The NF1 gene: a frequent mutational target in sporadic pheochromocytomas and beyond

in Endocrine-Related Cancer
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Jenny Welander Department of Clinical and Experimental Medicine, Department of Surgery, Faculty of Health Sciences, Linköping University, SE-58185 Linköping, Sweden

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Peter Söderkvist Department of Clinical and Experimental Medicine, Department of Surgery, Faculty of Health Sciences, Linköping University, SE-58185 Linköping, Sweden

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Oliver Gimm Department of Clinical and Experimental Medicine, Department of Surgery, Faculty of Health Sciences, Linköping University, SE-58185 Linköping, Sweden
Department of Clinical and Experimental Medicine, Department of Surgery, Faculty of Health Sciences, Linköping University, SE-58185 Linköping, Sweden

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Patients suffering from the neurofibromatosis type 1 syndrome, which is caused by germline mutations in the NF1 gene, have a tiny but not negligible risk of developing pheochromocytomas. It is, therefore, of interest that the NF1 gene has recently been revealed to carry somatic, inactivating mutations in a total of 35 (21.7%) of 161 sporadic pheochromocytomas in two independent tumor series. A majority of the tumors in both studies displayed loss of heterozygosity at the NF1 locus and a low NF1 mRNA expression. In view of previous findings that many sporadic pheochromocytomas cluster with neurofibromatosis type 1 syndrome-associated pheochromocytomas instead of forming clusters of their own, NF1 inactivation appears to be an important step in the pathogenesis of a large number of sporadic pheochromocytomas. A literature and public mutation database review has revealed that pheochromocytomas are among those human neoplasms in which somatic NF1 alterations are most frequent.

Abstract

Patients suffering from the neurofibromatosis type 1 syndrome, which is caused by germline mutations in the NF1 gene, have a tiny but not negligible risk of developing pheochromocytomas. It is, therefore, of interest that the NF1 gene has recently been revealed to carry somatic, inactivating mutations in a total of 35 (21.7%) of 161 sporadic pheochromocytomas in two independent tumor series. A majority of the tumors in both studies displayed loss of heterozygosity at the NF1 locus and a low NF1 mRNA expression. In view of previous findings that many sporadic pheochromocytomas cluster with neurofibromatosis type 1 syndrome-associated pheochromocytomas instead of forming clusters of their own, NF1 inactivation appears to be an important step in the pathogenesis of a large number of sporadic pheochromocytomas. A literature and public mutation database review has revealed that pheochromocytomas are among those human neoplasms in which somatic NF1 alterations are most frequent.

The neurofibromatosis type 1 syndrome, caused by germline mutations in the NF1 gene, is a multisystem tumor predisposition disorder associated with neurologic, cutaneous, and orthopedic manifestations. Only a small fraction, about 1% (range 0.1–5.7%), of patients with neurofibromatosis type 1 develop pheochromocytomas (Walther et al. 1999). Hereditary pheochromocytomas can also be observed in von Hippel–Lindau disease (10–26%) and multiple endocrine neoplasia type 2 (about 50%), as well as in patients with mutations in the succinate dehydrogenase (SDH) genes (having a wide range depending on the gene affected) and a few additional more recently discovered susceptibility genes (reviewed in Welander et al. (2011)). Until recently, somatic mutations in any of the genes involved in hereditary pheochromocytoma have been thought to be rare in the more common sporadic form of the tumor, as has repeatedly been reported for the RET, VHL, and SDHx genes (Burnichon et al. 2011). While ∼15% of all the pheochromocytomas or paragangliomas are thought to be associated with germline SDHx mutations (Gill et al. 2010, Welander et al. 2011), no single SDHx gene is affected in more than 10% of the cases at the most. Genome-wide expression studies have revealed that pheochromocytomas and paragangliomas cluster into two distinct groups based on their transcription profile: VHL- and SDHx-related tumors display a similar gene expression profile associated with hypoxia and angiogenesis, whereas RET- and NF1-related tumors express genes linked to an activation of kinase signaling pathways (Eisenhofer et al. 2004, Dahia et al. 2005). Interestingly, sporadic pheochromocytomas cluster into either of the two distinct groups instead of forming clusters of their own.

