A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization

Molatore, Sara; Marinoni, Ilaria; Lee, Misu; Pulz, Elke; Ambrosio, Maria Rosaria; Uberti, Ettore C. degli; Zatelli, Maria Chiara; Pellegata, Natalia S.

doi:10.1002/humu.21354

Cited by 97 publications

(78 citation statements)

References 20 publications

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“…This finding has prompted us to search CDKN1B mutations in MEN1-and RETnegative patients showing a MEN-like phenotype in the human. To date, six germline mutations have been identified leading to the definition of a new type of MEN-like syndrome in the human, named MEN4, though the phenotypic features are still undefined due to the small number of patients reported (1,2,3,4,5). Most CDKN1B mutations reported so far associated with MEN4 syndrome are inactivating mutations that lead to prematurely truncated protein (TGGOTAG at codon 76 (p.W76X)) (4) or to a premature stop at codon 69 caused by a 19 bp duplication (2), to a protein predicted to be 60 amino acids longer due to a change in the stop codon (TAA to CAA; stop to Q) (3).…”

Section: Discussionmentioning

confidence: 99%

“…Genetic studies in the rats predisposed to MENX identified a loss-of-function germline mutation in the Cdkn1b gene that encodes the cyclin-dependent kinase (Cdk) inhibitor p27 as the causative mutation for the MENX syndrome (1). Subsequently, mutations in the human homolog CDKN1B gene were identified in patients with multiple endocrine tumors that were negative for MEN1 or RET mutations (2,3,4). As a consequence of these observations, a novel human MEN-like syndrome, caused by germline mutations in CDKN1B, was recognized as a separate disease and denoted MEN4 (5).…”

Section: Introductionmentioning

confidence: 99%

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Functional characterization of a rare germline mutation in the gene encoding the cyclin-dependent kinase inhibitor p27Kip1 (CDKN1B) in a Spanish patient with multiple endocrine neoplasia-like phenotype

Malanga¹,

Gisi²,

Riccardi³

et al. 2012

European Journal of Endocrinology

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Objective: The aim of this study was to investigate the presence of germline mutations in the CDKN1B gene that encodes the cyclin-dependent kinase (Cdk) inhibitor p27 in multiple endocrine neoplasia 1 (MEN1)-like Spanish index patients. The CDKN1B gene has recently been identified as a tumor susceptibility gene for MEN4, with six germline mutations reported so far in patients with a MEN-like phenotype but negative for MEN1 mutations. Design and methods: Fifteen Spanish index cases with MEN-like symptoms were screened for mutations in the CDKN1B gene and the mutant variant was studied functionally by transcription/translation assays in vitro and in transiently transfected HeLa cells. Results: We report the identification of a heterozygous GAGA deletion in the 5 0 -UTR of CDKN1B, NM_004064.3:c.-32_-29del, in a patient affected by gastric carcinoid tumor and hyperparathyroidism. This deletion falls inside the region that is responsible for CDKN1B transcription and is predicted to destroy a secondary stem and loop structure that includes the GAGAGA element responsible for ribosome recruitment. Accordingly, in vitro studies of coupled transcription/translation assays and transient transfection in HeLa cells showed that the GAGA deletion in the CDKN1B 5 0 -UTR significantly impairs the transcription of downstream reporter luciferase (of w40-60%) and, possibly, the translation of the corresponding mRNA. This mutation was associated with a significant reduction in the amount of CDKN1B mRNA in peripheral blood leukocytes from the patient, as demonstrated by quantitative real-time PCR. Conclusions: Our results confirm that germline CDKN1B mutations may predispose to a human MEN4 condition and add novel evidence that alteration in the transcription/translation rate of CDKN1B mRNA might be the mechanism implicated in tumor susceptibility.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional characterization of a rare germline mutation in the gene encoding the cyclin-dependent kinase inhibitor p27Kip1 (CDKN1B) in a Spanish patient with multiple endocrine neoplasia-like phenotype

Malanga¹,

Gisi²,

Riccardi³

et al. 2012

European Journal of Endocrinology

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“…More recently, CDKN1B germline mutations have been described in multiple endocrine tumors (7). CDKN1B also harbors numerous polymorphisms that in several tumors have been variably associated with disease progression and patients' outcome (11)(12)(13)(14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

