Correspondence

PHD2 Mutation and Congenital Erythrocytosis with Paraganglioma

N Engl J Med 2009; 360:1361-1362March 26, 2009

Article

To the Editor:

Ladroue et al. (Dec. 18 issue)1 describe a patient with a newly discovered mutation of the gene encoding prolyl hydroxylase domain 2 (PHD2). In addition to erythrocytosis, this patient had recurrent abdominal tumors. The authors state that the PHD2 mutation affects the stability and functions of hypoxia-inducible factor (HIF) and that prolyl hydroxylase (PHD) inhibitors should be evaluated for an oncogenic effect. We think that the way in which PHD functions affect oncogenesis remains unclear. For example, did the authors detect elevated levels of HIF-1α or HIF-2α in the tumor in this patient? Do the authors have evidence that the PHD2 mutation stabilized HIF in this patient?

Holger K. Eltzschig, M.D., Ph.D.
Tobias Eckle, M.D., Ph.D.
Almut Grenz, M.D., Ph.D.
University of Colorado, Denver, Aurora, CO 80045
holger.eltzschig@uchsc.edu

1 References

1. 1

   Ladroue C, Carcenac R, Leporrier M, et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med 2008;359:2685-2692
   Full Text | Web of Science | Medline

Author/Editor Response

We agree with Eltzschig et al. that the mechanisms underlying the role of PHD proteins in oncogenesis remain unclear. Nonetheless, a link between the inhibition of PHD proteins due to the accumulation of Krebs-cycle intermediates and the occurrence of tumors in patients with germ-line fumarate hydratase (FH) and succinate dehydrogenase (SDH) mutations has been reported.1,2 We did not attempt to document an up-regulation of HIF in the tumor, because this phenomenon is such a common signature in tumors, and a link would be difficult to assess. Furthermore, PHD2 might have a role in an HIF-independent pathway in paragangliomas that is similar to the role played by PHD3 in neuronal apoptosis.3 The study of conditional inactivation of Phd2 in mice would certainly help to elucidate this issue. Finally, considering the potential tumor-suppressor function of PHD2 suggested by our study and other observations,4,5 we believe that it is legitimate to recommend stringent follow-up for carriers of a PHD2 mutation and also to raise the issue for patients exposed to PHD2-inhibition therapies in the future.

Betty Gardie, Ph.D.
Jean Feunteun, Ph.D.
Institut de Cancérologie Gustave Roussy, 94800 Villejuif, France

Stéphane Richard, M.D., Ph.D.
Faculté de Médecine Paris-Sud, 94276 Le Kremlin Bicêtre, France
stephane.richard@u-psud.fr

5 References

1. 1

   Isaacs JS, Jung YJ, Mole DR, et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 2005;8:143-153
   CrossRef | Web of Science | Medline

2. 2

   Pollard PJ, Briere JJ, Alam NA, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 2005;14:2231-2239
   CrossRef | Web of Science | Medline

3. 3

   Lee S, Nakamura E, Yang H, et al. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 2005;8:155-167
   CrossRef | Web of Science | Medline

4. 4

   Kato H, Inoue T, Asanoma K, Nishimura C, Matsuda T, Wake N. Induction of human endometrial cancer cell senescence through modulation of HIF-1alpha activity by EGLN1. Int J Cancer 2006;118:1144-1153
   CrossRef | Web of Science | Medline

5. 5

   Lee KA, Lynd JD, O'Reilly S, Kiupel M, McCormick JJ, LaPres JJ. The biphasic role of the hypoxia-inducible factor prolyl-4-hydroxylase, PHD2, in modulating tumor-forming potential. Mol Cancer Res 2008;6:829-842
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Susanne Schlisio. (2009) Neuronal apoptosis by prolyl hydroxylation: implication in nervous system tumours and the Warburg conundrum. Journal of Cellular and Molecular Medicine 13:10, 4104-4112
   CrossRef