Transcriptomics,Genomics

Dataset Information

42

P27 haploinsufficiency in rats associates with invasive medullary thyroid carcinoma


ABSTRACT: CDKN1B (p27) was formally established as a tumor suppressor gene (tsg) following the identification of inactivating germline mutations in rats (MENX syndrome) and patients (MEN4 syndrome) developing multiple neuroendocrine tumors (NETs). MENX-affected rats are homozygous for the predisposing p27 mutation, suggesting a canonical tsg function. In contrast, mice heterozygous for a defective Cdkn1b allele are already predisposed to tumor formation (haploinsufficiency). We here report that heterozygous mutant rats (p27+/mut) develop the same NETs seen in the homozygous (p27mut/mut) animals but with slower progression. In the tumors of p27+/mut rats, the wild-type allele is neither lost nor silenced, implying that p27 is haploinsufficient for tumor suppression also in this model. Transcriptome profiling of rat NETs having different p27 dosages revealed a tissue-specific, dose-dependent effect of p27 on gene expression. In p27+/mut rats, thyroid neoplasms progress to invasive and metastatic medullary thyroid carcinomas (MTCs) accompanied by increased calcitonin levels, as in humans. Comparison of expression signatures of late-stage versus early-stage MTCs from p27+/mut rats identified genes potentially involved in tumor aggressiveness. The expression of a subset of these genes was evaluated in human MTCs, and found associated with aggressive RET-M918T-positive tumors. Altogether, p27 haploinsufficiency in MENX rats uncovered a novel, representative model of invasive/metastatic MTC, exploitable for translational studies of this aggressive and often incurable cancer. Overall design: We compared medullary thyroid carcinomas from heterozygous and homozygous p27Kip1/Cdkn1b mutant rats. Heterozygous animals were analyzed at the age of 9 and 18 months

INSTRUMENT(S): [RaGene-1_0-st] Affymetrix Rat Gene 1.0 ST Array [transcript (gene) version]

SUBMITTER: Johannes Beckers  

PROVIDER: GSE98546 | GEO | 2017-11-15

SECONDARY ACCESSION(S): PRJNA385488

REPOSITORIES: GEO

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Publications

Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma.

Molatore Sara S   Kügler Andrea A   Irmler Martin M   Wiedemann Tobias T   Neff Frauke F   Feuchtinger Annette A   Beckers Johannes J   Robledo Mercedes M   Roncaroli Federico F   Pellegata Natalia S NS  

Endocrine-related cancer 20171115 2


Rats affected by the MENX syndrome spontaneously develop multiple neuroendocrine tumors (NETs) including adrenal, pituitary and thyroid gland neoplasms. MENX was initially reported to be inherited as a recessive trait and affected rats were found to be homozygous for the predisposing Cdkn1b mutation encoding p27. We here report that heterozygous MENX-mutant rats (p27+/mut) develop the same spectrum of NETs seen in the homozygous (p27mut/mut) animals but with slower progression. Consequently, p27  ...[more]

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