High-throughput mutation profiling improves diagnostic stratification of sporadic medullary thyroid carcinomas

Simbolo, Michele; Mian, Caterina; Barollo, Susi; Fassan, Matteo; Mafficini, Andrea; Neves, Diogo; Scardoni, Maria; Pennelli, Gianmaria; Rugge, Massimo; Pelizzo, Maria Rosa; Cavedon, Elisabetta; Fugazzola, Laura; Scarpa, Aldo

doi:10.1007/s00428-014-1589-3

Cited by 70 publications

(72 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Overall, RAS mutations were present in 69.2% (18/26) of the RET WT cases and in only 2.5% of the RET-positive sporadic MTC (P!0.0001), suggesting that activation of the protooncogenes RAS and RET represents alternative genetic events in sporadic MTC tumorigenesis. These results were confirmed by other groups , Schulten et al 2011, Boichard et al 2012, Mian et al 2012, Tamburrino et al 2012, Ciampi et al 2013, Nikiforova et al 2013, Lyra et al 2014, Simbolo et al 2014, Pennelli et al 2015. We found no other mutations in the entire coding region of the genes HRAS, KRAS and RET in the RET and RAS WT sporadic MTC (M M Moura, B M Cavaco and V Leite, unpublished observations).…”

Section: Ras Mutations In Mtcsupporting

confidence: 91%

RAS proto-oncogene in medullary thyroid carcinoma

Moura¹,

Cavaco²,

Leite³

2015

Endocrine-Related Cancer

View full text Add to dashboard Cite

Medullary thyroid carcinoma (MTC) is a rare malignancy originating from the calcitoninsecreting parafollicular thyroid C cells. Approximately 75% of cases are sporadic. Rearranged during transfection (RET) proto-oncogene plays a crucial role in MTC development. Besides RET, other oncogenes commonly involved in the pathogenesis of human cancers have also been investigated in MTC. The family of human RAS genes includes the highly homologous HRAS, KRAS, and NRAS genes that encode three distinct proteins. Activating mutations in specific hotspots of the RAS genes are found in about 30% of all human cancers. In thyroid neoplasias, RAS gene point mutations, mainly in NRAS, are detected in benign and malignant tumors arising from the follicular epithelium. However, recent reports have also described RAS mutations in MTC, namely in HRAS and KRAS. Overall, the prevalence of RAS mutations in sporadic MTC varies between 0-43.3%, occurring usually in tumors with WT RET and rarely in those harboring a RET mutation, suggesting that activation of these proto-oncogenes represents alternative genetic events in sporadic MTC tumorigenesis. Thus, the assessment of RAS mutation status can be useful to define therapeutic strategies in RET WT MTC. MTC patients with RAS mutations have an intermediate risk for aggressive cancer, between those with RET mutations in exons 15 and 16, which are associated with the worst prognosis, and cases with other RET mutations, which have the most indolent course of the disease. Recent results from exome sequencing indicate that, besides mutations in RET, HRAS, and KRAS, no other recurrent driver mutations are present in MTC.

show abstract

Section: Ras Mutations In Mtcsupporting

confidence: 91%

RAS proto-oncogene in medullary thyroid carcinoma

Moura¹,

Cavaco²,

Leite³

2015

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…The prevalence of RET somatic mutations (57,8%) in our analysed group is consistent with previous reports [15,[29][30][31], where the frequency of somatic RET mutation ranges between 38% [29] and 71% [15]. Moreover, similarly to other data [29,30], the most frequent somatic RET mutation in our group was M918T, which constituted nearly 50% of all RET somatic mutations.…”

Section: Discussionsupporting

confidence: 92%

“…However, when we look at Italian results only, some differences may also be noticed. Ciampi et al reported a very low prevalence of RAS mutation in RET-negative sporadic MTC (17.6%) [32] while in the Scarpa and Fugazzola group the frequency of RAS mutation was 57% [31]. This percentage was even higher in our group -68.7 % of RET-negative tumours showed RAS mutation.…”

Section: Discussioncontrasting

confidence: 43%

“…The second explanation could be the different methodologies used for mutational RAS screening and their sensitivity. This is also visible in the Italian results, where Ciampi et al used PCR and direct sequencing [32], while Simbolo et al applied next generation sequencing [31]. Nonetheless, these differences do not explain all discrepancies because PCR and direct sequencing were used in many studies.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Częstość występowania mutacji somatycznych RAS w raku rdzeniastym tarczycy — analiza populacji polskiej

Oczko‐Wojciechowska

Pfeifer

Rusinek

et al. 2015

Endokrynologia Polska

View full text Add to dashboard Cite

Introduction: Somatic RET mutations are detectable in two-thirds of sporadic cases of medullary thyroid cancer (MTC). Recent studies reported a high proportion of RAS somatic mutations in RET negative tumours, which may indicate RAS mutation as a possible alternative genetic event in sporadic MTC tumorigenesis. Thus, the aim of the study was to evaluate the frequency of somatic RAS mutations in sporadic medullary thyroid cancer in the Polish population and to relate the obtained data to the presence of somatic RET mutations. Material and methods: Somatic mutations (RET, RAS genes) were evaluated in 78 snap-frozen MTC samples (57 sporadic and 21 hereditary) by direct sequencing. Next, three randomly selected RET-negative MTC samples were analysed by the next generation sequencing. Results: RAS mutation was detected in 26.5% of 49 sporadic MTC tumours. None of all the analysed samples showed N-RAS mutation. When only RET-negative samples were considered, the prevalence of RAS mutation was 68.7%, compared to 6% observed in RET-positive samples. Most of these mutations were located in H-RAS codon 61 (72%). None of 21 hereditary MTC samples showed any RAS mutations.

show abstract

“…These studies reported few additional somatic alterations and recurrent mutations only in the gene MDC1, which was not profiled in this study [32,33].…”

Section: Discussionmentioning

confidence: 58%