Prevalenza delle mutazioni TMEM127 nel feocromocitoma sporadico

Transcription

1 Prevalenza delle mutazioni TMEM127 nel feocromocitoma sporadico Giuseppe Opocher Veneto Institute of Oncology and Department of Medical and Surgical Sciences, University of Padova, Italy

2 Sympathetic paraganglia secreting chest retroperitoneal

3 Sympathetic paraganglia secreting chest retroperitoneal

4 Parasympathetic paraganglia (non secreting) head neck aortic pulmonary

5 Genetics of Pheochromocytoma / Paraganglioma VHL RET NF1

6 Genetics of Pheochromocytoma / Paraganglioma VHL RET NF1 PHD2 KIF1B SDHB SDHC SDHD

7 Genetics of Pheochromocytoma / Paraganglioma VHL RET NF1 SDHAF2 PHD2 KIF1B SDHB SDHC SDHD

8 Genetics of Pheochromocytoma / Paraganglioma 2010 VHL RET NF1 SDHAF2 PHD2 KIF1B SDHB SDHC SDHD

9 familiarity and type of presentation n= % 90% 80% 70% 39% 12% 60% 50% 40% 30% 91% 100% 61% 88% 20% 10% 0% 9% familial syndromic multifocal wt sporadic mutated

10 Genome wide linkage analysis

11 Limits of FP locus had been redifined to a region containing 205 genes spanning the Mb between Mb and Mb. We used tumor DNA from one of the affected individuals (the index case of family 1) as a template for exon-based sequencing

12 Using this approach, we identified a splice-site variant (IVS3-2A<C) in the provisional transmembrane protein encoding gene TMEM127. This mutation was also present in this individual s germline DNA.

13

14

15

16 mtor Signaling Nutrients Amino acids Energy AMP: ATP AICAR metformin Stress Hypoxia LRP Wnt Frizzled Growth Factors, Hormones, Cytokines, etc. G q/o PI3K LKB1 REDD1/2 Dvl Erk PDK1 PIP 3 PIP 2 AMPK GSK-3 RSK Akt PTEN? TSC2 TSC1 Rheb PRAS40 Rag A/B Rag C/D Raptor G L rapamycin FKBP12 Sin1 Rictor G L mtor mtorc1 mtorc2 mtor HIF-1 VEGF/ Angiogenesis Rho PKC Akt ATG1 p70s6k 4E- BP1 PGC-1 Mitochondrial Metabolism Ribosome Biogenesis mrna translation PPAR Autophagy Cell Growth Transcription Adipogenesis Cytoskeletal Dynamics Actin Organization Survival

17 LETTERS Germline mutations in TMEM127 confer susceptibility to pheochromocytoma Yuejuan Qin 1, Li Yao 1, Elizabeth E King 1, Kalyan Buddavarapu 1, Romina E Lenci 1, E Sandra Chocron 2,3, James D Lechleiter 2,3, Meghan Sass 4, Neil Aronin 4, Francesca Schiavi 5, Francesca Boaretto 5, Giuseppe Opocher 5, Rodrigo A Toledo 6, Sergio P A Toledo 6, Charles Stiles 7, Ricardo C T Aguiar 1,8 & Patricia L M Dahia 1,2,8 America, Inc. All rights reserved. Pheochromocytomas, which are catecholamine-secreting tumors of neural crest origin, are frequently hereditary 1. However, the molecular basis of the majority of these tumors is unknown 2. We identified the transmembrane-encoding gene TMEM127 on chromosome 2q11 as a new pheochromocytoma susceptibility gene. In a cohort of 103 samples, we detected truncating germline TMEM127 mutations in approximately 30% of familial tumors and about 3% of sporadic-appearing pheochromocytomas without a known genetic cause. The wild-type allele was consistently deleted in tumor DNA, suggesting a classic mechanism of tumor suppressor gene inactivation. Pheochromocytomas with mutations in TMEM127 are transcriptionally related to tumors bearing NF1 mutations provisional transmembrane protein encoding gene TMEM127, also known as FLJ20507 (Table 1 and Supplementary Fig. 2a,b). This mutation was also present in this individual s germline DNA, as well as in each of six other affected siblings, but not in samples from two unaffected sibs. We next sequenced germline and/or tumor DNA from an additional 102 index cases with pheochromocytomas, of which 19 had a clear familial history and 83 were apparently sporadic. We detected six other TMEM127 mutations in these samples (Table 1 and Supplementary Fig. 2c). Six of the seven TMEM127 variants were splice-site or nonsense mutations predicted to interrupt the protein reading frame prematurely (Table 1 and Supplementary Fig. 2a,b). In total, we detected four TMEM127 variants (including

18 Genetics of Pheochromocytoma / Paraganglioma VHL RET NF1

19 Genetics of Pheochromocytoma / Paraganglioma VHL RET NF1 SDHAF2 PHD2 KIF1B SDHB SDHC SDHD TMEM 127 SDHA

20 231 soggetti con feocromocitoma sporadico Wilde Type mutati 86% 14%

21 231 soggetti con feocromocitoma sporadico Wilde Type VHL SDHB TMEM127 SDHD RET MEN1 4% 86% 3% 2% 1% 1% 3%

22 TMEM127 mutations 2% of sporadic pheochromocytoma 11% of bilateral adrenal pheochromocytoma 1/20 TMEM127 mutated was malignant

23 In conclusion TMEM127 is a new tumor suppressor gene associated with pheochromocytoma development TMEM127 limits mtorc1 and occupies the same intracellular domain as active mtor

24 In conclusion TMEM127 mutation screening may be recommended for patients presenting at an older age, with adrenal tumors; especially but not exclusively those with bilateral disease