Abstract
NF1 is notable for the variable expressivity of the disease. Although NF1 is fully penetrant, patients with the disease show a broad range of phenotypes. This presents a problem for patients and their doctors, because it is difficult to predict which disease complications an individual will develop. This has led to an interest in identifying the sources of phenotypic variation associated with the disease. Inherited factors, environmental factors, and diet can all influence phenotypic variation and differential susceptibility in many diseases, including NF1. Comparison of both inter- and intra-familial phenotypic variance in patients has implicated heritable factors independent of the inherited NF1 allele, as well as environmental factors. Studies in a mouse model of NF1 malignancies have demonstrated that modifier genes unlinked to NF1, as well as the sex of the individual and the inheritance of the disease from the mother or father, affects the risk for developing different types of tumors. Taken together, these data suggest that subtle differences in the genetic and epigenetic background of NF1 patients can have far reaching implications on the risk of developing NF1-associated tumors. In this chapter, we will focus on what is known about heritable factors affecting NF1 variable expressivity in both humans and mouse models. These factors, once characterized, can be used by patients and clinicians to predict the future course of the disease.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Airewele GE, Sigurdson AJ, Wiley KJ, Frieden BE, Caldarera LW, Riccardi VM, Lewis RA, Chintagumpala MM, Ater JL, Plon SE, Bondy ML (2001) Neoplasms in neurofibromatosis 1 are related to gender but not to family history of cancer. Genet Epidemiol 20:75–86
Amlin-Van Schaick J, Kim S, Broman KW, Reilly KM (2012a) Scram1 is a modifier of spinal cord resistance for astrocytoma on mouse Chr 5. Mamm Genome 23:277–285
Amlin-Van Schaick JC, Kim S, DiFabio C, Lee MH, Broman KW, Reilly KM (2012b) Arlm1 is a male-specific modifier of astrocytoma resistance on mouse Chr 12. Neuro Oncol 14:160–174
Amlin-Van Schaick J, Kim S, Broman KW, Reilly KM (2012c) Scram1 is a modifier of spinal cord resistance for astrocytoma on mouse Chr 5. Mamm Genome 23(3–4):277–85
Aylor DL, Valdar W, Foulds-Mathes W, Buus RJ, Verdugo RA, Baric RS, Ferris MT, Frelinger JA, Heise M, Frieman MB et al (2012) Genetic analysis of complex traits in the emerging Collaborative Cross. Genome Res 21:1213–1222
Bahuau M, Pelet A, Vidaud D, Lamireau T, LeBail B, Munnich A, Vidaud M, Lyonnet S, Lacombe D (2001) GDNF as a candidate modifier in a type 1 neurofibromatosis (NF1) enteric phenotype. J Med Genet 38:638–643
Bajenaru ML, Hernandez MR, Perry A, Zhu Y, Parada LF, Garbow JR, Gutmann DH (2003) Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res 63:8573–8577
Barron VA, Lou H (2012) Alternative splicing of the neurofibromatosis type I pre-mRNA. Biosci Rep 32:131–138
Bartelt-Kirbach B, Wuepping M, Dodrimont-Lattke M, Kaufmann D (2009) Expression analysis of genes lying in the NF1 microdeletion interval points to four candidate modifiers for neurofibroma formation. Neurogenetics 10:79–85
Buchberg AM, Buckwalter MS, Camper SA (1992) Mouse chromosome 11. Mamm Genome 3(Spec No):S162–S181
Carey JC, Laub JM, Hall BD (1979) Penetrance and variability in neurofibromatosis: a genetic study of 60 families. Birth Defects Orig Artic Ser 15:271–281
Churchill GA, Airey DC, Allayee H, Angel JM, Attie AD, Beatty J, Beavis WD, Belknap JK, Bennett B, Berrettini W et al (2004) The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet 36:1133–1137
