Mutational analysis of metastatic lymph nodes from papillary thyroid carcinoma in adult and pediatric patients

Shifrin, Alexander; Fischer, Michele; Paul, Trevor; Erler, Brian; Gheysens, Katherine; Baodhankar, Prachi; Song‐Yang, Joanna Wanmin; Taylor, S Mark; Timmaraju, Venkata Arun; Topilow, Arthur A.; Mireskandari, Alidad; Kumar, Gyanendra

doi:10.1016/j.surg.2016.10.002

Cited by 5 publications

(4 citation statements)

References 22 publications

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“…In sporadic pediatric PTC series from other countries, the prevalence of RAS point mutations ranged from 0 to 25% [8,9,24,28,36,[40][41][42][43][44], pooled 4.0% (20/498) without significant overall difference with our series (p = 0.631), demonstrating again that this type of oncogene is rather rare in PTC in young patients.…”

Section: The Ras Family Gene Mutations In Ptc Diagnosed In Pediatric/young Adult Patientscontrasting

confidence: 46%

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus

Rogounovitch

Mankovskaya

Fridman

et al. 2021

Cancers

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Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics have not been reported. Here, we determine the major oncogenic events in PTC from non-exposed Belarusian children and assess their clinicopathological correlations. Among the 34 tumors, 23 (67.6%) harbored one of the mutually exclusive oncogenes: 5 (14.7%) BRAFV600E, 4 (11.8%) RET/PTC1, 6 (17.6%) RET/PTC3, 2 (5.9%) rare fusion genes, and 6 (17.6%) ETV6ex4/NTRK3. No mutations in codons 12, 13, and 61 of K-, N- and H-RAS, BRAFK601E, or ETV6ex5/NTRK3 or AKAP9/BRAF were detected. Fusion genes were significantly more frequent than BRAFV600E (p = 0.002). Clinicopathologically, RET/PTC3 was associated with solid growth pattern and higher tumor aggressiveness, BRAFV600E and RET/PTC1 with classic papillary morphology and mild clinical phenotype, and ETV6ex4/NTRK3 with follicular-patterned PTC and reduced aggressiveness. The spectrum of driver mutations in sporadic childhood PTC in Belarus largely parallels that in Chernobyl PTC, yet the frequencies of some oncogenes may likely differ from those in the early-onset Chernobyl PTC; clinicopathological features correlate with the oncogene type.

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Section: The Ras Family Gene Mutations In Ptc Diagnosed In Pediatric/young Adult Patientscontrasting

confidence: 46%

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus

Rogounovitch

Mankovskaya

Fridman

et al. 2021

Cancers

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“…tumor and mutation-positive metastases were also frequently reported [13,14,34,35]. An interesting genomics study was reported by Le Pennec et al [15] who performed a systemic cDNA sequencing screening of a primary tumor (different subregions), lymph node metastases and distant (pleural) metastasis in a patient with an aggressive PTC.…”

Section: Discussionmentioning

confidence: 91%

Molecular Heterogeneity of Papillary Thyroid Cancer: Comparison of Primary Tumors and Synchronous Metastases in Regional Lymph Nodes by Mass Spectrometry Imaging

et al. 2019

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Intra-tumor heterogeneity results from both genetic heterogeneity of cancer (sub)clones and phenotypic plasticity of cancer cells that could be induced by different local microenvironments. Here, we used mass spectrometry imaging (MSI) to compare molecular profiles of primary tumors located in the thyroid gland and their synchronous metastases in regional lymph nodes to analyze phenotypic heterogeneity in papillary thyroid cancer. Two types of cancerous (primary tumor and metastasis) and two types of not cancerous (thyroid gland and lymph node) regions of interest (ROIs) were delineated in postoperative material from 11 patients, then the distribution of tryptic peptides (spectral components) was analyzed by MSI in all tissue regions. Moreover, tryptic peptides identified by shotgun proteomics in corresponding tissue lysates were matched to components detected by MSI to enable their hypothetical protein annotation. Unsupervised segmentation of all cancer ROIs revealed that different clusters dominated in tumor ROIs and metastasis ROIs. The intra-patient similarity between thyroid and tumor ROIs was higher than the intra-patient similarity between tumor and metastasis ROIs. Moreover, the similarity between tumor and its metastasis from the same patients was lower than similarities among tumors and among metastases from different patients (inter-patient similarity was higher for metastasis ROIs than for tumor ROIs). Components differentiating between tumor and its metastases were annotated as proteins involved in the organization of the cytoskeleton and chromatin, as well as proteins involved in immunity-related functions. We concluded that phenotypical heterogeneity between primary tumor and lymph node metastases from the same patient was higher than inter-tumor heterogeneity between primary tumors from different patients.

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“…A discordant mutational status between the primary site and the metastases supports this mechanism and it was recorded in several human tumors (including lung, melanoma, colorectal, gastric, breast) [4]. In TC, discordant patterns were reported for BRAF V600E , TERT, RAS and other mutations [27,39,40,51,52,[58][59][60][61][62][63][64][65]. Data related to PTC are reviewed in Table 3.…”

Section: Discordant Mutational Status Between Primary Site and Metastmentioning

confidence: 83%

“…Interestingly, the two selected areas of the primary tumor and the two selected areas of on regional metastasis presented similar genetic profiles, whereas the two selected areas of another regional metastasis had more divergent mutations and fusions [55]. Striking heterogeneity was also observed between paired primary tumors and metastases in studies done by means of NGS and WES studies [58,60,63,64]. Mass spectrometry imaging lymph node discordant Gawin et al 2019 [65] Legend: * for likely pathogenic cancer genes.…”

Section: Discordant Mutational Status Between Primary Site and Metastmentioning

confidence: 99%

Intratumoral Genetic Heterogeneity in Papillary Thyroid Cancer: Occurrence and Clinical Significance

Fugazzola

Muzza

Pogliaghi

et al. 2020

Cancers

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Intratumoral heterogeneity (ITH) refers to a subclonal genetic diversity observed within a tumor. ITH is the consequence of genetic instability and accumulation of genetic alterations, two mechanisms involved in the progression from an early tumor stage to a more aggressive cancer. While this process is widely accepted, the ITH of early stage papillary thyroid carcinoma (PTC) is debated. By different genetic analysis, several authors reported the frequent occurrence of PTCs composed of both tumor cells with and without RET/PTC or BRAFV600E genetic alterations. While these data, and the report of discrepancies in the genetic pattern between metastases and the primary tumor, demonstrate the existence of ITH in PTC, its extension and biological significance is debated. The ITH takes on a great significance when involves oncogenes, such as RET rearrangements and BRAFV600E as it calls into question their role of driver genes. ITH is also predicted to play a major clinical role as it could have a significant impact on prognosis and on the response to targeted therapy. In this review, we analyzed several data indicating that ITH is not a marginal event, occurring in PTC at any step of development, and suggesting the existence of unknown genetic or epigenetic alterations that still need to be identified.

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Mutational analysis of metastatic lymph nodes from papillary thyroid carcinoma in adult and pediatric patients

Cited by 5 publications

References 22 publications

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus

Molecular Heterogeneity of Papillary Thyroid Cancer: Comparison of Primary Tumors and Synchronous Metastases in Regional Lymph Nodes by Mass Spectrometry Imaging

Intratumoral Genetic Heterogeneity in Papillary Thyroid Cancer: Occurrence and Clinical Significance

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