Pathogenicity of DNA Variants and Double Mutations in Multiple Endocrine Neoplasia Type 2 and Von Hippel-Lindau Syndrome

Erlic, Zoran; Hoffmann, Michael M.; Sullivan, Maren; Franke, Gerlind; Pęczkowska, Mariola; Harsch, Igor Alexander; Schott, M.; Gabbert, Helmut E.; Välimäki, Matti; Preuss, Simon F.; Hasse-Lazar, Kornelia; Waligórski, Dariusz; Robledo, Mercedes; Januszewicz, Andrzej; Eng, Charis; Neumann, Hartmut P. H.

doi:10.1210/jc.2009-1728

Cited by 71 publications

(73 citation statements)

References 19 publications

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“…Notably, the A883T mutation that we previously reported ) is associated with MTC only in homozygous subjects, suggesting a low transforming activity of this mutation, which is likely counterbalanced by the normal allele in heterozygous subjects. Other RET mutations, such as Y791F, may also occur more frequently than currently recognised if the development of MTC only occurs in homozygous subjects (Erlic et al 2010). However, although the Y791F mutation seems to have a high prevalence in the normal German population, none of the six new mutations have been detected in the 200 normal subjects examined in this study; thus, this finding excludes the polymorphic nature of our new mutations and makes the possibility of a homozygous condition in children of non-consanguineous parents very unlikely.…”

Section: Discussionmentioning

confidence: 99%

In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer

Cosci¹,

Vivaldi²,

Romei³

et al. 2011

Endocrine-Related Cancer

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Germline and somatic RET oncogene mutations are found in 98% hereditary and 40% sporadic medullary thyroid carcinomas. Our aim was to analyse by in silico and in vitro assays the transforming activity of six rare RET mutations (T338I, V648I, M918V, A883T, S904F and M848T). Six known RET mutations were used as controls. The in silico analysis showed the highest score value (i.e. 65) for S904F, M848T, M918T and C634R, whereas L790F, G691S, T338I and V648I had 0 score. Intermediate score values were obtained by A883T (scoreZ55), M918V, V804M and Y791F (scoreZ15). The in vitro focus formation assay showed that cells transfected with S904F, M918T, M848T or C634R generated the largest number of focus formation units (FFU). Intermediate numbers of FFU were observed in cells transfected with M918V, V804M, Y791F or A883T, while cells transfected with L790F, G691S, T338I or V648I showed a number of FFU similar to control cells. A positive correlation between the in silico score and in vitro FFU was found (PZ0.0005). Only cells transfected with M918T or C634R grew faster and generated higher number of colonies in soft agar than control cells. However, the cells that were transfected with V804M produced an intermediate number of colonies. In conclusion, two of the six rare RET mutations, S904F and M848T possessed a relatively high transforming activity but a low aggressiveness; the other four mutations T338I, V648I, M918V and A883T were low or non-transforming, and their ability to induce tumoural transformation might be related to particular genetic conditions.

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Section: Discussionmentioning

confidence: 99%

In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer

Cosci¹,

Vivaldi²,

Romei³

et al. 2011

Endocrine-Related Cancer

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“…At present, these mutations could be considered as allelic variants (41,42). While the phenotype of MEN 2A and 2B is relatively easy to be defined because based on the positive family history and/or the association with other endocrine and non-endocrine diseases (7,15,26), the definition of FMTC is more challenging because it may be thought that the other endocrine neoplasms are not yet developed at the time of FMTC diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes

Romei

Mariotti

Fugazzola

et al. 2010

European Journal of Endocrinology

114

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Objective: Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not familial MTC (FMTC) with other endocrine neoplasia due to germline RET gene mutations. The prevalence of these rare genetic diseases and their corresponding RET mutations are unknown due to the small size of the study population. Methods: We collected data on germline RET mutations of 250 families with hereditary MTC followed in 20 different Italian centres. Results and conclusions: The most frequent RET amino acid substitution was Val804Met (19.6%) followed by Cys634Arg (13.6%). A total of 40 different germline RET mutations were present. Six families (2.4%) were negative for germline RET mutations. The comparison of the prevalence of RET germline mutations in the present study with those published by other European studies showed a higher prevalence of Val804Met and Ser891Ala mutations and a lower prevalence of Leu790Phe and Tyr791Phe (P!0.0001). A statistically significant higher prevalence of mutations affecting non-cysteine codons was also found (P!0.0001). Furthermore, the phenotype data collection showed an unexpected higher prevalence of FMTC (57.6%) with respect to other MEN 2 syndromes (34% MEN 2A and 6.8% of MEN 2B). In conclusion, we observed a statistically significant different pattern of RET mutations in Italian MEN 2 families with respect to other European studies and a higher prevalence of FMTC phenotype. The different ethnic origins of the patients and the particular attention given to analysing apparently sporadic MTC for RET germline mutations may explain these findings.

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“…2,18 However, the c.340 C 5G > C mutation, which was associated with VHL type 1B disease, 2,18 has always been disputed because some researchers suggest that it is a benign polymorphism. 19,20 Our in silico analysis also revealed that it did not affect the splicing site alteration. The other missense mutation, c.256C > T (p.P86S), was previously reported in VHL type 1 or type 2B patients.…”

Section: Discussionmentioning

confidence: 63%

Germline mutations in theVHLgene associated with 3 different renal lesions in a Chinese von Hippel-Lindau disease family

Yuan

Sun

Hao

et al. 2016

Cancer Biology & Therapy

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Von Hippel-Lindau (VHL) disease is a rare autosomal dominant inherited cancer syndrome that is characterized by hemangioblastomas in the central nervous system and retina, renal cell carcinoma and cysts, pancreatic tumors and cysts, and pheochromocytoma. The underlying gene in this disease is the VHL tumor suppressor gene. We characterized a family with 2 affected siblings. The brother and sister displayed VHL type 2B and type 2A features, respectively. Renal lesions in the brother exhibited 3 different phenotypes, including simple renal cysts, multilocular cystic renal cell carcinoma and clear cell renal cell carcinoma. The phenotypes of the 3 concurrent renal lesions were first reported in this study. Mutation detection of the VHL gene revealed 2 recurrent mutations, namely c.256C>T (p.P86S) and c.340 C 5G > C. The former was predicted to be deleterious and to destabilize the hydrophobic core and lead to VHL dysfunction; however, the latter was predicted to be a benign variant. Our findings provided new data for the genotype-phenotype of VHL diseases and elucidated the pathogenic mechanism with in silico analysis.

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Pathogenicity of DNA Variants and Double Mutations in Multiple Endocrine Neoplasia Type 2 and Von Hippel-Lindau Syndrome

Abstract: RET p.Tyr791Phe and p.Ser649Leu and VHL p.Pro81Ser are definitely not pathogenic mutations for VHL and MEN 2. Misinterpretation results in irreversible clinical consequences.

Cited by 71 publications

References 19 publications

In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer

In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer

Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes

Germline mutations in theVHLgene associated with 3 different renal lesions in a Chinese von Hippel-Lindau disease family

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