Cichowski K, Shih TS, Schmitt E, Santiago S, Reilly K, McLaughlin ME, Bronson RT, Jacks T (1999) Mouse models of tumor development in neurofibromatosis type 1. Science 286:2172–2176
Collaborative Cross Consortium (2012) The genome architecture of the Collaborative Cross mouse genetic reference population. Genetics 190:389–401
Durrant C, Tayem H, Yalcin B, Cleak J, Goodstadt L, de Villena FP, Mott R, Iraqi FA (2011) Collaborative Cross mice and their power to map host susceptibility to Aspergillus fumigatus infection. Genome Res 21:1239–1248
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
Evans DG, O’Hara C, Wilding A, Ingham SL, Howard E, Dawson J, Moran A, Scott-Kitching V, Holt F, Huson SM (2011) Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989. Eur J Hum Genet 19:1187–1191
Harder A, Titze S, Herbst L, Harder T, Guse K, Tinschert S, Kaufmann D, Rosenbaum T, Mautner VF, Windt E et al (2010) Monozygotic twins with neurofibromatosis type 1 (NF1) display differences in methylation of NF1 gene promoter elements, 5′ untranslated region, exon and intron 1. Twin Res Hum Genet 13:582–594
Hawes JJ, Tuskan RG, Reilly KM (2007) Nf1 expression is dependent on strain background: implications for tumor suppressor haploinsufficiency studies. Neurogenetics 8:121–130
Huson SM, Hughes RAC (1994) The neurofibromatoses: a pathogenetic and clinical overview, 1st edn. Chapman & Hall Medical, London
Ingham S, Huson SM, Moran A, Wylie J, Leahy M, Evans DG (2011) Malignant peripheral nerve sheath tumours in NF1: improved survival in women and in recent years. Eur J Cancer 47:2723–2728
Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA (1994) Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet 7:353–361
Jentarra GM, Rice SG, Olfers S, Rajan C, Saffen DM, Narayanan V (2012) Skewed allele-specific expression of the NF1 gene in normal subjects: a possible mechanism for phenotypic variability in neurofibromatosis type 1. J Child Neurol 27:695–702
Jhanwar SC, Chen Q, Li FP, Brennan MF, Woodruff JM (1994) Cytogenetic analysis of soft tissue sarcomas. Recurrent chromosome abnormalities in malignant peripheral nerve sheath tumors (MPNST). Cancer Genet Cytogenet 78:138–144
Kehrer-Sawatzki H, Schmid E, Funsterer C, Kluwe L, Mautner VF (2008) Absence of cutaneous neurofibromas in an NF1 patient with an atypical deletion partially overlapping the common 1.4 Mb microdeleted region. Am J Med Genet A 146A:691–699
Kleihues P, Burger PC, Scheithauer BW (1993) The new WHO classification of brain tumours. Brain Pathol 3:255–268
Lazaro C, Gaona A, Ainsworth P, Tenconi R, Vidaud D, Kruyer H, Ars E, Volpini V, Estivill X (1996) Sex differences in mutational rate and mutational mechanism in the NF1 gene in neurofibromatosis type 1 patients. Hum Genet 98:696–699
Li H, Zhang X, Fishbein L, Kweh F, Campbell-Thompson M, Perrin GQ, Muir D, Wallace M (2010) Analysis of steroid hormone effects on xenografted human NF1 tumor schwann cells. Cancer Biol Ther 10:758–764
Masocco M, Kodra Y, Vichi M, Conti S, Kanieff M, Pace M, Frova L, Taruscio D (2011) Mortality associated with neurofibromatosis type 1: a study based on Italian death certificates (1995-2006). Orphanet J Rare Dis 6:11
Menon AG, Anderson KM, Riccardi VM, Chung RY, Whaley JM, Yandell DW, Farmer GE, Freiman RN, Lee JK, Li FP 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
Mensink KA, Ketterling RP, Flynn HC, Knudson RA, Lindor NM, Heese BA, Spinner RJ, Babovic-Vuksanovic D (2006) Connective tissue dysplasia in five new patients with NF1 microdeletions: further expansion of phenotype and review of the literature. J Med Genet 43:e8
Mertens F, Rydholm A, Bauer HF, Limon J, Nedoszytko B, Szadowska A, Willen H, Heim S, Mitelman F, Mandahl N (1995) Cytogenetic findings in malignant peripheral nerve sheath tumors. Int J Cancer 61:793–798