Two independent studies (Burnichon et al. 2012a, Welander et al. 2012) have recently revealed that the NF1 gene is the most frequent target of somatic, truncating mutations in sporadic pheochromocytomas known to date. This suggests one cause for the observation that subgroups of sporadic pheochromocytomas share a common transcriptional profile with hereditary NF1/RET-related tumors. The study carried out by Burnichon et al. (2012a,b) reported mutations in 25 of the 61 (41%) of investigated tumors. Here, the authors pre-selected pheochromocytomas by genome-wide expression cluster analysis and carried out NF1 mutation analysis on a subset of those displaying a NF1/RET-like gene expression pattern, giving a mutation frequency in their entire cohort of 119 sporadic pheochromocytomas of 21.8%. This is in agreement with the study carried out by Welander et al. (2012), where 10 of the 42 (23.8%) unselected sporadic pheochromocytomas exhibited somatic NF1 mutations. Thus, current data suggest that roughly one-fifth to one-fourth of the sporadic pheochromocytomas harbor somatic NF1 mutations. In agreement with the classic tumor suppressor gene model, a majority of the tumors in both studies displayed loss of heterozygosity (LOH) at the NF1 locus and a low NF1 mRNA expression. In addition, a previous study has reported LOH at the NF1 locus in a substantial proportion of sporadic pheochromocytomas (Sandgren et al. 2010), while another early study has reported a lack of neurofibromin protein expression in one of the four sporadic pheochromocytomas (Gutmann et al. 1995). It is noteworthy that high plasma levels of catecholamines emerged as common features in affected patients of the NF1-mutated pheochromocytomas (Welander et al. 2012). However, the biochemical data were non-centralized and incomplete in this study, limiting the significance of this finding. Still, the observation of high catecholamine levels in patients with neurofibromatosis type 1 and pheochromocytomas and the finding that PNMT, the enzyme responsible for the conversion of norepinephrine to epinephrine, is normally expressed in NF1 and RET tumors in contrast to the other hereditary pheochromocytomas would support this finding (Eisenhofer et al. 2011a,b, Burnichon et al. 2012b).

Inactivation of neurofibromin leads to the activation of the RAS/RAF/MEK/ERK pathway (Ballester et al. 1990, Martin et al. 1990). The importance of this signaling pathway in sporadic pheochromocytoma development has been very recently confirmed when somatic H-RAS mutations were reported in these tumors (Crona et al. 2013), and studies of additional factors in the pathway may thus be warranted.

Somatic NF1 gene mutations have in recent years also been detected in other forms of sporadic neoplasms, including glioblastomas (The Cancer Genome Atlas Research Network 2008), malignant peripheral nerve sheath tumors (MPNSTs; Bottillo et al. 2009), acute myelogenous leukemia (Parkin et al. 2010), neuroblastomas (Holzel et al. 2010), lung adenocarcinomas (Ding et al. 2008), and ovarian carcinomas (The Cancer Genome Atlas Research Network 2011), indicating that the NF1 gene may represent a significant mutational target in both neural- and non-neural-derived sporadic tumors (Fig. 1). The public mutation database COSMIC (http://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=NF1#dist) has revealed that NF1 is a target with a varying mutation frequency in a large number of different human neoplasms (Table 1). Apart from MPNSTs and the large group of soft-tissue tumors (including blood vessels, fat, and fibrous tissue, as well as smooth and striated muscle), sporadic pheochromocytomas appear to be the most frequent target. Interestingly, LOH at the NF1 locus, not associated with the mutation, appears in a proportion of all the neoplasms studied (Fig. 1). Concerning pheochromocytomas, NF1 mutations are sometimes observed in samples without LOH (Burnichon et al. 2012a). This opens up a discussion of other potential factors affecting NF1 expression (hypermethylation has been excluded in some but not all positions in the promoter (Welander et al. 2012)) or possibly haploinsufficient behavior.

Figure 1
Figure 1

Frequency of somatic NF1 gene alterations in different sporadic human neoplasms. MPNST, malignant peripheral nerve sheath tumor; AML, acute myelogenous leukemia.