“…In humans, a MEN 1-like syndrome has recently been described and referred as MEN 4 (3,4). No mutations in CDKN1B have been found in 16 patients with a MEN 1 phenotype without MEN 1 mutations (5, 6), suggesting that CDKN1B germline mutations can predispose to the development of endocrine tumors in humans (3,4,7). A total of 21 single nucleotide polymorphisms in CDKN1B have also been described, 11 of which have low allelic frequency (5%) and 9 occur within the non-coding regions of the gene (8,9).…”

Section: Introductionmentioning

confidence: 99%

CDKN1B V109G polymorphism a new prognostic factor in sporadic medullary thyroid carcinoma

Pasquali¹,

Circelli

Faggiano³

et al. 2011

European Journal of Endocrinology

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Context: CDKN1B encodes the cyclin-dependent kinase inhibitor p27Kip1 and is mutated in multiple endocrine neoplasia-like syndromes. CDKN1B also harbors single nucleotide polymorphisms; the T/G transversion at nucleotide 326 (the V109G variant) has been reported to be protective in breast, hereditary prostate, and pancreatic tumors. Association of CDNK1B mutations or polymorphisms with sporadic medullary thyroid carcinoma (MTC) has not been investigated yet. Objective and design: We screened germline DNA from 84 patients affected by sporadic MTC and 90 healthy age-and gender-matched controls for CDKN1B mutations or polymorphisms by PCR amplification and sequencing of the amplicons. We also tested all germline and 50 tumor tissue DNA for RET proto-oncogene mutations. Computed tomography, ultrasound scans, and serum calcitonin were carried out before surgery and during the follow-up and associated with CDKN1B polymorphism and disease remission. Results: The T/G transversion at nucleotide 326 was the only DNA variation detected. The overall frequency of the T/G and G/G alleles in combination was 46.4%. This variant (V109G) was correlated with post-operative calcitonin levels in the normal range and biochemical remission. Conversely, the wild-type (T/T) allele was associated with post-operative calcitonin levels above normal and a higher risk to develop clinical recurrence and distant metastases. Somatic RET mutations were significantly associated with a more aggressive behavior especially in wild-type allele-bearing patients. Conclusions: Collectively, in sporadic MTC, the CDKN1B V109G polymorphism correlates with a more favorable disease progression than the wild-type allele and might be considered a new promising prognostic marker.

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“…A new mutation recognized is CDKN1B, which encodes cyclin dependent kinase p27. This mutation leads to development of multiple small intestinal neuroendocrine tumors [11]. …”

Section: Discussionmentioning

confidence: 99%

Case series of multiple primary cancers in single individuals: diagnostic and therapeutic dilemmas

Malik

Ali

Durrani

et al. 2017

Journal of Community Hospital Internal Medicine Perspectives

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Background and Objectives: Cancer recurrence represents treatment failure; the development of new primary tumors is suggestive of persistent exposure to etiological risk factors or genetic predisposition due to mutations in multiple cell lines. Case presentation/Design/Methods: The first case is a 65-years-old Caucasian male who presented with esophageal and lung cancer diagnosed synchronously. Smoking was the common risk factor for both cancers, underscoring field cancerization. The diagnosis and management was a challenge and different from either cancer presenting alone. Multidisciplinary approach was used and led to good outcomes.The second case is a 72-years-old Caucasian male presenting a rare dilemma of genetic mutation leading to multiple primary gastrointestinal cancers in a single individual. The gene explaining this group of cancers has not been diagnosed yet and the field needs to be explored further. Conclusion: Multiple primary cancers can be secondary to a common environmental risk factor or genetic mutations.

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A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization

Cited by 97 publications

References 20 publications

Functional characterization of a rare germline mutation in the gene encoding the cyclin-dependent kinase inhibitor p27Kip1 (CDKN1B) in a Spanish patient with multiple endocrine neoplasia-like phenotype

Functional characterization of a rare germline mutation in the gene encoding the cyclin-dependent kinase inhibitor p27Kip1 (CDKN1B) in a Spanish patient with multiple endocrine neoplasia-like phenotype

CDKN1B V109G polymorphism a new prognostic factor in sporadic medullary thyroid carcinoma

Case series of multiple primary cancers in single individuals: diagnostic and therapeutic dilemmas

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