Skip to main content
SpringerLink
Log in

The Somatic Mutational Spectrum of the NF1 Gene

  • Chapter
  • First Online:
Neurofibromatosis Type 1

Abstract

Neurofibromatosis type 1 (NF1) affects 1/3,000–4,000 individuals worldwide and is caused by the inactivation of the NF1 tumour suppressor gene which encodes the protein neurofibromin. Consistent with Knudson’s two-hit hypothesis, NF1 patients harbouring a heterozygous germline NF1 mutation develop several NF1-associated tumours upon somatic inactivation of the second (wild-type) NF1 allele. Although the identification of somatic mutations in NF1 patients has always been problematic on account of the extensive cellular heterogeneity manifested by neurofibromas, their classification is a prerequisite for understanding the complex molecular mechanisms underlying NF1 tumorigenesis. Here, we have performed a meta-analysis of known somatic NF1 mutations identified in a range of NF1-associated neoplasms including peripheral nerve sheath tumours (neurofibromas), malignant peripheral nerve sheath tumours (MPNSTs), astrocytomas, gastrointestinal stromal tumours, gastric carcinoid, juvenile myelomonocytic leukaemia, glomus tumours, neuroblastomas, breast cancer and phaeochromocytomas. Comparison of the frequencies of the different types of somatic NF1 mutation so far observed with those of their previously reported germline counterparts reveals significant differences (p = 0.00014), with the somatic mutational spectrum being characterised by a greater proportion of nonsense mutations and a smaller proportion of splice-site mutations. Finally, C>T and G>A changes in CpG and CpHpG oligonucleotides resulting in missense/nonsense mutations in the NF1 gene were significantly overrepresented in the soma as compared to the germline (p = 0.007).

Some of the unpublished mutations in Supplementary Table 2 of Laycock-van Spyk et al. (2011) have now been published by Thomas et al. (2012a, b).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ars E, Kruyer H, Gaona A, Casquero P et al (1998) A clinical variant of neurofibromatosis type 1: familial spinal neurofibromatosis with a frameshift mutation in the NF1 gene. Am J Hum Genet 62:834–841

    Article  PubMed  CAS  Google Scholar 

  • Ballester R, Marchuk D, Boguski M, Saulino A et al (1990) The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63:851–859

    Article  PubMed  CAS  Google Scholar 

  • Bandipalliam P (2005) Syndrome of early onset colon cancers, hematologic malignancies & features of neurofibromatosis in HNPCC families with homozygous mismatch repair gene mutations. Fam Cancer 4:323–333

    Article  PubMed  CAS  Google Scholar 

  • Bausch B, Borozdin W, Mautner VF, Hoffmann MM et al (2007) Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1. J Clin Endocrinol Metab 92:2784–2792

    Article  PubMed  CAS  Google Scholar 

  • Beert E, Brems H, Daniëls B, De Wever I, Van Calenbergh F, Schoenaers J, Debiec-Rychter M, Gevaert O, De Raedt T, Van Den Bruel A, de Ravel T, Cichowski K, Kluwe L, Mautner V, Sciot R, Legius E (2011) Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosomes Cancer 50:1021–1032

    Article  PubMed  CAS  Google Scholar 

  • Bennett E, Thomas N, Upadhyaya M (2009) Neurofibromatosis type 1: its association with the Ras/MAPK pathway syndromes. J Paediatr Neurol 7:105–115

    CAS  Google Scholar 

  • Benz MR, Czernin J, Dry SM, Tap WD et al (2010) Quantitative F18-fluorodeoxyglucose positron emission tomography accurately characterizes peripheral nerve sheath tumors as malignant or benign. Cancer 116:451–458

    Article  PubMed  CAS  Google Scholar 

  • Bien E, Stachowicz-Stencel T, Sierota D, Polczynska K, Szolkiewicz A, Stefanowicz J, Adamkiewicz-Drozynska E, Czauderna P, Kosiak W, Dubaniewicz-Wybieralska M, Izycka-Swieszewska E, Balcerska A (2007) Sarcomas in children with neurofibromatosis type 1-poor prognosis despite aggressive combined therapy in four patients treated in a single oncological institution. Childs Nerv Syst 23:1147–1153