Citation: Endocrine-Related Cancer 20, 4; 10.1530/ERC-13-0046

Table 1

NF1 mutation distribution in human neoplasms according to the COSMIC public mutation database (http://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=NF1#dist) as of May 8th 2013

Primary tissueSubstitution nonsenseSubstitution missenseSubstitution synonymousInsertion inframeInsertion frameshiftDeletion inframeDeletion frameshiftComplexOtherUnique mutated samplesTotal unique samplesPercentage of mutated samples
Adrenal gland20.00
Autonomic ganglia1118112264.87
Biliary tract160.00
Bone500.00
Breast16121105501.82
CNS181332119115811045.25
Cervix12232611.54
Endometrium2722122385.04
Eye920.00
Gastrointestinal tracta10.00
Hematopoietic/lymphoid171987375111174.57
Kidney161195351.68
Large intestine319124111348533.99
Liver11811.23
Lung195713141710112628.00
Meninges100.00
Esophagus460.00
Ovary492131197242.62
Pancreas3143891.03
Placenta20.00
Pleura60.00
Prostate223990.50
Salivary gland20.00
Skin5122342322210.36
Small intestine10.00
Soft tissue62181748256124874433.33
Stomach112603.33
Testis40.00
Thyroid11119.09
Upper aerodigestive tract13151383.62
Urinary tract17196114.75
Vulva30.00
Total138185360315121612660390486.66

Site indeterminate.

Many, but not all, of the neoplasms with somatic NF1 mutations have also been reported in patients with neurofibromatosis type 1 syndrome. Thus, the role of NF1 as a tumor suppressor in other malignancies not associated with neurofibromatosis type 1 syndrome warrants further studies.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the commentary reported.

Funding

This commentary did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • PubMed
    • Search Google Scholar
    • Export Citation
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    • PubMed
    • Search Google Scholar
    • Export Citation
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    • PubMed
    • Search Google Scholar
    • Export Citation
  • The Cancer Genome Atlas Research Network Comprehensive genomic characterization defines human glioblastoma genes and core pathways Nature 455 2008 10611068. (doi:10.1038/nature07385).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • The Cancer Genome Atlas Research Network Integrated genomic analyses of ovarian carcinoma Nature 474 2011 609615. (doi:10.1038/nature10166).

  • Walther MM, Herring J, Enquist E, Keiser HR & Linehan WM 1999 von Recklinghausen's disease and pheochromocytomas. Journal of Urology 162 15821586. (doi:10.1016/S0022-5347(05)68171-2).

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    • Search Google Scholar
    • Export Citation
  • Welander J, Soderkvist P & Gimm O 2011 Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine-Related Cancer 18 R253R276. (doi:10.1530/ERC-11-0170).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Welander J, Larsson C, Backdahl M, Hareni N, Sivler T, Brauckhoff M, Soderkvist P & Gimm O 2012 Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas. Human Molecular Genetics 21 54065416. (doi:10.1093/hmg/dds402).

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    • Search Google Scholar
    • Export Citation

 

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  • Frequency of somatic NF1 gene alterations in different sporadic human neoplasms. MPNST, malignant peripheral nerve sheath tumor; AML, acute myelogenous leukemia.

  • Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M & Collins F 1990 The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63 851859. (doi:10.1016/0092-8674(90)90151-4).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bottillo I, Ahlquist T, Brekke H, Danielsen SA, van den Berg E, Mertens F, Lothe RA & Dallapiccola B 2009 Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours. Journal of Pathology 217 693701. (doi:10.1002/path.2494).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Burnichon N, Vescovo L, Amar L, Libe R, de Reynies A, Venisse A, Jouanno E, Laurendeau I, Parfait B & Bertherat J et al. 2011 Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Human Molecular Genetics 20 39743985. (doi:10.1093/hmg/ddr324).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Burnichon N, Buffet A, Parfait B, Letouze E, Laurendeau I, Loriot C, Pasmant E, Abermil N, Valeyrie-Allanore L & Bertherat J et al. 2012a Somatic NF1 inactivation is a frequent event in sporadic pheochromocytoma. Human Molecular Genetics 21 53975405. (doi:10.1093/hmg/dds374).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, Abermil N, Inglada-Perez L, de Cubas AA, Amar L & Barontini M et al. 2012b MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clinical Cancer Research 18 28282837. (doi:10.1158/1078-0432.CCR-12-0160).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Crona J, Delgado Verdugo A, Maharjan R, Stalberg P, Granberg D, Hellman P & Bjorklund P Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing Journal of Clinical Endocrinology and Metabolism 2013 [in press] doi:10.1210/jc.2012-4257).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF & Tischler AS et al. 2005 A HIF1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genetics 1 7280. (doi:10.1371/journal.pgen.0010008).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM & Morgan MB et al. 2008 Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455 10691075. (doi:10.1038/nature07423).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein DS & Elkahloun AG 2004 Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel–Lindau syndrome. Endocrine-Related Cancer 11 897911. (doi:10.1677/erc.1.00838).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein SR, Tiebel O, Adams K & Bratslavsky G et al. 2011a Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clinical Chemistry 57 411420. (doi:10.1373/clinchem.2010.153320).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eisenhofer G, Pacak K, Huynh TT, Qin N, Bratslavsky G, Linehan WM, Mannelli M, Friberg P, Grebe SK & Timmers HJ et al. 2011b Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocrine-Related Cancer 18 97111. (doi:10.1677/ERC-10-0211).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gill AJ, Benn DE, Chou A, Clarkson A, Muljono A, Meyer-Rochow GY, Richardson AL, Sidhu SB, Robinson BG & Clifton-Bligh RJ 2010 Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma–pheochromocytoma syndromes. Human Pathology 41 805814. (doi:10.1016/j.humpath.2009.12.005).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gutmann DH, Geist RT, Rose K, Wallin G & Moley JF 1995 Loss of neurofibromatosis type I (NF1) gene expression in pheochromocytomas from patients without NF1. Genes, Chromosomes & Cancer 13 104109. (doi:10.1002/gcc.2870130206).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Holzel M, Huang S, Koster J, Ora I, Lakeman A, Caron H, Nijkamp W, Xie J, Callens T & Asgharzadeh S et al. 2010 NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell 142 218229. (doi:10.1016/j.cell.2010.06.004).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H, Conroy L, Clark R, O'Connell P & Cawthon RM et al. 1990 The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63 843849. (doi:10.1016/0092-8674(90)90150-D).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Parkin B, Ouillette P, Wang Y, Liu Y, Wright W, Roulston D, Purkayastha A, Dressel A, Karp J & Bockenstedt P et al. 2010 NF1 inactivation in adult acute myelogenous leukemia. Clinical Cancer Research 16 41354147. (doi:10.1158/1078-0432.CCR-09-2639).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sandgren J, Diaz de Stahl T, Andersson R, Menzel U, Piotrowski A, Nord H, Backdahl M, Kiss NB, Brauckhoff M & Komorowski J et al. 2010 Recurrent genomic alterations in benign and malignant pheochromocytomas and paragangliomas revealed by whole-genome array comparative genomic hybridization analysis. Endocrine-Related Cancer 17 561579. (doi:10.1677/ERC-09-0310).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • The Cancer Genome Atlas Research Network Comprehensive genomic characterization defines human glioblastoma genes and core pathways Nature 455 2008 10611068. (doi:10.1038/nature07385).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • The Cancer Genome Atlas Research Network Integrated genomic analyses of ovarian carcinoma Nature 474 2011 609615. (doi:10.1038/nature10166).

  • Walther MM, Herring J, Enquist E, Keiser HR & Linehan WM 1999 von Recklinghausen's disease and pheochromocytomas. Journal of Urology 162 15821586. (doi:10.1016/S0022-5347(05)68171-2).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Welander J, Soderkvist P & Gimm O 2011 Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine-Related Cancer 18 R253R276. (doi:10.1530/ERC-11-0170).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Welander J, Larsson C, Backdahl M, Hareni N, Sivler T, Brauckhoff M, Soderkvist P & Gimm O 2012 Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas. Human Molecular Genetics 21 54065416. (doi:10.1093/hmg/dds402).

    • PubMed
    • Search Google Scholar
    • Export Citation