Mertens F, Dal Cin P, De Wever I, Fletcher CD, Mandahl N, Mitelman F, Rosai J, Rydholm A, Sciot R, Tallini G et al (2000) Cytogenetic characterization of peripheral nerve sheath tumours: a report of the CHAMP study group. J Pathol 190:31–38
Pasmant E, Sabbagh A, Masliah-Planchon J, Ortonne N, Laurendeau I, Melin L, Ferkal S, Hernandez L, Leroy K, Valeyrie-Allanore L et al (2011) Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. J Natl Cancer Inst 103:1713–1722
Philip VM, Sokoloff G, Ackert-Bicknell CL, Striz M, Branstetter L, Beckmann MA, Spence JS, Jackson BL, Galloway LD, Barker P et al (2011) Genetic analysis in the Collaborative Cross breeding population. Genome Res 21:1223–1238
Rasmussen SA, Yang Q, Friedman JM (2001) Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. Am J Hum Genet 68:1110–1118
Reilly KM (2009) Brain tumor susceptibility: the role of genetic factors and uses of mouse models to unravel risk. Brain Pathol 19:121–131
Reilly KM (2010) The Nf1−/+;Trp53−/+cis mouse model of anaplastic astrocytoma and secondary glioblastoma: dissecting genetic susceptibility to brain cancer. In: Van Meir EG (ed) CNS cancer: models, markers, prognostic factors, targets, and therapeutic approaches. Springer, Berlin
Reilly KM, Loisel DA, Bronson RT, McLaughlin ME, Jacks T (2000) Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet 26:109–113
Reilly KM, Tuskan RG, Christy E, Loisel DA, Ledger J, Bronson RT, Smith CD, Tsang S, Munroe DJ, Jacks T (2004) Susceptibility to astrocytoma in mice mutant for Nf1 and Trp53 is linked to chromosome 11 and subject to epigenetic effects. Proc Natl Acad Sci USA 101:13008–13013
Reilly KM, Broman KW, Bronson RT, Tsang S, Loisel DA, Christy ES, Sun Z, Diehl J, Munroe DJ, Tuskan RG (2006) An imprinted locus epistatically influences Nstr1 and Nstr2 to control resistance to nerve sheath tumors in a neurofibromatosis type 1 mouse model. Cancer Res 66:62–68
Rey JA, Bello MJ, Kusak ME, de Campos JM, Pestana A (1993) Involvement of 22q12 in a neurofibrosarcoma in neurofibromatosis type 1. Cancer Genet Cytogenet 66:28–32
Riva P, Corrado L, Natacci F, Castorina P, Wu BL, Schneider GH, Clementi M, Tenconi R, Korf BR, Larizza L (2000) NF1 microdeletion syndrome: refined FISH characterization of sporadic and familial deletions with locus-specific probes. Am J Hum Genet 66:100–109
Sabbagh A, Pasmant E, Laurendeau I, Parfait B, Barbarot S, Guillot B, Combemale P, Ferkal S, Vidaud M, Aubourg P et al (2009) Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Genet 18:2768–2778
Schmidt H, Taubert H, Wurl P, Bache M, Bartel F, Holzhausen HJ, Hinze R (2001) Cytogenetic characterization of six malignant peripheral nerve sheath tumors: comparison of karyotyping and comparative genomic hybridization. Cancer Genet Cytogenet 128:14–23
Skuse GR, Cappione AJ (1997) RNA processing and clinical variability in neurofibromatosis type I (NF1). Hum Mol Genet 6:1707–1712
Spiegel M, Oexle K, Horn D, Windt E, Buske A, Albrecht B, Prott EC, Seemanova E, Seidel J, Rosenbaum T et al (2005) Childhood overgrowth in patients with common NF1 microdeletions. Eur J Hum Genet 13:883–888
Steinmann K, Cooper DN, Kluwe L, Chuzhanova NA, Senger C, Serra E, Lazaro C, Gilaberte M, Wimmer K, Mautner VF, Kehrer-Sawatzki H (2007) Type 2 NF1 deletions are highly unusual by virtue of the absence of nonallelic homologous recombination hotspots and an apparent preference for female mitotic recombination. Am J Hum Genet 81:1201–1220
Stephens K, Weaver M, Leppig KA, Maruyama K, Emanuel PD, Le Beau MM, Shannon KM (2006) Interstitial uniparental isodisomy at clustered breakpoint intervals is a frequent mechanism of NF1 inactivation in myeloid malignancies. Blood 108:1684–1689