    Article  PubMed  Google Scholar 

  • Brems H, Park C, Maertens O, Pemov A et al (2009) Glomus tumors in neurofibromatosis type 1: genetic functional, and clinical evidence of a novel association. Cancer Res 69:7393–7401

    Article  PubMed  CAS  Google Scholar 

  • Brennan C, Momota H, Hambardzumyan D, Ozawa T et al (2009) Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PLoS One 4:e7752

    Article  PubMed  CAS  Google Scholar 

  • Burnichon N, Vescovo L, Amar L, Libé R, de Reynies A, Venisse A, Jouanno E, Laurendeau I, Parfait B, Bertherat J, Plouin PF, Jeunemaitre X, Favier J, Gimenez-Roqueplo AP (2011) Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum Mol Genet 20:3974–3985

    Article  PubMed  CAS  Google Scholar 

  • Carroll SL, Ratner N (2008) How does the Schwann cell lineage form tumors in NF1? Glia 56(14):1590–1605

    Article  PubMed  Google Scholar 

  • Chen JM, Cooper DN, Ferec C, Kehrer-Sawatzki H et al (2010) Genomic rearrangements in inherited disease and cancer. Semin Cancer Biol 20:222–233

    Article  PubMed  CAS  Google Scholar 

  • Cichowski K, Jacks T (2001) NF1 tumor suppressor gene function: narrowing the GAP. Cell 104:593–604

    Article  PubMed  CAS  Google Scholar 

  • Cichowski K, Shih T, Schmitt E, Santiago S et al (1999) Mouse models of tumor development in neurofibromatosis type 1. Science 286:2172–2176

    Article  PubMed  CAS  Google Scholar 

  • De Raedt T, Brems H, Wolkenstein P, Vidaud D et al (2003) Elevated risk for MPNST in NF1 microdeletion patients. Am J Hum Genet 72:1288–1292

    Article  PubMed  Google Scholar 

  • Ding L, Getz G, Wheeler D, Mardis E et al (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–1075

    Article  PubMed  CAS  Google Scholar 

  • Ducatman B, Scheithauer B, Piepgras D, Reiman H et al (1986) Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 57:2006–2021

    Article  PubMed  CAS  Google Scholar 

  • Dugoff L, Sujansky E (1996) Neurofibromatosis type 1 and pregnancy. Am J Med Genet 66:7–10

    Article  PubMed  CAS  Google Scholar 

  • Dworkin AM, Ridd K, Bautista D, Allain DC et al (2010) Germline variation controls the architecture of somatic alterations in tumors. PLoS Genet 6:e1001136

    Article  CAS  Google Scholar 

  • Easton DF, Ponder MA, Huson SM, Ponder BA (1993) An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet 53:305–313

    Google Scholar 

  • Eisenbarth I, Beyer K, Krone W, Assum G (2000) Toward a survey of somatic mutation of the NF1 gene in benign neurofibromas of patients with neurofibromatosis type 1. Am J Hum Genet 66:393–401

    Article  PubMed  CAS  Google Scholar 

  • Evans D, Baser M, McGaughran J, Sharif S et al (2002) Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 39:311–314

    Article  PubMed  CAS  Google Scholar 

  • Flotho C, Steinemann D, Mullighan C, Neale G et al (2007) Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11. Oncogene 26:5816–5821

    Article  PubMed  CAS  Google Scholar 

  • Friedman JM, Arbiser J, Epstein JA, Gutmann DH, Huot SJ, Lin AE, McManus B, Korf BR (2002) Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force. Genet Med 4:105–111

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Linares C, Fernandez-Rodriguez J, Terribas E, Mercade J et al (2011) Dissecting loss of heterozygosity (LOH) in neurofibromatosis type 1-associated neurofibromas: importance of copy neutral LOH. Hum Mutat 32:78–90

