Mutational activation of BRAF is not a major event in sporadic childhood papillary thyroid carcinoma

Rosenbaum, Eli; Hosler, Gregory A.; Zahurak, Marianna; Cohen, Yoram; Sidransky, David; Westra, William H.

doi:10.1038/modpathol.3800252

Cited by 63 publications

(49 citation statements)

References 18 publications

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“…36 A point mutation in codon 600 of BRAF is the most prevalent mutation in adult papillary thyroid carcinoma; however, in childhood patients this mutation is very uncommon. [37][38][39][40][41][42] Of note is that in the youngest patients with papillary carcinoma, mutant BRAF is virtually absent whereas in older children and adolescents the frequency of mutant BRAF rises with increasing age. The BRAF protein is an effector of the MAP-kinase pathway; its impairment through missense mutation leads to increased cellular proliferation, dedifferentiation and genomic instability (reviewed by Xing 43 ).…”

Section: Point Mutationsmentioning

confidence: 96%

Mechanisms of Disease: molecular genetics of childhood thyroid cancers

Yamashita

Saenko

2007

Nat Rev Endocrinol

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Childhood thyroid cancers are uncommon and have a fairly good prognosis. Papillary adenocarcinoma is the most prevalent malignant tumor of the thyroid in children and adults with radiation-induced or sporadic cancer. The incidence of thyroid cancer in children increased dramatically in the territories affected by the Chernobyl nuclear accident; this increase is probably attributable to (131)I and other short-lived isotopes of iodine released into the environment. There was a broad range of latency periods in children who developed thyroid cancer; some periods were less than 5 years. The mutational spectrum of childhood thyroid cancers demonstrates that gene rearrangements that lead to the activation of mitogen-activated protein kinase signaling seem to have a pivotal role; point mutations are rare. So far none of the cancer genes or tumor suppressors, or a peculiar gene expression pattern, has been specifically implicated in radiation-induced thyroid carcinogenesis. The frequency of certain oncogenes does, however, vary in tumors that develop after different periods of latency. Such differences in the distribution of gene abnormalities in radiation-related cancers implies that they associate with patients' age at exposure and diagnosis, clinicopathological manifestations of disease and depend on an individual's genetic characteristics. Here we review results of pathological and molecular studies in childhood thyroid cancer.

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Section: Point Mutationsmentioning

confidence: 96%

Mechanisms of Disease: molecular genetics of childhood thyroid cancers

Yamashita

Saenko

2007

Nat Rev Endocrinol

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“…In an orthotopic mouse model for papillary thyroid carcinoma (PTC), sorafenib dramatically reduced tumor growth in PTC with RET/PTC1 mutation to a greater extent than in PTC with BRAF mutation [20]. This was compelling since children with PTC are more likely to have RET/PTC rearrangements and less likely to harbor somatic BRAF mutations [21,22]. …”

Section: Introductionmentioning

confidence: 99%

Phase 2 trial of sorafenib in children and young adults with refractory solid tumors: A report from the Children's Oncology Group

Kim

Widemann

Krailo

et al. 2015

Pediatric Blood & Cancer

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Background Sorafenib is an oral small molecule inhibitor of multiple kinases controlling tumor growth and angiogenesis. The purpose of this phase 2 study was to determine the response rate of sorafenib and gain further information on the associated toxicities, pharmacokinetics, and pharmacodynamics of sorafenib in children and young adults with relapsed or refractory tumors including rhabdomyosarcoma, Wilms tumor, hepatocellular carcinoma (HCC) and papillary thyroid carcinoma (PTC). Procedure Sorafenib, 200 mg/m2/dose, was administered every 12 hours continuously for 28 day cycles using a two-stage design in two primary strata (rhabdomyosarcoma and Wilms tumor) and two secondary strata (HCC and PTC). Correlative studies in consenting patients included determination of sorafenib steady state trough concentrations and assessments of VEGF and sVEGFR2. Results Twenty patients (median age of 11 years; range, 5–21) enrolled. No objective responses (RECIST) were observed in the 10 evaluable patients enrolled in each of the two primary disease strata of rhabdomyosarcoma and Wilms tumor. No patients with HCC or PTC were enrolled. Sorafenib was not associated with an excessive rate of DLT. The mean ± SD steady state concentration during cycle 1 day 15 was 6.5 ± 3.9 µg/mL (n=10). Conclusions Sorafenib was well tolerated in children at 200 mg/m2/dose twice daily on a continuous regimen with toxicity profile and steady state drug concentrations similar to those previously reported. Single agent sorafenib was inactive in children with recurrent or refractory rhabdomyosarcoma or Wilms tumor.

