Routine Screening for &lt;b&gt;&lt;i&gt;KIT&lt;/i&gt;&lt;/b&gt; M541L Is Not Warranted in the Diagnostic Work-Up of Patients with Hypereosinophilia

Hoade, Yvette; Metzgeroth, Georgia; Schwaab, Juliana; Reiter, Andreas; Cross, Nicholas C. P.

doi:10.1159/000485959

Cited by 5 publications

(2 citation statements)

References 12 publications

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“…The substitution of methionine for leucine at position 541, at the end of the transmembrane domain (exon 10), increased activation by the KIT receptor of the PI3K/AKT and MAPK signalling pathways compared to wild-type KIT. However, KIT p.(Met541Leu) was not associated with responses to imatinib in GISTs [ 81 , 83 ], aggressive fibromatosis [ 84 ], or hypereosinophilia [ 85 ].…”

Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas

Szpechcinski¹,

Szołkowska²,

Winiarski³

et al. 2022

Cancers

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A better understanding of the molecular pathogenesis of thymic epithelial tumours (TETs) could revolutionise their treatment. We evaluated thymomas and thymic carcinomas by next-generation sequencing (NGS) of somatic or germline single nucleotide variants (SNVs) in genes commonly mutated in solid tumours. In total, 19 thymomas and 34 thymic carcinomas were analysed for nonsynonymous SNVs in 15 genes by targeted NGS (reference genome: hg19/GRCh37). Ten SNVs in TP53 (G154V, R158P, L194H, R267fs, R273C, R306 *, Q317 *), ERBB2 (V773M), KIT (L576P), and KRAS (Q61L) considered somatic and pathogenic/likely pathogenic were detected in 10 of 34 (29.4%) thymic carcinomas. No somatic SNVs confirmed as pathogenic/likely pathogenic were found in thymomas. Rare SNVs of uncertain or unknown functional and clinical significance, to our knowledge not reported previously in TETs, were found in ERBB2 (S703R), KIT (I690V), and FOXL2 (P157S) in 3 of 19 (16%) thymomas. The most frequent germline SNVs were TP53 P72R (94% TETs), ERBB2 I655V (40% TETs), and KIT M541L (9% TETs). No significant difference in median disease-free survival (DFS) was found between thymic carcinoma patients with and without pathogenic SNVs (p = 0.190); however, a trend toward a longer DFS was observed in the latter (16.0 vs. 30.0 months, respectively). In summary, NGS analysis of TETs revealed several SNVs in genes related to the p53, AKT, MAPK, and K-Ras signalling pathways. Thymic carcinomas showed greater genetic dysregulation than thymomas. The germline and rare SNVs of uncertain clinical significance reported in this study add to the number of known genetic alterations in TETs, thus extending our molecular understanding of these neoplasms. Druggable KIT alterations in thymic carcinomas have potential as therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas

Szpechcinski¹,

Szołkowska²,

Winiarski³

et al. 2022

Cancers

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“…1621 A>С, определявшаяся в 5 пробах (7,5 %, при 95 % ДИ от 3,2 до 16,3 %). Однако, по данным литературы, она является полиморфным аллельным вариантом и не имеет патогенетического значения в развитии опухолей [6,7]. Выявленные синонимичные замены c. 1638 A>G (n=9, 13,4 %, при 95 % ДИ от 7,2 до 23,6 %), c. 2586 G>C -(n=7, 13,4 %, при 95 % ДИ от 5,2 до 20,0 %) и c. 2394 C>T (n=1, 1,5 %, при 95 % ДИ от 0,2 до 8,0 %) не приводят к изменению структуры кодируемого белка, а потому также не могут рассматриваться как генетические события, являющиеся драйверными в лейкомогенезе.…”

Section: пцрunclassified

Molecular genetic analisys of c-Kiт gene mutations in acute myeloid leukemia in the age aspect

Vinogradov¹,

Izotov²,

Rezaykin³

et al. 2020

Medical news of the North Caucasus

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1 sverdlovsk regional ministry of health, ekaterinburg, russian federation 2 ural state medical university, ekaterinburg, russian federation 3 institute of medical cell Technology, ekaterinburg, russian federation 4 stavropol state medical university, stavropol, russian federation Методом прямого автоматического секвенирования изучали онкогенный потенциал мутаций гена c-Kit в экзонах 7-12 и 16-19 гена у 67 больных c впервые выявленными формами острого миелоидного лейкоза (ОМЛ). Кроме того, 56 проб дополнительно обследованы на наличие инсерций в экзоне 12 гена NPM1 молекулярно-генетическим и иммуногистохимическим методами. Частота функционально значимых мутаций в гене с-Kit составила 13,4 % (n=9), из них 5-в группе больных ОМЛ в возрасте 15-45 лет (15,2 %), 4-у пациентов пожилого и старческого возраста (11,8 %). То есть частота мутаций гена c-Kit у больных в зависимости от возрастной принадлежности статистически не отличалась. В трех пробах выявлены инсерции в гене NPM1 (5,4 %). Однако методом компьютерного моделирования с использованием распределенной сети предсказания структуры показано, что онкогенным потенциалом среди выявленных молекулярных изменений обладали лишь миссенс-мутация с. 2447 A>Т, а также инсерции и делеции экзонов 10 и 11 (6,0 %, n=4). При этом наиболее часто встречающаяся несинонимичная трансверсия с. 1621 A>С (7,5 %, n=5), как изолированная, так и в сочетании с транзицией с. 1636 А>G, не оказывала какого-либо существенного влияния на третичную структуру и не приводила к спонтанной активации белка c-Kit. Прогностическое значение выявленных мутаций в гене c-Kit при ОМЛ было неблагоприятным, однако применение ингибиторов тирозинкиназ имеет клинические перспективы наряду с высокодозной химиотерапией и аллогенной трансплантацией костного мозга. Ключевые слова: острый миелоидный лейкоз, ген c-Kit, молодой возраст, пожилой и старческий возраст, секвенирование, моделирование структуры белка Direct automatic sequencing was used to study the oncogenic potential of mutations of the c-Kit gene in exons 7-12 and 16-19 of the gene in 67 patients with newly identified forms of acute myeloid leukemia (AML). Besides, 56 samples were additionally tested for insertion in exon 12 of the NPM1 gene using molecular genetic and immunohistochemical methods. The frequency of functionally significant mutations in the c-Kit gene was 13.4 % (n=9), 5 of which were in the group of AML patients aged 15-45 years (15.2 %), 4-in elderly patients (11.8 %). That is, the frequency of mutations of the c-Kit gene in patients, depending on age, did not differ statistically significantly. Three samples revealed insertions in the NPM1 gene (5.4 %). However, by computer modeling using Protein Homology/AnalogY Recognition Engine, it was shown that only the missense mutation of с. 2447 A>T, as well as insertions and deletions of exons 10 and 11 (6.0 %, n=4) had oncogenic potential among the detected molecular changes. At the same time, the most common non-synonymous transversion of c. 1621 A>C (7.5 %, n=5), both isolated and combined with ...

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Tyrosine Kinase Inhibitors in Systemic Mastocytosis

2019

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Routine Screening for <b><i>KIT</i></b> M541L Is Not Warranted in the Diagnostic Work-Up of Patients with Hypereosinophilia

Cited by 5 publications

References 12 publications

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas

Molecular genetic analisys of c-Kiт gene mutations in acute myeloid leukemia in the age aspect

Tyrosine Kinase Inhibitors in Systemic Mastocytosis

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