Whole exome sequencing identifies a germline <i>MET</i>
 mutation in two siblings with hereditary wild-type <i>RET</i>
 medullary thyroid cancer

Sponziello, Marialuisa; Benvenuti, Silvia; Gentile, Alessandra; Pecce, Valeria; Rosignolo, Francesca; Virzì, Anna Rita; Milan, Melissa; Comoglio, Paolo M.; Londin, Eric; Fortina, Paolo; Barnabei, Agnese; Appetecchia, Marialuisa; Marandino, Ferdinando; Russo, Diego; Durante, Cosimo; Verrienti, Antonella

doi:10.1002/humu.23378

Cited by 27 publications

(15 citation statements)

References 31 publications

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“…Interestingly, by NGS MET mutations were exclusively found in the two “progressed” DMPMs (p.R359Q case #16 and p.E168D case #17). Even if these MET mutations have conflicting interpretations of pathogenicity, they are located in the MET Sema domain that is necessary for HGF binding and receptor dimerization/activation, and mutations in this domain can promote an invasive malignant phenotype [14].…”

Section: Resultsmentioning

confidence: 99%

Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma

Belfiore

Busico

Bozzi

et al. 2019

IJMS

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Background—There are currently no effective therapies for diffuse malignant peritoneal mesothelioma (DMPM) patients with disease recurrence. In this study, we investigated the biology of DMPM by analyzing the EGFR family, Axl, and MET, in order to assess the presence of cross-talk between these receptors, suggesting the effectiveness of combined targeted treatments in DMPM. Method—We analyzed a series of 22 naïve epithelioid DMPM samples from a single institute, two of which showed higher-grade malignancy (“progressed”). EGFR, HER2, HER3, Axl, and MET activation and expression were investigated by biochemical analysis, real-time PCR immunofluorescence, immunohistochemistry, next-generation sequencing, miRNA, and mRNA in situ hybridization. Results—In most DMPMs, a strong EGFR activation was associated with HER2, HER3, Axl, and MET co-activation, mediated mainly by receptor heterodimerization and autocrine-paracrine loops induced by the expression of their cognate ligands. Axl expression was downregulated by miRNA34a. Mutations in MET Sema domain were exclusively found in two “progressed” DMPMs, and the combined Axl and MET inhibition reduced cellular motility in a DMPM cell line obtained from a “progressed” DMPM. Conclusion—The results indicate that the coordinated activity of multiple cross-talks between RTKs is directly involved in the biology of DMPM, suggesting the combined inhibition of PIK3 and mTOR as an effective strategy that may be easily implemented in clinical practice, and indicating that the combined inhibition of EGFR/HER2 and HER3 and of Axl and MET deserves further investigation.

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Section: Resultsmentioning

confidence: 99%

Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma

Belfiore

Busico

Bozzi

et al. 2019

IJMS

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“…In 2-5% of cases of apparently hereditary MTC, no RET mutations are found (Leboulleux et al 2004). Of note, whole exome sequencing has recently identified a germline MET mutation in two siblings with hereditary WT RET MTC (Sponziello et al 2018).…”

Section: Figurementioning

confidence: 99%

Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

Ceolin

Duval

Benini

et al. 2019

Endocrine-Related Cancer

109

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Medullary thyroid carcinoma (MTC) is a rare type of tumor that originates from thyroid C cells and accounts for 2–4% of all malignant thyroid neoplasms. MTC may occur sporadically or be inherited, as part of the MEN 2 syndrome. Germline mutations of the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, whereas somatic RET mutations and, less frequently, RAS mutations have been described in sporadic MTC samples. Since early surgery with complete resection of tumor mostly determines the likelihood of attaining cure for MTC, the broader use of RET genetic screening has dramatically changed the prognostic of gene carriers in hereditary MTC. Nevertheless, despite recent advances, the management of advanced, progressive MTC remains challenging. The multikinase inhibitors (MKI), vandetanib and cabozantinib, were approved for the treatment of progressive or symptomatic MTC, and several other compounds have exhibited variable efficacy. Although these drugs have been shown to improve progression-free survival, no MKI has been shown to increase the overall survival. As these drugs are nonselective, significant off-target toxicities may occur, limiting achievement of the required TK-specific inhibition. Recently, next-generation small-molecule TKI has been developed. These TKI are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. Here, we summarize the current understanding of the intracellular signaling pathways involved in MTC pathogenesis as well as the therapeutic approaches and challenges for the management of advanced MTC, focusing on targeted molecular therapies.

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“…All MEN2 subtypes are inherited in an autosomal dominant pattern with high penetrance. Nearly all MEN2 cases are caused by germline gain of function mutations of the REarranged during Transfection (RET) proto-oncogene, with the exception of two families having germline mutations in ESR2 or MET gene that are predisposed to MTC (2,6,7). Over the last two decades, identification of RET mutations as the cause of MEN2 significantly changed MEN2 disease management, including disease prevention, diagnosis, risk prediction, and treatment of MEN2-specific tumors; together these approaches represent a paradigm of precision medicine (2).…”

Section: Introductionmentioning

confidence: 99%

5P Strategies for Management of Multiple Endocrine Neoplasia Type 2: A Paradigm of Precision Medicine

Ding

et al. 2020

Front. Endocrinol.

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Multiple endocrine neoplasia type 2 (MEN2) is a neuroendocrine cancer syndrome characterized by medullary thyroid carcinoma, in combination or not with pheochromocytoma, hyperparathyroidism, and extra-endocrine features. MEN2 syndrome includes two clinically distinct forms subtyped as MEN2A and MEN2B. Nearly all MEN2 cases are caused by germline mutations of the RET proto-oncogene. In this review, we propose "5P" strategies for management of MEN2: prevention, prediction, personalization, psychological support, and participation, which could effectively improve clinical outcomes of patients. Based on RET mutations, MEN2 could be prevented through prenatal diagnosis or preimplantation genetic testing. Identification of pathogenic mutations in RET can enable early diagnosis of MEN2. Combining RET mutation testing with measurement of serum calcitonin, plasma or urinary metanephrine/normetanephrine, and serum parathyroid hormone levels could allow risk stratification and accurately prediction of MEN2 progression, thus facilitating implementation of personalized precision treatments to increase disease-free survival and overall survival. Furthermore, increased awareness of MEN2 is needed, which requires participation of physicians, patients, family members, and related organizations. Psychological support is also important for patients with MEN2 to promote comprehensive management of MEN2 symptoms. The "5P" strategies for management of MEN2 represent a typical clinical example of precision medicine. These strategies could effectively improve the health of MEN2 patient, and avoid adverse outcomes, including death and major morbidity, from MEN2.

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Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer

Cited by 27 publications

References 31 publications

Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma

Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma

Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

5P Strategies for Management of Multiple Endocrine Neoplasia Type 2: A Paradigm of Precision Medicine

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