    Article  PubMed  CAS  Google Scholar 

  • Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D et al (2012) Intratumour heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883–892

    Article  PubMed  CAS  Google Scholar 

  • Gregorian C, Nakashima J, Dry S, Nghiemphu P et al (2009) PTEN dosage is essential for neurofibroma development and malignant transformation. Proc Natl Acad Sci USA 106:19479–19484

    Article  PubMed  CAS  Google Scholar 

  • Gutmann DH, Cole JL, Stone WJ, Ponder BA, Collins FS (1994) Loss of neurofibromin in adrenal gland tumors from patients with neurofibromatosis type I. Genes Chromosomes Cancer 10:55–58

    Article  PubMed  CAS  Google Scholar 

  • 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(2):104–109

    Article  PubMed  CAS  Google Scholar 

  • Gutmann D, Donahoe J, Brown T, James C et al (2000) Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas. Neuropathol Appl Neurobiol 26:361–367

    Article  PubMed  CAS  Google Scholar 

  • Gutmann D, James C, Poyhonen M, Louis D et al (2003) Molecular analysis of astrocytomas presenting after age 10 in individuals with NF1. Neurology 61:1397–1400

    Article  PubMed  CAS  Google Scholar 

  • Haferlach C, Dicker F, Kohlmann A, Schindela S et al (2010) AML with CBFB-MYH11 rearrangement demonstrate RAS pathway alterations in 92% of all cases including a high frequency of NF1 deletions. Leukemia 24:1065–1069

    Article  PubMed  CAS  Google Scholar 

  • Hölzel M, Huang S, Koster J, Ora I et al (2010) NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell 142:218–229

    Article  PubMed  CAS  Google Scholar 

  • Huson S, Harper P, Compston D (1988) von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales. Brain 111(Pt 6):1355–1381

    Article  PubMed  Google Scholar 

  • Ivanov D, Hamby SE, Stenson PD, Phillips AD et al (2011) Comparative analysis of germline and somatic microlesion mutational spectra in 17 human tumor suppressor genes. Hum Mutat 32:620–632

    Article  CAS  Google Scholar 

  • John A, Ruggieri M, Ferner R, Upadhyaya M (2000) A search for evidence of somatic mutations in the NF1 gene. J Med Genet 37:44–49

    Article  PubMed  CAS  Google Scholar 

  • Joseph N, Mosher J, Buchstaller J, Snider P et al (2008) The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells. Cancer Cell 13:129–140

    Article  PubMed  CAS  Google Scholar 

  • Kehrer-Sawatzki H (2008) Structure of the NF1 gene region and mechanisms underlying gross NF1 deletions. In: Kaufmann D (ed) Neurofibromatoses. Karger, Basel, pp 46–62

    Google Scholar 

  • Kehrer-Sawatzki H, Cooper DN (2008) Mosaicism in sporadic neurofibromatosis type 1: variations on a theme common to other hereditary cancer syndromes? J Med Genet 45:622–631

    Article  PubMed  CAS  Google Scholar 

  • Knudson AJ (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823

    Article  PubMed  Google Scholar 

  • Kourea H, Orlow I, Scheithauer B, Cordon-Cardo C et al (1999) Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas. Am J Pathol 155:1855–1860

    Article  PubMed  CAS  Google Scholar 

  • Kushner BH, Hajdu SI, Helson L (1985) Synchronous neuroblastoma and von Recklinghausen’s disease: a review of the literature. J Clin Oncol 3:117–120

    PubMed  CAS  Google Scholar 

  • Lamlum H, Ilyas M, Rowan A, Clark S et al (1999) The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson’s ‘two-hit’ hypothesis. Nat Med 5:1071–1075

    Article  PubMed  CAS  Google Scholar 

  • Lammert M, Friedman JM, Kluwe L, Mautner VF (2005) Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol 141:71–74

    Article  PubMed  Google Scholar 

  • Laycock-van Spyk S, Thomas N, Cooper DN, Upadhyaya M (2011) Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis. Hum Genomics 5:623–690