Szudek J, Joe H, Friedman JM (2002) Analysis of intrafamilial phenotypic variation in neurofibromatosis 1 (NF1). Genet Epidemiol 23:150–164
Szudek J, Evans DG, Friedman JM (2003) Patterns of associations of clinical features in neurofibromatosis 1 (NF1). Hum Genet 112:289–297
Threadgill DW, Churchill GA (2012a) Ten years of the Collaborative Cross. Genetics 190:291–294
Threadgill DW, Churchill GA (2012b) Ten years of the collaborative cross. G3 (Bethesda) 2:153–156
Threadgill DW, Hunter KW, Williams RW (2002) Genetic dissection of complex and quantitative traits: from fantasy to reality via a community effort. Mamm Genome 13:175–178
Tischler AS, Shih TS, Williams BO, Jacks T (1995) Characterization of pheochromocytomas in a mouse strain with a targeted disruptive mutation of the neurofibromatosis gene Nf1. Endocr Pathol 6:323–335
Titze S, Peters H, Wahrisch S, Harder T, Guse K, Buske A, Tinschert S, Harder A (2010) Differential MSH2 promoter methylation in blood cells of Neurofibromatosis type 1 (NF1) patients. Eur J Hum Genet 18:81–87
Tuskan RG, Tsang S, Sun Z, Baer J, Rozenblum E, Wu X, Munroe DJ, Reilly KM (2008) Real-time PCR analysis of candidate imprinted genes on mouse chromosome 11 shows balanced expression from the maternal and paternal chromosomes and strain-specific variation in expression levels. Epigenetics 3:43–50
Upadhyaya M, Ruggieri M, Maynard J, Osborn M, Hartog C, Mudd S, Penttinen M, Cordeiro I, Ponder M, Ponder BA et al (1998) Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. Hum Genet 102:591–597
Upadhyaya M, Huson SM, Davies M, Thomas N, Chuzhanova N, Giovannini S, Evans DG, Howard E, Kerr B, Griffiths S 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
van Meyel DJ, Ramsay DA, Casson AG, Keeney M, Chambers AF, Cairncross JG (1994) p53 mutation, expression, and DNA ploidy in evolving gliomas: evidence for two pathways of progression. J Natl Cancer Inst 86:1011–1017
Venturin M, Guarnieri P, Natacci F, Stabile M, Tenconi R, Clementi M, Hernandez C, Thompson P, Upadhyaya M, Larizza L, Riva P (2004) Mental retardation and cardiovascular malformations in NF1 microdeleted patients point to candidate genes in 17q11.2. J Med Genet 41:35–41
Walrath JC, Fox K, Truffer E, Gregory Alvord W, Quinones OA, Reilly KM (2009) Chr 19(A/J) modifies tumor resistance in a sex- and parent-of-origin-specific manner. Mamm Genome 20:214–223
Watanabe K, Sato K, Biernat W, Tachibana O, von Ammon K, Ogata N, Yonekawa Y, Kleihues P, Ohgaki H (1997) Incidence and timing of p53 mutations during astrocytoma progression in patients with multiple biopsies. Clin Cancer Res 3:523–530
Wiest V, Eisenbarth I, Schmegner C, Krone W, Assum G (2003) Somatic NF1 mutation spectra in a family with neurofibromatosis type 1: toward a theory of genetic modifiers. Hum Mutat 22:423–427
Wu J, Williams JP, Rizvi TA, Kordich JJ, Witte D, Meijer D, Stemmer-Rachamimov AO, Cancelas JA, Ratner N (2008) Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cancer Cell 13:105–116
Zhu Y, Ghosh P, Charnay P, Burns DK, Parada LF (2002) Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296:920–922
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Jones, G.N., Reilly, K.M. (2012). Dissection of Complex Genetic and Epigenetic Interactions Underlying NF1 Cancer Susceptibility Using Mouse Models. In: Upadhyaya, M., Cooper, D. (eds) Neurofibromatosis Type 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-32864-0_19
Download citation
DOI: https://doi.org/10.1007/978-3-642-32864-0_19
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-32863-3
Online ISBN: 978-3-642-32864-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)