scholarly journals MEN4 and CDKN1B mutations: the latest of the MEN syndromes

2017 ◽  
Vol 24 (10) ◽  
pp. T195-T208 ◽  
Author(s):  
Rami Alrezk ◽  
Fady Hannah-Shmouni ◽  
Constantine A Stratakis

Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor geneMEN1. MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not haveMEN1mutations or deletions. A novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressorCDKN1B. The most common phenotype of the 19 established cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic or germline mutations inCDKN1Bwere also identified in patients with sporadic PHPT, small intestinal neuroendocrine tumors, lymphoma and breast cancer, demonstrating a novel role forCDKN1Bas a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4.

2001 ◽  
Vol 287 (2) ◽  
pp. 427-434 ◽  
Author(s):  
Sophie Deltour ◽  
Sébastien Pinte ◽  
Cateline Guérardel ◽  
Dominique Leprince

Cell ◽  
1992 ◽  
Vol 69 (1) ◽  
pp. 111-117 ◽  
Author(s):  
Mae R. Gailani ◽  
Sherri J. Bale ◽  
David J. Leffell ◽  
John J. DiGiovanna ◽  
Gary L. Peck ◽  
...  

1994 ◽  
Vol 14 (1) ◽  
pp. 641-645
Author(s):  
M R Johnson ◽  
J E DeClue ◽  
S Felzmann ◽  
W C Vass ◽  
G Xu ◽  
...  

The NF1 gene, which is altered in patients with type 1 neurofibromatosis, has been postulated to function as a tumor suppressor gene. The NF1 protein product neurofibromin stimulates the intrinsic GTPase activity of active GTP-bound Ras, thereby inactivating it. Consistent with a tumor suppressor function, we have found that the introduction of NF1 in melanoma cell lines that are deficient in neurofibromin inhibited their growth and induced their differentiation. In addition, overexpression of neurofibromin in NIH 3T3 cells was growth inhibitory but did not alter the level of GTP.Ras in the cells. Transformation by v-ras, whose protein product is resistant to GTPase stimulation by neurofibromin, was inhibited in a cell line overexpressing neurofibromin, while transformation by v-raf was not altered. The results demonstrate that NF1 is a tumor suppressor gene that can inhibit Ras-dependent growth by a regulatory mechanism that is independent of neurofibromin's ability to stimulate Ras GTPase.


1996 ◽  
Vol 17 (8) ◽  
pp. 1751-1755 ◽  
Author(s):  
Dawei Li ◽  
Hua Yan ◽  
Jucheng Chen ◽  
Bruce C. Casto ◽  
Karl S. Theil ◽  
...  

2020 ◽  
Author(s):  
Giorgia Foggetti ◽  
Chuan Li ◽  
Hongchen Cai ◽  
Jessica A. Hellyer ◽  
Wen-Yang Lin ◽  
...  

AbstractCancer genome sequencing has uncovered substantial complexity in the mutational landscape of tumors. Given this complexity, experimental approaches are necessary to establish the impact of combinations of genetic alterations on tumor biology and to uncover genotype-dependent effects on drug sensitivity. In lung adenocarcinoma, EGFR mutations co-occur with many putative tumor suppressor gene alterations, however the extent to which these alterations contribute to tumor growth and their response to therapy in vivo has not been explored experimentally. By integrating a novel mouse model of oncogenic EGFR-driven Trp53-deficient lung adenocarcinoma with multiplexed CRISPR–Cas9-mediated genome editing and tumor barcode sequencing, we quantified the effects of inactivation of ten putative tumor suppressor genes. Inactivation of Apc, Rb1, or Rbm10 most strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2 – which are the strongest drivers of tumor growth in an oncogenic Kras-driven model – reduced EGFR-driven tumor growth. These results are consistent with the relative frequency of these tumor suppressor gene alterations in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduces the sensitivity of EGFR-driven Trp53-deficient tumors to the EGFR inhibitor osimertinib. Importantly, in human EGFR/TP53 mutant lung adenocarcinomas, mutations in the KEAP1 pathway correlated with decreased time on tyrosine kinase inhibitor treatment. Our study highlights how genetic alterations can have dramatically different biological consequences depending on the oncogenic context and that the fitness landscape can shift upon drug treatment.


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