    Article  PubMed  Google Scholar 

  • Le L, Shipman T, Burns D, Parada L (2009) Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas. Cell Stem Cell 4:453–463

    Article  PubMed  CAS  Google Scholar 

  • Lee J, Wang J, Torbenson M, Lu Y et al (2010) Loss of SDHB and NF1 genes in a malignant phyllodes tumor of the breast as detected by oligo-array comparative genomic hybridization. Cancer Genet Cytogenet 196:179–183

    Article  PubMed  CAS  Google Scholar 

  • Legius E, Dierick H, Wu R, Hall B et al (1994) TP53 mutations are frequent in malignant NF1 tumors. Genes Chromosomes Cancer 10:250–255

    Article  PubMed  CAS  Google Scholar 

  • Listernick R, Charrow J, Greenwald M, Mets M (1994) Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. J Pediatr 125:63–66

    Article  PubMed  CAS  Google Scholar 

  • Maertens O, Prenen H, Debiec-Rychter M, Wozniak A et al (2006) Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet 15:1015–1023

    Article  PubMed  CAS  Google Scholar 

  • Mantripragada K, Spurlock G, Kluwe L, Chuzhanova N et al (2008) High-resolution DNA copy number profiling of malignant peripheral nerve sheath tumors using targeted microarray-based comparative genomic hybridization. Clin Cancer Res 14:1015–1024

    Article  PubMed  CAS  Google Scholar 

  • Mautner VF, Kluwe L, Friedrich RE, Roehl AC et al (2010) Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions. J Med Genet 47:623–630

    Article  PubMed  CAS  Google Scholar 

  • McCaughan J, Holloway S, Davidson R, Lam W (2007) Further evidence of the increased risk for malignant peripheral nerve sheath tumour from a Scottish cohort of patients with neurofibromatosis type 1. J Med Genet 44:463–466

    Article  PubMed  CAS  Google Scholar 

  • McGillicuddy LT, Fromm JA, Hollstein PE, Kubek S et al (2009) Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 16:44–54

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin ME, Jacks T (2003) Progesterone receptor expression in neurofibromas. Cancer Res 63:752–755

    PubMed  CAS  Google Scholar 

  • Menon A, Anderson K, Riccardi V, Chung R et al (1990) Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proc Natl Acad Sci USA 87:5435–5439

    Article  PubMed  CAS  Google Scholar 

  • Miettinen M, Fetsch J, Sobin L, Lasota J (2006) Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol 30:90–96

    Article  PubMed  Google Scholar 

  • Nielsen G, Stemmer-Rachamimov A, Ino Y, Moller M et al (1999) Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation. Am J Pathol 155:1879–1884

    Article  PubMed  CAS  Google Scholar 

  • Padmanabhan A, Lee JS, Ismat FA, Lu MM, Lawson ND, Kanki JP, Look AT, Epstein JA (2009) Cardiac and vascular functions of the zebrafish orthologues of the type I neurofibromatosis gene NFI. Proc Natl Acad Sci USA 106:22305–22310

    Article  PubMed  CAS  Google Scholar 

  • Pao W, Girard N (2011) New driver mutations in non-small-cell lung cancer. Lancet Oncol 12:175–180

    Article  PubMed  CAS  Google Scholar 

  • Parsons DW, Jones S, Zhang X, Lin JC et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    Article  PubMed  CAS  Google Scholar 

  • Pasmant E, Vidaud D, Harrison M, Upadhyaya M (2010) Different sized somatic NF1 locus rearrangements in neurofibromatosis 1-associated malignant peripheral nerve sheath tumors. J Neurooncol 102:341–346

    Article  PubMed  CAS  Google Scholar 

  • Poyhonen M, Leisti E, Kytölä S, Leisti J (1997) Hereditary spinal neurofibromatosis: a rare form of NF1? J Med Genet 34:184–187

    Article  PubMed  CAS  Google Scholar 

  • Pulst SM, Riccardi VM, Fain P, Korenberg JR (1991) Familial spinal neurofibromatosis: clinical and DNA linkage analysis. Neurology 41:1923–1927

