Skip to main content

Advertisement

SpringerLink
Log in

Novel NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor

  • Case report
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Many mutations of the NF1 gene have been reported in patients with neurofibromatosis type 1 (NF1); however, there have been no documented NF1 gene mutations in Japanese NF1 patients. In the present study, we used the polymerase chain reaction (PCR) and DNA sequencing analysis to characterize the NF1 gene in a 53-year-old Japanese patient with NF1 who suffered from neurofibroma, pheochromocytoma, and gastrointestinal stromal tumor (GIST). Direct sequence analyses revealed a single base substitution in the splicing donor site of intron 6 (IVS6 888+1, G → A) in one NF1 allele, resulting in an altered splice site (ss) in the mutated allele. Splicing at the cryptic 5′ ss in the mutated allele generated mRNA with an insertion of 60 nucleotides. In addition, we screened for mutations in exons 9, 11, 13, and 17 of the c-kit gene in GIST and the succinate dehydrogenase subunit D (SDHD) gene in the pheochromocytoma, but we did not detect any somatic mutations. We report here the first case of an NF1 patient with four neoplasms: neurofibroma, pheochromocytoma, astrocytoma and GIST. Our results suggest that the molecular pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. M Upadhyaya DN Cooper (1998) The mutational spectrum in neurofibromatosis 1 and its underlying mechanisms M Upadhyaya DN Cooper (Eds) Neurofibromatosis type 1: from genotype to phenotype Bios Scientific Oxford 65–88

    Google Scholar 

  2. R Cawthon R Weiss G Xu D Viskochil M Vulver J Stevens et al. (1990) ArticleTitleA major segment of neurofibromatosis type 1 gene: cDNA sequence genomic structure and point mutations Cell 62 193–201 Occurrence Handle2114220 Occurrence Handle1:CAS:528:DyaK3cXkvFalsrs%3D Occurrence Handle10.1016/0092-8674(90)90253-B

    Article  PubMed  CAS  Google Scholar 

  3. GA Martin D Viskochil G Bollag (1990) ArticleTitleThe GAP-related domain of the NF1 gene interacts with ras p21 Cell 63 843–9 Occurrence Handle2121370 Occurrence Handle1:CAS:528:DyaK3MXjvVSisg%3D%3D Occurrence Handle10.1016/0092-8674(90)90150-D

    Article  PubMed  CAS  Google Scholar 

  4. Y Li P O'Connell HH Breidenbach R Cawthon J Stevens G Xu et al. (1995) ArticleTitleGenomic organization of the neurofibromatosis 1 gene (NF1) Genomics 25 9–18 Occurrence Handle7774960 Occurrence Handle1:CAS:528:DyaK2MXjsFOisbs%3D Occurrence Handle10.1016/0888-7543(95)80104-T

    Article  PubMed  CAS  Google Scholar 

  5. R Fahsold S Hoffmeyer C Mischung C Gille C Ehlers N Kucukceylan et al. (2000) ArticleTitleMinor lesion mutational spectrum of the entire NF1 gene does not explain is high mutability but points to a functional domain upstream of the GAP-related domain Am J Hum Genet 66 790–818 Occurrence Handle10712197 Occurrence Handle1:CAS:528:DC%2BD3cXisFShsLw%3D Occurrence Handle10.1086/302809

    Article  PubMed  CAS  Google Scholar 

  6. Ars E, Kruyer H, Morell M, Pros E, Serra E, Ravella A, et al. Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J Med Genet 2003;40–82

  7. SA Thomson L Fishbein MR Wallace (2002) ArticleTitle NF1 mutations and molecular testing J Child Neurol 17 555–61 Occurrence Handle12403553

    PubMed  Google Scholar 

  8. A De Luca A Schirinzi A Buccino I Bottillo L Sinibaldi I Torrente et al. (2004) ArticleTitleNovel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1 Hum Mutat 23 629 Occurrence Handle15146469 Occurrence Handle10.1002/humu.9245

    Article  PubMed  Google Scholar 

  9. L Kluwe RE Fredrich B Korf R Fahsold VF Mautner (2002) ArticleTitle NF1 mutation in neurofibromatosis 1 patients with plexiform neurofibroma Hum Mutat 19 309–13 Occurrence Handle11857752 Occurrence Handle10.1002/humu.9018

    Article  PubMed  Google Scholar 

  10. RK Yantiss AE Rosenberg L Sarran P Besmer CR Antonescu (2005) ArticleTitleMultiple gastrointestinal stromal tumors in type I neurofibromatosis: a pathologic and molecular study Mod Pathol 18 475–84 Occurrence Handle15540118 Occurrence Handle1:CAS:528:DC%2BD2MXisVShtLY%3D Occurrence Handle10.1038/modpathol.3800334

    Article  PubMed  CAS  Google Scholar 

  11. S Hirota K Isozaki Y Moriyama K Hashimoto T Nishida S Ishiguro et al. (1998) ArticleTitleGain-of-function mutations of c-kit in human gastrointestinal stromal tumors Science 279 577–80 Occurrence Handle9438854 Occurrence Handle1:CAS:528:DyaK1cXotVyhsw%3D%3D Occurrence Handle10.1126/science.279.5350.577

    Article  PubMed  CAS  Google Scholar 

  12. DE Williams J Eisenman A Baird (1990) ArticleTitleIdentification of a ligand for the c-kit proto-oncogene Cell 63 167–74 Occurrence Handle1698553 Occurrence Handle1:CAS:528:DyaK3MXnsFOgsw%3D%3D Occurrence Handle10.1016/0092-8674(90)90297-R

