FP35-4 Association between the p27 V109G variant and tumor multiplicity in patients harboring MEN1 germline mutations

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP35-Neoplasia of Endocrine Tissues
Bench to Bedside
Monday, June 17, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:00 AM
Room 122 (Moscone Center)

Poster Board MON-296
Rodrigo A Toledo*1, Viviane Longuini2, Delmar Muniz Lourenco Jr.3, Marcello D Bronstein4, Maria Candida Barisson Villares Fragoso5, Natalia Pellegata6 and Sergio P A Toledo7
1Univ of Sao Paulo Schl of Med, Sao Paulo, Brazil, 2University of Sao Paulo, Sao Paulo, Brazil, 3University of Sao Paulo, São Paulo SP, Brazil, 4Hosp das Clin/Univ Sao Paulo, Sao Paulo SP, Brazil, 5Hosp Das Clinicas- FMUSP, Sao Paulo SP, Brazil, 6GSF-National Res Center for, Neuherberg, Germany, 7Univ of Sao Paulo Schl of Med, Sao Paulo SP, Brazil
Objetive: To date, no evidence of robust genotype-phenotype correlation or disease modifiers for Multiple endocrine neoplasia type 1 (MEN1) syndrome have been described, leaving the highly variable clinical presentation of the patients unaccounted for.

Design: Because CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (Menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The casuistic consisted of one hundred patients carrying germline MEN1 gene mutations and 855 population-matched control individuals.

Methods: Genotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression.

Results: There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR= 2.55, p= 0.019, C.I.= 1.013-5.76). Among patients ≥30 y old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (3-4 glands affected vs. 1-2 glands affected; OR=18.33; p=0.002, C.I.=2.88-16.41). This finding remained significant after Bonferroni multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, enteropancreatic and adrenocortical tumors.

Conclusions: Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.

Nothing to Disclose: RAT, VL, DML Jr., MDB, MCBVF, NP, SPAT

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: The study was funded by the DAAD/CAPES PROBRAL program (Brazil/Germany collaboration) with research grants to Dr. S.P.A.T. and Dr. N.S.P., T.S., D.M.L and R.T. received doctorate and postdoctoral fellowships from FAPESP, and S.P.A.T. received research and productivity grants from CNPq.