Endocrine Abstracts

Neuroendocrine tumors do not share many classical pathways of tumorigenesis with their non-endocrine counterparts. In recent years, the molecular understanding of of pancreatic neuroendocrine tumors (PanNET) tumorigenesis has made major advances. A whole exome NGS analysis described frequent mutations of two new genes DAXX and ATRX. 40% of unselected panNET show mutations in one of these genes. Mutations in these genes are associated with loss of the respective proteins.^1,2 Interestingly, DAXX and ATRX negative panNET are characterized by a telomerase independent mechanism of telomere length maintenance termed ALT.³ The mechanisms leading to ALT activation upon DAXX/ATRX loss are still unknown. DAXX or ATRX knock down is not sufficient to induce ALT activation in telomerase positive PanNET cell lines^4,5 (and Marinoni unpublished data). Increasing evidence indicates that DAXX and ATRX are involved in histone 3 deposition at telomeric sequences thereby participating in the maintenance of the epigenetic status of telomeres. Additionally, ATRX is part of the ADD domain (ATRX-DNMT3-DNMT3L) of DNMT3A, responsible of de novo DNA methylation while DAXX binds and mediates DNMT1 recruitment at specific genes promoters. We have shown that ALT as well as loss of DAXX/ATRX is associated with chromosomal instability in PanNET and with the adverse outcome associated with this.² DAXX/ATRX loss seems to be a late event in PanNET tumorigenesis leading to a potential advantage of clonal heterogeneity via chromosomal instability and telomerase independent survival mechanisms.

References

1. Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 2011 331 (6021) 199–203.

2. Marinoni I, Kurrer AS, Vassella E, Dettmer M, Rudolph T, Banz V, Hunger F, Pasquinelli S, Speel EJ, Perren A. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology 2014 146 (2) 453–460 e5.

3. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science 2011 333 (6041) 425.

4. Napier CE, Huschtscha LI, Harvey A, Bower K, Noble JR, Hendrickson EA, Reddel RR. ATRX represses alternative lengthening of telomeres. Oncotarget 2015 6 (18) 16543–16558.

5. Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, Bersani F, Pineda JR, Suvà ML, Benes CH et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 2015 347 (6219) 273–277.