RESUMEN
The origin of primary mucinous ovarian tumors is unknown. We explore the hypothesis that they originate from either Brenner tumors or teratomas and examine differences between the tumors that arise in these settings. A total of 104 Brenner tumor-associated mucinous tumors and 58 teratoma-associated mucinous tumors were analyzed. Immunohistochemistry for 21 antigens and fluorescence in situ hybridization for ERBB2 and MYC were performed. Genome-wide copy number analysis and mutation analysis for 56 cancer-related genes was carried out on a subset of mucinous ovarian tumors and their complementary Brenner tumor or teratoma. Patients with teratoma-associated mucinous tumors were significantly younger than patients with Brenner tumor-associated mucinous tumors (43 vs. 61 years). During progression from cystadenoma to atypical proliferative mucinous (borderline) tumor to carcinoma expression of typical gastrointestinal markers was increased in both Brenner tumor-associated and teratoma-associated mucinous tumors. Brenner tumor-associated mucinous tumors showed more frequently calcifications and Walthard cell nests, rarely expressed SATB2 and showed more often co-deletion of CDKN2A and MTAP. Teratoma-associated mucinous tumors were characterized by mucinous stromal dissection, SATB2 expression and RNF43 mutations. Other frequent mutations in both Brenner tumor-associated and teratoma-associated mucinous tumors were TP53 and KRAS mutations. Based on identical mutations or copy number profiles clonal relationships were indicated in two mucinous tumors and their associated Brenner tumor. Teratomas and Brenner tumors give rise to different subtypes of mucinous ovarian tumors. Subsequent progression pathways are comparable since both Brenner tumor-associated and teratoma-associated mucinous tumors develop a gastrointestinal immunophenotype during progression and show early mutations in KRAS and TP53. Teratoma-associated mucinous tumors may more closely resemble true gastrointestinal tumors, indicated by their expression of SATB2 and the presence of RNF43 mutations.
Asunto(s)
Adenocarcinoma Mucinoso/genética , Biomarcadores de Tumor/genética , Tumor de Brenner/genética , Cistoadenoma Mucinoso/genética , Neoplasias Ováricas/genética , Teratoma/genética , Adenocarcinoma Mucinoso/química , Adenocarcinoma Mucinoso/patología , Adulto , Baltimore , Biomarcadores de Tumor/análisis , Tumor de Brenner/química , Tumor de Brenner/patología , Cistoadenoma Mucinoso/química , Cistoadenoma Mucinoso/patología , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Dosificación de Gen , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Proteínas de Unión a la Región de Fijación a la Matriz/análisis , Persona de Mediana Edad , Mutación , Países Bajos , Neoplasias Ováricas/química , Neoplasias Ováricas/patología , Fenotipo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor ErbB-2/genética , Teratoma/química , Teratoma/patología , Factores de Transcripción/análisis , Proteína p53 Supresora de Tumor/genéticaRESUMEN
PURPOSE: To investigate the prognostic value of multiple cell cycle-associated proteins in a large series of stage II and III colon cancers. METHODS: From formalin-fixed, paraffin-embedded tumor samples of 386 patients with stage II and III colon cancer, DNA was isolated and tissue microarrays were constructed. Tissue microarray slides were immunohistochemically stained for p21, p27, p53, epidermal growth factor receptor, Her2/Neu, ß-catenin, cyclin D1, Ki-67, thymidylate synthase, and Aurora kinase A (AURKA). Polymerase chain reaction-based microsatellite instability analysis was performed to allow for stratification of protein expression by microsatellite instability status. RESULTS: Overall, low p21, high p53, low cyclin D1, and high AURKA expression were significantly associated with recurrence (P = 0.01, P < 0.01, P = 0.04, and P < 0.01, respectively). In stage II patients who did not receive adjuvant chemotherapy (n = 190), significantly more recurrences were observed in case of low-p21 and high-p53-expressing tumors (P < 0.01 and P = 0.03, respectively). In stage III patients who did not receive chemotherapy, high p53 expression was associated with recurrence (P = 0.02), and in patients who received chemotherapy, high AURKA expression was associated with relapse (P < 0.01). In patients with microsatellite stable tumors, high levels of p53 and AURKA were associated with recurrence (P = 0.01 and P < 0.01, respectively). Multivariate analysis showed p21 (odds ratio 1.6, 95% confidence interval 0.9-2.8) and AURKA (odds ratio 2.7, 95% confidence interval 1.3-5.6) to be independently associated with disease recurrence. CONCLUSIONS: p21, p53, cyclin D1, and AURKA could possibly be used as prognostic markers to identify colon cancer patients with high risk of disease recurrence.