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      BRAF V600E mutation in papillary thyroid carcinoma: it’s relation to clinical features and oncologic outcomes in a single cancer centre experience

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          Abstract

          Purpose

          This study focuses on the oncologic influence of BRAF V600E mutations in a cohort of Middle Eastern papillary thyroid carcinoma (PTC) patients treated at a single centre. We tested the association of BRAF V600E mutation with papillary thyroid carcinoma at King Hussein Cancer Center.

          Methods

          Patients with histologically confirmed PTC who underwent surgical treatment between 2006 and 2015 were included in this study. Oncological outcomes, both short- and long-termed, were collected.

          Results

          A total of 128 patients (68% females) were included in this study with a mean age of 38 years (±13.8). The median follow-up period was 50 months. The BRAF V600E mutation was found in 71% of patients. The tumour size for patients with a negative BRAF V600E mutation was significantly larger in comparison to patients who tested positive for the mutation (3.47 cm vs 2.31 cm, respectively, P = 0.009). The two groups showed similar disease-free survival (DFS) rates; positive = 75% (median 43 months (0–168)) compared to 78% for the negative BRAF V600E mutation (median 38 months (3–142)) ( P = 0.162, HR = 0.731) Furthermore, both groups showed similar overall survival rates, positive = 94.5% (median 56 months (0–228)) compared to 94.6% for the negative BRAF V600E mutation (median 43 months (3–157)) ( P = 0.941, HR = 0.940).

          Conclusion

          BRAF V600E mutation had no effect on loco-regional recurrence, distant metastasis, overall survival, or DFS. These findings may be attributed to geographic variations or reflect that BRAF V600E may only serve as an indicator of poor prognosis in high-risk group as such.

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          Most cited references25

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          Mutational heterogeneity in cancer and the search for new cancer genes

          Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention.
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            • Record: found
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            Is Open Access

            Integrated genomic characterization of papillary thyroid carcinoma.

            (2014)
            Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.
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              BRAF mutation in thyroid cancer.

              M Xing (2005)
              Genetic alteration is the driving force for thyroid tumorigenesis and progression, based upon which novel approaches to the management of thyroid cancer can be developed. A recent important genetic finding in thyroid cancer is the oncogenic T1799A transversion mutation of BRAF (the gene for the B-type Raf kinase, BRAF). Since the initial report of this mutation in thyroid cancer 2 years ago, rapid advancements have been made. BRAF mutation is the most common genetic alteration in thyroid cancer, occurring in about 45% of sporadic papillary thyroid cancers (PTCs), particularly in the relatively aggressive subtypes, such as the tall-cell PTC. This mutation is mutually exclusive with other common genetic alterations, supporting its independent oncogenic role, as demonstrated by transgenic mouse studies that showed BRAF mutation-initiated development of PTC and its transition to anaplastic thyroid cancer. BRAF mutation is mutually exclusive with RET/PTC rearrangement, and also displays a reciprocal age association with this common genetic alteration in thyroid cancer. The T1799A BRAF mutation occurs exclusively in PTC and PTC-derived anaplastic thyroid cancer and is a specific diagnostic marker for this cancer when identified in cytological and histological specimens. This mutation is associated with a poorer clinicopathological outcome and is a novel independent molecular prognostic marker in the risk evaluation of thyroid cancer. Moreover, preclinical and clinical evaluations of the therapeutic value of novel specific mitogen-activated protein kinase pathway inhibitors in thyroid cancer are anticipated. This newly discovered BRAF mutation may prove to have an important impact on thyroid cancer in the clinic.
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                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                03 November 2021
                01 December 2021
                : 10
                : 12
                : 1531-1537
                Affiliations
                [1 ]Department of Surgery, King Hussein Cancer Center, Amman , Jordan
                [2 ]Department of Internal Medicine , Endocrine, King Hussein Cancer Center, Amman, Jordan
                [3 ]Department of Pathology & Laboratory Medicine , King Hussein Cancer Center, Amman, Jordan
                [4 ]Department of Cell Therapy & Applied Genomics , King Hussein Cancer Center, Amman, Jordan
                [5 ]School of Medicine , University of Jordan, Amman, Jordan
                Author notes
                Correspondence should be addressed to M Al-Masri: malmasri@ 123456khcc.jo
                Author information
                http://orcid.org/0000-0001-5156-623X
                Article
                EC-21-0410
                10.1530/EC-21-0410
                8679880
                34734568
                1ef4954e-279b-4e49-aed2-eea12866da27
                © The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 21 September 2021
                : 03 November 2021
                Categories
                Research

                thyroid cancer,papillary,neoplasms,mutation,middle east
                thyroid cancer, papillary, neoplasms, mutation, middle east

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