Mortality Risk Stratification by Combining <i>BRAF </i>V600E and <i>TERT</i> Promoter Mutations in Papillary Thyroid Cancer

Liu, Rengyun; Bishop, Justin A.; Zhu, Guangwu; Zhang, Tao; Ladenson, Paul W.; Xing, Minzhi

doi:10.1001/jamaoncol.2016.3288

Cited by 237 publications

(226 citation statements)

References 37 publications

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“…33,34 Moreover, TERT promoter mutation alone has limited or virtually no effect on PTC-specific mortality. 35,36 Therefore, lack of information on TERT promoter mutation should not affect the clinical implications of this study on the use of BRAF V600E status in differentiating patient age-related mortality risk in PTC.…”

Section: Discussionmentioning

confidence: 99%

“…[38][39][40] Another potential and more likely mechanism is the coexistence of BRAF V600E and TERT promoter mutations, which are synergistically associated with poor clinical outcomes in PTC, including disease recurrence and patient mortality. 35,36 Both BRAF V600E 20-22 and TERT promoter mutations 34 occur in PTC more commonly in older patients. The present results are also consistent with a previous finding that BRAF V600E and older patient age had a synergistic effect on PTC-related mortality.…”

Section: Discussionmentioning

confidence: 99%

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Patient Age–Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer

Shen

Zhu

Liu

et al. 2018

JCO

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107

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For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and MethodsWe conducted a comparative study of the relationship between patient age at diagnosis and PTCspecific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. ResultsThere was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. ConclusionThe long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Patient Age–Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer

Shen

Zhu

Liu

et al. 2018

JCO

Self Cite

107

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“…On the other hand, alterations in the telomere 3D profile have been reported in a murine model of thyroid tumors [41]. Recurrent somatic mutations in the promoter of TERT, the catalytic subunit of the enzyme telomerase, has been reported in PTC [42], often in concomitance with mutated BRAF [43]. A subclonal distribution in the rare PTC that harbor the alteration, in contrast to a clonal distribution in the poorly-differentiated and anaplastic tumors has been observed [44].…”

Section: Discussionmentioning

confidence: 99%

Genetic Heterogeneity of HER2 Amplification and Telomere Shortening in Papillary Thyroid Carcinoma

Caria

Cantara

Frau

et al. 2016

IJMS

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Extensive research is dedicated to understanding if sporadic and familial papillary thyroid carcinoma are distinct biological entities. We have previously demonstrated that familial papillary thyroid cancer (fPTC) cells exhibit short relative telomere length (RTL) in both blood and tissues and that these features may be associated with chromosome instability. Here, we investigated the frequency of HER2 (Human Epidermal Growth Factor Receptor 2) amplification, and other recently reported genetic alterations in sporadic PTC (sPTC) and fPTC, and assessed correlations with RTL and BRAF mutational status. We analyzed HER2 gene amplification and the integrity of ALK, ETV6, RET, and BRAF genes by fluorescence in situ hybridization in isolated nuclei and paraffin-embedded formalin-fixed sections of 13 fPTC and 18 sPTC patients. We analyzed BRAFV600E mutation and RTL by qRT-PCR. Significant HER2 amplification (p = 0.0076), which was restricted to scattered groups of cells, was found in fPTC samples. HER2 amplification in fPTCs was invariably associated with BRAFV600E mutation. RTL was shorter in fPTCs than sPTCs (p < 0.001). No rearrangements of other tested genes were observed. These findings suggest that the association of HER2 amplification with BRAFV600E mutation and telomere shortening may represent a marker of tumor aggressiveness, and, in refractory thyroid cancer, may warrant exploration as a site for targeted therapy.

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“…Some groups report that co-occurrence of TERT promoter and BRAF mutations are associated with worse prognosis factors in thyroid cancer (Allory et al 2014, 2016a, Song et al 2016, whereas other authors have not found this association in other series (Melo et al 2014, George et al 2015, Nasirden et al 2016.…”

Section: Tert Promoter Mutations In Thyroid Cancermentioning

confidence: 94%

TERT biology and function in cancer: beyond immortalisation

Pestana

Vinagre

Sobrinho-Simões

et al. 2017

Journal of Molecular Endocrinology

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Evasion of replicative senescence and proliferation without restriction, sometimes designated as immortalisation, is one of the hallmarks of cancer that may be attained through reactivation of telomerase in somatic cells. In contrast to most normal cells in which there is lack of telomerase activity, upregulation of TERT transcription/activity is detected in 80-90% of malignant tumours. In several types of cancer, there is a relationship between the presence of TERT promoter mutations, TERT mRNA expression and clinicopathological features, but the biological bridge between the occurrence of TERT promoter mutations and the aggressive/invasive features displayed by the tumours remains unidentified. We and others have associated the presence of TERT promoter mutations with metastisation/survival in several types of cancer. In follicular cell-derived thyroid cancer, such mutations are associated with worse prognostic features (age of patients, tumour size and tumour stage) as well as with distant metastases, worse response to treatment and poorer survival. In this review, we analyse the data reported in several studies that imply TERT transcription reactivation/activity with cell proliferation, tumour invasion and metastisation. A particular attention is given to the putative connections between TERT transcriptional reactivation and signalling pathways frequently altered in cancer, such as c-MYC, NF-κB and B-Catenin.

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Mortality Risk Stratification by Combining BRAF V600E and TERT Promoter Mutations in Papillary Thyroid Cancer

Cited by 237 publications

References 37 publications

Patient Age–Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer

Patient Age–Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer

Genetic Heterogeneity of HER2 Amplification and Telomere Shortening in Papillary Thyroid Carcinoma

TERT biology and function in cancer: beyond immortalisation

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