    Article  PubMed  CAS  Google Scholar 

  • Roehl AC, Mussotter T, Cooper DN, Kluwe L, Wimmer K, Högel J, Zetzmann M, Vogt J, Mautner VF, Kehrer-Sawatzki H (2012) Tissue-specific differences in the proportion of mosaic large NF1 deletions are suggestive of a selective growth advantage of hematopoietic del(+/−) stem cells. Hum Mutat 33:541–550

    Article  PubMed  CAS  Google Scholar 

  • Roth T, Ramamurthy P, Muir D, Wallace M et al (2008) Influence of hormones and hormone metabolites on the growth of Schwann cells derived from embryonic stem cells and on tumor cell lines expressing variable levels of neurofibromin. Dev Dyn 237:513–524

    Article  PubMed  CAS  Google Scholar 

  • Sangha N, Wu R, Kuick R, Powers S et al (2008) Neurofibromin 1 (NF1) defects are common in human ovarian serous carcinomas and co-occur with TP53 mutations. Neoplasia 10:1362–1372

    PubMed  CAS  Google Scholar 

  • Sawada S, Florell S, Purandare S, Ota M et al (1996) Identification of NF1 mutations in both alleles of a dermal neurofibroma. Nat Genet 14:110–112

    Article  PubMed  CAS  Google Scholar 

  • Serra E, Rosenbaum T, Winner U, Aledo R et al (2000) Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations. Hum Mol Genet 9:3055–3064

    Article  PubMed  CAS  Google Scholar 

  • Serra E, Rosenbaum T, Nadal M, Winner U et al (2001) Mitotic recombination effects homozygosity for NF1 germline mutations in neurofibromas. Nat Genet 28:294–296

    Article  PubMed  CAS  Google Scholar 

  • Sharif S, Moran A, Huson SM, Iddenden R, Shenton A, Howard E, Evans DG (2007) Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J Med Genet 44:481–484

    Article  PubMed  CAS  Google Scholar 

  • Sharif S, Upadhyaya M, Ferner R, Majounie E, Shenton A, Baser M, Thakker N, Evans DG (2011) A molecular analysis of individuals with neurofibromatosis type 1 (NF1) and optic pathway gliomas (OPGs), and an assessment of genotype-phenotype correlations. J Med Genet 48:256–260

    Article  PubMed  CAS  Google Scholar 

  • Spurlock G, Griffiths S, Uff J, Upadhyaya M (2007) Somatic alterations of the NF1 gene in an NF1 individual with multiple benign tumours (internal and external) and malignant tumour types. Fam Cancer 6:463–471

    Article  PubMed  CAS  Google Scholar 

  • Spurlock G, Knight SJ, Thomas N, Kiehl TR, Guha A, Upadhyaya M (2010) Molecular evolution of a neurofibroma to malignant peripheral nerve sheath tumor (MPNST) in an NF1 patient: correlation between histopathological, clinical and molecular findings. J Cancer Res Clin Oncol 136:1869–1880

    Article  PubMed  CAS  Google Scholar 

  • Staser K, Yang FC, Clapp DW (2012) Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression. Annu Rev Pathol 7:469–495

    Article  PubMed  CAS  Google Scholar 

  • Steinemann D, Arning L, Praulich I, Stuhrmann M et al (2010) Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia and neurofibromatosis type 1. Haematologica 95:320–323

    Article  PubMed  CAS  Google Scholar 

  • Stenson PD, Ball E, Howells K, Phillips A et al (2008) Human Gene Mutation Database: towards a comprehensive central mutation database. J Med Genet 45:124–126

    Article  PubMed  CAS  Google Scholar 

  • Stephens K, Weaver M, Leppig K, Maruyama K et al (2006) Interstitial uniparental isodisomy at clustered breakpoint intervals is a frequent mechanism of NF1 inactivation in myeloid malignancies. Blood 108:1684–1689

