Heritable Cancer Syndromes Related to the Hypoxia Pathway

Overview

Journal Front Oncol

Specialty Oncology

Date 2016 Apr 6

PMID 27047799

Citations 8

Authors

John Clark Henegan Jr

Christian R Gomez

Affiliations

Soon will be listed here.

Abstract

Families of tumor-suppressor genes, such as those involved in homologous recombination or mismatch repair, contain individual genes implicated in hereditary cancer syndromes. Collectively, such groupings establish that inactivating germline changes in genes within pathways related to genomic repair can promote carcinogenesis. The hypoxia pathway, whose activation is associated with aggressive and resistant sporadic tumors, is another pathway in which tumor-suppressor genes have been identified. von Hippel-Lindau disease, some of the hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes, and the syndrome of hereditary leiomyomatosis and renal cell carcinoma are heritable conditions associated with genes involved or associated with the hypoxia pathway. This review links these heritable cancer syndromes to the hypoxia pathway while also comparing the relative aggression and treatment resistance of syndrome-associated tumors to similar, sporadic tumors. The reader will become aware of shared phenotypes (e.g., PGL/PCC, renal cell carcinoma) among these three hypoxia-pathway-associated heritable cancer syndromes as well as the known associations of tumor aggressiveness and treatment resistance within these pathways.

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References

Span P, Rao J, Oude Ophuis S, Lenders J, Sweep F, Wesseling P . Overexpression of the natural antisense hypoxia-inducible factor-1alpha transcript is associated with malignant pheochromocytoma/paraganglioma. Endocr Relat Cancer. 2011; 18(3):323-31. DOI: 10.1530/ERC-10-0184. View

Semenza G . Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med. 2010; 2(3):336-361. DOI: 10.1002/wsbm.69. View

Lonser R, Glenn G, Walther M, Chew E, Libutti S, Linehan W . von Hippel-Lindau disease. Lancet. 2003; 361(9374):2059-67. DOI: 10.1016/S0140-6736(03)13643-4. View

Tomlinson I, Alam N, Rowan A, Barclay E, Jaeger E, Kelsell D . Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002; 30(4):406-10. DOI: 10.1038/ng849. View

Oudijk L, Neuhofer C, Lichtenauer U, Papathomas T, Korpershoek E, Stoop H . Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations. Eur J Endocrinol. 2015; 173(1):43-52. DOI: 10.1530/EJE-14-1164. View

Smit D, Mensenkamp A, Badeloe S, Breuning M, Simon M, van Spaendonck K . Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet. 2010; 79(1):49-59. DOI: 10.1111/j.1399-0004.2010.01486.x. View

Roma A, Maruzzo M, Basso U, Brunello A, Zamarchi R, Bezzon E . First-Line sunitinib in patients with renal cell carcinoma (RCC) in von Hippel-Lindau (VHL) disease: clinical outcome and patterns of radiological response. Fam Cancer. 2014; 14(2):309-16. DOI: 10.1007/s10689-014-9771-y. View

Ratcliffe P . Fumarate hydratase deficiency and cancer: activation of hypoxia signaling?. Cancer Cell. 2007; 11(4):303-5. DOI: 10.1016/j.ccr.2007.03.015. View

Motzer R, Hutson T, Tomczak P, Michaelson M, Bukowski R, Rixe O . Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007; 356(2):115-24. DOI: 10.1056/NEJMoa065044. View

10.

Nevoux J, Nowak C, Vellin J, Lepajolec C, Sterkers O, Richard S . Management of endolymphatic sac tumors: sporadic cases and von Hippel-Lindau disease. Otol Neurotol. 2014; 35(5):899-904. DOI: 10.1097/MAO.0000000000000299. View

11.

Adam J, Hatipoglu E, OFlaherty L, Ternette N, Sahgal N, Lockstone H . Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell. 2011; 20(4):524-37. PMC: 3202623. DOI: 10.1016/j.ccr.2011.09.006. View

12.

Vicha A, Taieb D, Pacak K . Current views on cell metabolism in SDHx-related pheochromocytoma and paraganglioma. Endocr Relat Cancer. 2014; 21(3):R261-77. PMC: 4016161. DOI: 10.1530/ERC-13-0398. View

13.

Dhani N, Fyles A, Hedley D, Milosevic M . The clinical significance of hypoxia in human cancers. Semin Nucl Med. 2015; 45(2):110-21. DOI: 10.1053/j.semnuclmed.2014.11.002. View

14.

Saito Y, Ishii K, Aita Y, Ikeda T, Kawakami Y, Shimano H . Loss of SDHB Elevates Catecholamine Synthesis and Secretion Depending on ROS Production and HIF Stabilization. Neurochem Res. 2015; 41(4):696-706. DOI: 10.1007/s11064-015-1738-3. View

15.

Maddock I, Moran A, Maher E, Teare M, Norman A, Payne S . A genetic register for von Hippel-Lindau disease. J Med Genet. 1996; 33(2):120-7. PMC: 1051837. DOI: 10.1136/jmg.33.2.120. View

16.

Maher E, Yates J, Harries R, Benjamin C, Harris R, Moore A . Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990; 77(283):1151-63. DOI: 10.1093/qjmed/77.2.1151. View

17.

Selak M, Duran R, Gottlieb E . Redox stress is not essential for the pseudo-hypoxic phenotype of succinate dehydrogenase deficient cells. Biochim Biophys Acta. 2006; 1757(5-6):567-72. DOI: 10.1016/j.bbabio.2006.05.015. View

18.

Isaacs J, Jung Y, Mole D, Lee S, Torres-Cabala C, Chung Y . 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(2):143-53. DOI: 10.1016/j.ccr.2005.06.017. View

19.

Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J . Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007; 92(10):3822-8. DOI: 10.1210/jc.2007-0709. View

20.

Sanz-Ortega J, Vocke C, Stratton P, Linehan W, Merino M . Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol. 2012; 37(1):74-80. PMC: 3524342. DOI: 10.1097/PAS.0b013e31825ec16f. View