Genomic profiling by array comparative genomic hybridization reveals novel DNA copy number changes in breast phyllodes tumours.

Breast phyllodes tumour (PT) is a rare fibroepithelial tumour. The genetic alterations contributing to its tumorigenesis are largely unknown. To identify genomic regions involved in pathogenesis and progression of PTs we obtained genome-wide copy number profiles by array comparative genomic hybridization (CGH).DNA was isolated from fresh-frozen tissue samples. 11 PTs and 3 fibroadenomas, a frequently occurring fibroepithelial breast tumour, were analyzed. Arrays composed of 2464 genomic clones were used, providing a resolution of ~1.4 Mb across the genome. Each clone contains at least one STS for linkage to the human genome sequence.No copy number changes were detected in fibroadenomas. On the other hand, 10 of 11 PT (91%) showed DNA copy number alterations. The mean number of chromosomal events in PT was 5.5 (range 0-16) per case. A mean of 2.0 gains (range 0-10) and 3.0 losses (range 0-9) was seen per case of PT. Three cases showed amplifications. DNA copy number change was not related to PT grade. We observed recurrent loss on chromosome 1q, 4p, 10, 13q, 15q, 16, 17p, 19 and X. Recurrent copy number gain was seen on 1q, 2p, 3q, 7p, 8q, 16q, 20.In this study we used array CGH for genomic profiling of fibroepithelial breast tumours. Whereas most PT showed chromosomal instability, fibroadenomas lacked copy number changes. Some copy number aberrations had not previously been associated with PT. Several well-known cancer related genes, such as TP53 and members of the Cadherin, reside within the recurrent regions of copy number alteration. Since copy number change was found in all benign PT, genomic instability may be an early event in PT genesis.

A metastasis of an adenocarcinoma in a BRCA1 mutation carrier, a diagnostic problem not solved by morphology alone.

To increase awareness of the possible coexistence of an ovarian and breast carcinoma in a BRCA1 mutation carrier, we describe a patient with primary ovarian cancer who developed distant metastases after 3 years and again after 6 years. Surprisingly, at that time an occult breast carcinoma was identified to be the origin of the 2 metastatic locations as confirmed by molecular analysis. Eventually the patient could be treated accordingly.

Androgen pathway dysregulation in BRCA1-mutated breast tumors.

BACKGROUND: Using array analysis for screening RNA from BRCA1-mutated and sporadic breast tumors, we observed that AIGF/FGF-8 expression was lost in BRCA1-mutated breast tumors. Since this growth factor is induced by androgens, we studied the androgen receptor (AR) expression in BRCA-mutated tumors and in matched sporadic breast tumors. METHODS: Paraffin embedded breast tumors of carriers of a BRCA1 mutation (n=41, median age of patients at time of surgery was 41 years [range 28-59 years]) or a BRCA2 mutation (n=14, median age 41 years [range 31-85 years]) were analyzed for the presence of ER-alpha, PR, P53 and AR using standard immunohistochemical techniques. All statistical tests used, Pearson chi2 and Fisher exact, were two-sided. RESULTS: The AR was only present in 12% of BRCA1-mutated tumors, with mutations located at the C-terminal half of the BRCA1-gene. The AR expression was significantly more prevalent, however, in a series of 61 sporadic breast tumors (80%) and in BRCA2-mutated tumors (50%). In contrast to an increased percentage of p53 positive cells, in 66% of the BRCA1-mutated tumors, the ER-alpha expression was observed only in 25% and the PR in 13% of these specimens. The three steroid hormone receptors were expressed in about half of the BRCA2-mutated specimens studied. CONCLUSIONS: Our data add to the emerging evidence that the biological phenotype of BRCA1-associated tumors may be different from BRCA2 and non-hereditary cases. The loss of the AR expression, as shown by immunohistochemistry, together with the observed loss of other steroid hormone receptors in BRCA1-mutated tumors may lead to a hormone-independent growth or to anti-hormone resistant growth of these tumors.

Surveillance with microsatellite analysis of urine in bladder cancer patients treated by radiotherapy.

OBJECTIVES: The interpretation of cystoscopy and cytology may be troublesome in bladder cancer patients previously treated by radiotherapy. We evaluated polymerase chain reaction (PCR)-based molecular cytology by microsatellite analysis (MA) and routine urine cytology (RUC) and expert urine cytology (EUC) as modes of surveillance for patients previously treated by radiotherapy with curative intent. METHODS: Eighty-one voided urine samples were obtained from 49 patients prior to cystoscopy and subjected to MA, RUC and EUC. RESULTS: During the follow-up period, six patients developed a recurrence. Sensitivity of MA, RUC and EUC was 83%, 50% and 33%, respectively. The specificity of MA, RUC and EUC was 93%, 85% and 97%, respectively. Cystoscopy was positive in 15 cases. Therefore, the positive predictive value of cystoscopy remained limited to 40%. CONCLUSIONS: Next to recent studies demonstrating a high accuracy for MA in non-irradiated patients, our results indicate that molecular cytology by MA may also be a useful tool to improve the surveillance of bladder cancer patients previously treated by radiotherapy.