    Article  PubMed  CAS  Google Scholar 

  • Stewart W, Traynor JP, Cooke A, Griffiths S et al (2007a) Gastric carcinoid: germline and somatic mutation of the neurofibromatosis type 1 gene. Fam Cancer 6:147–152

    Article  PubMed  CAS  Google Scholar 

  • Stewart D, Corless C, Rubin B, Heinrich M et al (2007b) Mitotic recombination as evidence of alternative pathogenesis of gastrointestinal stromal tumours in neurofibromatosis type 1. J Med Genet 44:e61

    Article  PubMed  Google Scholar 

  • Stewart DR, Pemov A, Van Loo P, Beert E, Brems H, Sciot R, Claes K, Pak E, Dutra A, Richard Lee CC, Legius E (2012) Mitotic recombination of chromosome arm 17q as a cause of loss of heterozygosity of NF1 in neurofibromatosis type 1-associated glomus tumors. Genes Chromosomes Cancer 51:429–437

    Article  PubMed  CAS  Google Scholar 

  • Stiller C, Chessells J, Fitchett M (1994) Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70:969–972

    Article  PubMed  CAS  Google Scholar 

  • Stratton MR (2011) Exploring the genomes of cancer cells: progress and promise. Science 331:1553–1558

    Article  PubMed  CAS  Google Scholar 

  • Sugimoto Y, Muramatsu H, Makishima H, Prince C et al (2009) Spectrum of molecular defects in juvenile myelomonocytic leukaemia includes ASXL1 mutations. Br J Haematol 150:83–87

    Google Scholar 

  • Sung L, Anderson JR, Arndt C, Raney RB, Meyer WH, Pappo AS (2004) Neurofibromatosis in children with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma study IV. J Pediatr 144:666–668

    Article  PubMed  Google Scholar 

  • The I, Murthy AE, Hannigan GE, Jacoby LB, Menon AG, Gusella JF, Bernards A (1993) Neurofibromatosis type 1 gene mutations in neuroblastoma. Nat Genet 3:62–66

    Article  PubMed  CAS  Google Scholar 

  • Thomas L, Kluwe L, Chuzhanova N, Mautner V et al (2010) Analysis of NF1 somatic mutations in cutaneous neurofibromas from patients with high tumor burden. Neurogenetics 11:391–400

    Article  PubMed  CAS  Google Scholar 

  • Thomas L, Spurlock G, Eudall C, Thomas NS, Mort M, Hamby SE, Chuzhanova N, Brems H, Legius E, Cooper DN, Upadhyaya M (2012a) Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas. Eur J Hum Genet 20(4):411–419

    Article  PubMed  CAS  Google Scholar 

  • Thomas L, Mautner VF, Cooper D, Upadhyaya M (2012) Molecular heterogeneity in malignant peripheral nerve sheath tumors (MPNSTs) associated with neurofibromatosis type 1 (NF1). Hum Genomics 6:18

    Google Scholar 

  • Upadhyaya M (2008) NF1 gene structure and NF1 genotype/phenotype correlations. In: Kaufmann D (ed) Neurofibromatoses. Karger, Basel, pp 46–62

    Chapter  Google Scholar 

  • Upadhyaya M (2010) Neurofibromatosis type 1 (NF1): diagnosis and recent advances. Expert Opin Med Genet 4:307–322

    Article  CAS  Google Scholar 

  • Upadhyaya M (2011) Genetic basis of tumorigenesis in NF1 malignant peripheral nerve sheath tumors. Front Biosci 16:937–951

    Article  PubMed  CAS  Google Scholar 

  • Upadhyaya M, Han S, Consoli C et al (2004) Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors. Hum Mutat 23:134–146

    Article  PubMed  CAS  Google Scholar 

  • Upadhyaya M, Spurlock G, Majounie E, Griffiths S et al (2006) The heterogeneous nature of germline mutations in NF1 patients with malignant peripheral serve sheath tumours (MPNSTs). Hum Mutat 27:716

    Article  PubMed  Google Scholar 

  • Upadhyaya M, Huson S, Davies M, Thomas N et al (2007) An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet 80:140–151