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“…Further studies focused on searching the relationship between the mutation and other features of an unfavorable course of the disease (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). As early as in 2003 Nikiforova et al (23) paid attention to the relationship between BRAF mutation and advanced age of patients and also histological subtypes of cancer (classic and tall cell PTC, extracapsular extension and a frequent incidence in patients in III and IV stages.…”

Section: The Relationship Of Braf Mutation With Other Clinico-patholomentioning

confidence: 99%

“…Other observations were noted in the following years. A number of studies from single centers were reported, which analyzed the prevalence of the mutation and its relationship with other clinicopathological risk factors (24)(25)(26)(27)(28)(29)(30)(31)(32)(33). However, the studies resulted in different, often conflicting results, which were related to differences in methodology, i.e., group selection, group size, time of the follow-up and the type of statistical analyses (uni-and/or multi-variable), the differences in BRAF mutation occurrence in different populations, the methodology of BRAF identification and also lack of the results of validations.…”

Section: The Relationship Of Braf Mutation With Other Clinico-patholomentioning

confidence: 99%

BRAF V600E mutation in prognostication of papillary thyroid cancer (PTC) recurrence

Czarniecka¹,

Oczko-Wojciechowska²,

Barczyński³

2016

Gland Surg.

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Papillary thyroid cancer (PTC) offers excellent prognosis, however relapse risk or persistent disease is related to ~30%. Currently, attention is paid to the possibility of patient group selection of different risk of unfavorable outcome to match a particular therapeutic approach. Therefore, interest in new prognostic and predictive markers known preoperatively is observed. BRAF V600E mutation is such a marker. Many studies analyzing the prevalence of the mutation and its relationship with other clinicopathological risk factors were reported but with controversial conclusions. The prognostic significance of BRAF mutation was confirmed by some single centre studies, a few meta-analyses and a large multicenter retrospective international study. They confirmed a correlation between the mutation and the risk of recurrence. The strongest argument against using BRAF mutation as an independent prognostic and predictive factor in PTC is its high prevalence (30-80%). At present it seems that BRAF mutation is one of the factors influencing the prognosis and it should be analyzed in correlation with other prognostic factors.The most recent ATA recommendations do not indicate a routine application of BRAF status for initial risk stratification in differentiated thyroid cancer due to a lack of evident confirmation of a direct influence of mutation on the increase in relapse risk. However, ATA demonstrates the continuous risk scale for the relapse risk assessment, considering BRAF and/or TERT status. At present, researchers are working on determining the role of BRAF mutation in patients from a low-risk group and its correlations with others molecular events. Currently, BRAF mutation cannot be used as a single, independent predictive factor. However, its usefulness in the context of other molecular and clinico-pathological risk factors cannot be excluded. They may be used to make modern prognostic scales of relapse risk and be applied to individualized diagnostic and therapeutic strategy for PTC patients.

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Mutational activation of BRAF is not a major event in sporadic childhood papillary thyroid carcinoma

Cited by 63 publications

References 18 publications

Mechanisms of Disease: molecular genetics of childhood thyroid cancers

Mechanisms of Disease: molecular genetics of childhood thyroid cancers

Phase 2 trial of sorafenib in children and young adults with refractory solid tumors: A report from the Children's Oncology Group

BRAF V600E mutation in prognostication of papillary thyroid cancer (PTC) recurrence

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