The above observation implies that most of the detected mutations

The above observation implies that most of the detected mutations were present in the primary tumor and that very little, if any selection has occurred thereafter. The most compelling hypothesis regarding the origin of BRCA1 related high grade serous selleck chem ovarian carcinoma is that in fact the majority of them arise in the fallopian tube. Our findings suggest that most of the critical tumor driving clonal evolution occurs very early in the life of BRCA1 related highgrade serous carcinomas. One can reasonably speculate that the three tumors we studied here were all in fact secondary to the primary origin of the tumor and metastases from the now obscured primary tumor, likely in the fallopian tube. Surgery and chemother apy failed to eradicate the original clone.

Inhibitors,Modulators,Libraries Furthermore, when taking into account the relatively lower purity of the primary tumor, it is highly likely that most of the somatic mutations detected in this study were already present at high allelic frequency and high level of clonality in the tumor arising in the ovary. In agreement with our data, Castellarin et al. have recently suggested that Inhibitors,Modulators,Libraries in high grad serous carcinoma patients, most somatic mutations found in recurrent tumors during platinum based chemotherapy were present in primary tumors. Our data thus sug gests that little genetic evolution of the tumor has taken place from time of diagnosis to relapse following Inhibitors,Modulators,Libraries three courses of highly active chemotherapy. It is possible that the 2.

5 fold increase in allele frequency of the NF1 mutation from the primary tumor to the metastasis indicates that this mutation appeared in the pri mary tumor later than Inhibitors,Modulators,Libraries for example, TP53 mutation but was required for the full metastatic phenotype. It is likely that the primary tumor that is detected in patients is descended from cells that already contain a significant and potentially lethal mutational load. Another notable feature of our results is the presence of important cancer related mutations and their corresponding structural rearrangements in all three tumors. Clear examples are the above mentioned BRCA1 mutation, the missense mutation in TP53 resulting in R110P, the Inhibitors,Modulators,Libraries mutation in NF1 damaging the donor site for splicing, and the deletion in region 17q11 17q21 which re moved one copy of each of these three genes.

In the recent selleck bio companion study of ovarian carcinoma, TP53 mutations were present in the primary, first recurrent and second recurrent tumors in three high grade serous carcinoma pa tients. Frequent somatic mutations in NF1 have been previously shown to co occur with TP53 mutations. The NF1 associated RAS pathway is also activated in many ovarian cancer cases. Novel mutations identified in other genes should also be considered as candi dates for intensive investigation, since they were identified from all three samples. An interesting candidate mutation is the D891N change in TARBP1. TARBP1 encodes an RNA binding protein with a methyltransferase domain.

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