    Article  PubMed  CAS  Google Scholar 

  • Upadhyaya M, Kluwe L, Spurlock G, Monem B et al (2008a) Germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs). Hum Mutat 29:74–82

    Article  PubMed  CAS  Google Scholar 

  • Upadhyaya M, Spurlock G, Monem B, Thomas N et al (2008b) Germline and somatic NF1 gene mutations in plexiform neurofibromas. Hum Mutat 29:E103–E111

    Article  PubMed  Google Scholar 

  • Upadhyaya M, Spurlock G, Kluwe L, Chuzhanova N et al (2009) The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas. Neurogenetics 10:251–263

    Article  PubMed  CAS  Google Scholar 

  • Upadhyaya M, Spurlock G, Thomas L, Thomas NS, Richards M, Mautner VF, Cooper DN, Guha A, Yan J (2012) Microarray-based copy number analysis of neurofibromatosis type-1 (NF1)-associated malignant peripheral nerve sheath tumours (MPNSTs) reveals a role for Rho-GTPase pathway genes in NF1 tumorigenesis. Hum Mutat. 33:763–776

    Google Scholar 

  • Vogel K, Klesse L, Velasco-Miguel S, Meyers K et al (1999) Mouse tumor model for neurofibromatosis type 1. Science 286:2176–2179

    Article  PubMed  CAS  Google Scholar 

  • Walker L, Thompson D, Easton D, Ponder B, Ponder M, Frayling I, Baralle D (2006) A prospective study of neurofibromatosis type1 cancer incidence in the UK. Br J Cancer 95:233–238

    Article  PubMed  CAS  Google Scholar 

  • Wiest V, Eisenbarth I, Schmegner C, Krone W et al (2003) Somatic NF1 mutation spectra in a family with neurofibromatosis type 1: toward a theory of genetic modifiers. Hum Mutat 22:423–427

    Article  PubMed  CAS  Google Scholar 

  • Wimmer K, Etzler J (2008) Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 124:105–122

    Article  PubMed  Google Scholar 

  • Wu J, Williams J, Rizvi T, Kordich J et al (2008) Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cancer Cell 13:105–116

    Article  PubMed  CAS  Google Scholar 

  • Yang FC, Ingram DA, Chen S, Zhu Y et al (2008) Nf1-dependent tumors require a microenvironment containing Nf1+/− and c-kit-dependent bone marrow. Cell 135:437–448

    Article  PubMed  CAS  Google Scholar 

  • Yoshimi A, Kojima S, Hirano N (2010) Juvenile myelomonocytic leukemia: epidemiology etiopathogenesis, diagnosis, and management considerations. Paediatr Drugs 12:11–21

    PubMed  Google Scholar 

  • Zheng H, Chang L, Patel N, Yang J, Lowe L et al (2008) Induction of abnormal proliferation by nonmyelinating Schwann cells triggers neurofibroma formation. Cancer Cell 13:117–128

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, Ghosh P, Charnay P, Burns D et al (2002) Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296:920–922

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to all our NF1 patients and their families for their support.

Author information

Authors and Affiliations

  1. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK

    Meena Upadhyaya & David N. Cooper

  2. School of Science and Technology, Nottingham Trent University, Nottingham, UK

    Nadia Chuzhanova

Authors
  1. Meena Upadhyaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nadia Chuzhanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David N. Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meena Upadhyaya .

Editor information

Editors and Affiliations

  1. School of Medicine, Institute of Medical Genetics, Cardiff University, Heath Park Campus, Cardiff, 144XN, United Kingdom

    Meena Upadhyaya

  2. School of Medicine, Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, United Kingdom

    David N. Cooper

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Upadhyaya, M., Chuzhanova, N., Cooper, D.N. (2012). The Somatic Mutational Spectrum of the NF1 Gene. In: Upadhyaya, M., Cooper, D. (eds) Neurofibromatosis Type 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-32864-0_15

Download citation

Publish with us

Policies and ethics

Search

Navigation