To identify new immortalizing genes with potential roles in tumorigenesis, we performed a genetic screen aimed to bypass the rapid and tight senescence arrest of primary fibroblasts deficient for the oncogene Bmi1. We identified the T-box member TBX2 as a potent immortalizing gene that acts by downregulating Cdkn2a (p19(ARF)). TBX2 represses the Cdkn2a (p19(ARF)) promoter and attenuates E2F1, Myc or HRAS-mediated induction of Cdkn2a (p19(ARF)). We found TBX2 to be amplified in a subset of primary human breast cancers, indicating that it might contribute to breast cancer development.

#6050 Background: Breast cancer cells lacking the DNA repair mechanism Homologous Recombination (HR) have recently been shown to be hypersensitive to bifunctional alkylating agents such as carboplatin and poly(ADP-ribose)polymerase(PARP)-inhibitors, a novel class of targeted agents. We have previously reported the construction of an array Comparative Genomic Hybridization (aCGH) classifier that detects the characteristic copy number aberrations of BRCA1-mutated tumors which are thought to be caused by HR deficiency. We hypothesized that metastatic breast cancer patients with tumors harboring such a BRCA1-profile may specifically benefit (longer progression-free survival (PFS)) from intensive treatment with bifunctional alkylating agents compared to patients without this tumor-profile.
 Methods: We isolated DNA from formalin-fixed paraffin-embedded primary tumor tissue collected from 3 prior studies carried out in our institute, in which metastatic breast cancer patients received intensive alkylating chemotherapy with carboplatin, thiotepa and cyclophosphamide (CTC). DNA from 40 tumors was tested for the presence of the BRCA1-profile by aCGH. Furthermore, we screened for the majority of BRCA1 and BRCA2 mutations that frequently occur in Dutch BRCA1 and BRCA2 families.
 Results: Sixteen patients had a tumor with a BRCA1-profile and had a better response to CTC-treatment, defined by achievement of a complete remission (p=0.01) and longer PFS (p=0.001, figure 1), with a hazard ratio for progression of 0.30 (p=0.002).
 
 All 6 patients who remain in continuous complete remission (56+ to 150+ months) had a tumor with a BRCA1 profile. Two BRCA1 and 2 BRCA2 mutations were found in 4 patients of whom 3 had a BRCA1-profile and a long PFS (> 30months), linking HR deficiency (BRCA1 and BRCA2 mutations) in breast cancer patients to good outcome on platinum-based chemotherapy.
 Discussion: Using an aCGH classifier initially constructed to identify BRCA1-mutated tumors we were able to identify a group of metastatic breast cancer patients treated with platinum-based chemotherapy with a high complete remission-rate and long progression free survival. Moreover, this group contained all patients who were apparently cured by intensive alkylating chemotherapy. Our aCGH assay may represent an effective test for BRCA-ness and could be important to select patients with sporadic tumors for therapy targeted at cells deficient in Homologous Recombination. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6050.

Aims: To examine the clonal origin of a tumour, made up of a neuroendocrine component and a papillary serous component by comparing the pattern of loss of heterozygosity (LOH) and the immunohistochemical protein expression of both components. Methods/Results: A 70 year old woman, known to have a metastasised neuroendocrine carcinoma, underwent resection of the distal part of the ileum because of obstruction by a mesenterial mass. The macroscopically homogeneous mesenterial mass consisted histologically of an admixture of a neuroendocrine component and a papillary serous carcinoma. Loss of heterozygosity (LOH) analysis of both components with a panel of 15 polymorphic microsatellite markers showed a distinctive pattern of LOH, and both components showed LOH on chromosome 4q and 17, but involving different alleles at the same locus. Moreover, both components showed different immunohistochemical staining patterns for neuroendocrine markers, cytokeratin 7, carcinoembryonic antigen, and CA125. Conclusion: Both LOH analysis of the neuroendocrine and papillary serous components of this tumour and the immunohistochemical profile of both components are consistent with a different clonal origin. The tumour is probably a collision tumour, in which the papillary serous carcinoma must have been of peritoneal origin because necropsy revealed a normal uterus and normal ovaries.

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