogen receptor (ER) or progesterone receptor (PgR) negative breast tumors harbor genetic alterations at 17q21 3-fold and 2-fold more frequent, than tumors that retained both alleles, while decreased mRNA levels of BRCA1 gene correlates to AI at 17q21. Microsatellite instability was not detected in high incidence, indicating the absence of a replication error-positive (RER+) phenotype. CONCLUSIONS: Molecular biology of breast cancer is still incompletely understood; genetic and epigenetic changes may interact with the environment to produce the disease phenotype. Although BRCA1 and BRCA2 tumor-suppressor genes account for approximately 27% of familiar breast cancer cases, they seem to be involved in sporadic cases also. Allelic imbalances correlate to the mRNA level changes of the genes affected, as well as to certain clinicopathological parameters. Therefore, specific microsatellite DNA markers could be used as potent prognostic tools for breast cancer progression.

For more information, contact spandido@hol.gr

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Predictive Markers.

http://www.cancerprev.org/Journal/Issues/26/101/1002/4417