Molecular Genetic Alterations In Endometrial And Ovarian Cancers

Detta är en avhandling från Department of Oncology, The Jubileum Institute, SE-221 85

Sammanfattning: Endometrial cancer is the most common gynecological cancer diagnosed in western countries. Complex atypical hyperplasia (CAH) reflects a state of hyperestrinism and its role as a precursor lesion of this cancer is established. Endometrial cancers arising in association with CAH are reported in women of younger age, with early stage disease, favorable histological types, higher progesterone receptor levels and clinically better survival prognosis. However, the molecular events delineated in these two pathogenetic types are less known. Hereditary nonpolyposis colon cancer is caused by germline mutations in DNA mismatch repair (MMR) genes, and associated mainly with cancer in the colon, while endometrial and ovarian cancer are the most common extracolonic malignancies in these patients. Tumors from mutation carriers are characterized by an microsatellite instability (MSI) phenotype, and a subset of sporadic colon cancer demonstrates MSI and somatic mutations in MMR genes. MSI is also reported in a subset of sporadic endometrial cancers, although without identifiable mutation in MMR genes. In this study, endometrial cancers histologically checked for presence/absence of CAH were analyzed for mutations in the TP53, PTEN, KRAS, B-catenin, CDKN2A, BRCA1, and BRCA2 genes, as well as for their DNA ploidy and MSI. Two thirds of the endometrial tumors included in the study contained mutation in either of the seven genes analyzed, but very few cases with coexisting mutations were recorded, suggesting alternate genetic pathways in tumorigenesis. We found that PTEN, KRAS, B-catenin, and TP53 mutations were present in tumors both with and without CAH. PTEN mutations associated with MSI and DNA diploidy, while TP53 mutations related to DNA nondiploidy. Approximately 90% of all endometrial cancers are diagnosed in surgical stage disease I and II, with a five-year survival of 85% to 70%, respectively. A consensus opinion regarding useful prognostic markers to identify a “high-risk” subset among these patients is, however, lacking. In this study, TP53 alterations (mutation or protein overexpression) correlated to several clinicopathological markers of poor prognosis in endometrial cancer, and decreased progression-free survival in both early and advanced stage disease. However, DNA nondiploidy seemed to be an even better marker of poor prognosis in patients with early stage disease (I-II). The strongest risk factor for ovarian cancer is a positive family history of ovarian or breast cancer. While the majority of familial cases are associated with germline BRCA1 or BRCA2 mutation, the frequency of mutations in cases unselected for family history is still unclear. In the present pilot study of ovarian tumors, we detected a surprisingly high frequency of both germline and somatic BRCA-gene mutations, emphasizing the importance of extended analysis of population-based series of patients to determine the true contribution of these predisposing genes to the overall incidence of ovarian cancer in this population. BRCA-gene mutations strongly associated with a serous/seropapillary histological type. Unexpectedly, BRCA1 mutations were seen in two cases of ovarian cancer with brain metastasis.

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