    Article  PubMed  CAS  Google Scholar 

  13. M Yamaguchi G Tate Y Endo M Miyaki (2003) ArticleTitleImmunohistochemistry and c-kit gene analysis in determining malignancy in gastrointestinal stromal tumors Hepatogastroenterology 50 1431–5 Occurrence Handle14571755 Occurrence Handle1:CAS:528:DC%2BD3sXot1Clt7o%3D

    PubMed  CAS  Google Scholar 

  14. S Hirota T Nishida K Isozaki (2002) ArticleTitleFamilial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene Gastroenterology 122 1493–9 Occurrence Handle11984533 Occurrence Handle10.1053/gast.2002.33024

    Article  PubMed  Google Scholar 

  15. K Kinoshita K Isozaki S Hirota (2003) ArticleTitlec-kit gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumors J Gastroenterol Hepatol 18 147–51 Occurrence Handle12542597 Occurrence Handle1:CAS:528:DC%2BD3sXjslOgtbg%3D Occurrence Handle10.1046/j.1440-1746.2003.02911.x

    Article  PubMed  CAS  Google Scholar 

  16. G Tate T Suzuki K Kishimoto T Mitsuya (2005) ArticleTitleA c-kit codon 816 mutation, D816H in the testicular germ cell tumor: case report of a Japanese patient with bilateral testicular seminomas Acta Med Okayama 59 33–6 Occurrence Handle15902997 Occurrence Handle1:CAS:528:DC%2BD2MXis1Kgsb0%3D

    PubMed  CAS  Google Scholar 

  17. K Kinoshita S Hirota K Isozaki A Ohashi T Nishida Y Kitamura et al. (2004) ArticleTitleAbsence of c-kit gene mutations in gastrointestinal stromal tumors from neurofibromatosis type 1 patients J Pathol 202 80–5 Occurrence Handle14694524 Occurrence Handle1:CAS:528:DC%2BD2cXnslCntg%3D%3D Occurrence Handle10.1002/path.1487

    Article  PubMed  CAS  Google Scholar 

  18. MJ Frost PT Ferrao TP Hughes LK Ashman (2002) ArticleTitleJuxtamembrane mutant V560GKit is more sensitive to imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant Mol Cancer Ther 1 1115–24 Occurrence Handle12481435 Occurrence Handle1:CAS:528:DC%2BD3sXmtFamsQ%3D%3D

    PubMed  CAS  Google Scholar 

  19. H Murata AW Burgess (1994) ArticleTitleRegulation of the Ras signaling network Bioessays 16 489–96 Occurrence Handle10.1002/bies.950160708

    Article  Google Scholar 

  20. GF Xu P O'Connell D Viskochil (1990) ArticleTitleThe neurofibromatosis type 1 gene encodes a protein related to GAP Cell 62 599–608 Occurrence Handle2116237 Occurrence Handle1:CAS:528:DyaK3cXlt1Omt7w%3D Occurrence Handle10.1016/0092-8674(90)90024-9

    Article  PubMed  CAS  Google Scholar 

  21. D Linnekin (1999) ArticleTitleEarly signaling pathways activated by c-kit in hematopoietic cells Int J Biochem Cell Biol 31 1053–74 Occurrence Handle10582339 Occurrence Handle1:CAS:528:DyaK1MXmsVWitrc%3D Occurrence Handle10.1016/S1357-2725(99)00078-3

    Article  PubMed  CAS  Google Scholar 

  22. ZQ Ning J Li RJ Arceci (2001) ArticleTitleSignal transducer and activator of transcription 3 activation is required for Asp (816) mutant c-kit-mediated cytokine-independent survival and proliferation in human leukemia cells Blood 97 3559–67 Occurrence Handle11369651 Occurrence Handle1:CAS:528:DC%2BD3MXktFOkurw%3D Occurrence Handle10.1182/blood.V97.11.3559

    Article  PubMed  CAS  Google Scholar 

  23. O Gimm M Armanios H Dziema (2000) ArticleTitleSomatic and occult germ-line mutations in SDHD a mitochondrial complex II gene, in nonfamilial pheochromocytoma Cancer Res 60 6822–5 Occurrence Handle11156372 Occurrence Handle1:CAS:528:DC%2BD3MXjsVKrsQ%3D%3D

    PubMed  CAS  Google Scholar 

  24. PH Neumann B Bausch SR McWhinney (2002) ArticleTitleGerm-line mutations in nonsyndromic pheochromocytoma N Engl J Med 346 1459–66 Occurrence Handle12000816 Occurrence Handle1:CAS:528:DC%2BD38XjsVynsLc%3D Occurrence Handle10.1056/NEJMoa020152

    Article  PubMed  CAS  Google Scholar 

  25. E Ars E Serra J Garcia H Kruyer A Gaona C Lazaro et al. (2000) ArticleTitleMutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1 Hum Mol Genet 9 237–47 Occurrence Handle10607834 Occurrence Handle1:CAS:528:DC%2BD3cXhtVaksLw%3D Occurrence Handle10.1093/hmg/9.2.237

    Article  PubMed  CAS  Google Scholar 

  26. B Dasgupta DH Gutmann (2005) ArticleTitleNeurofibromin regulates neural stem cell proliferation, survival, and astroglia differentiation in vitro and in vivo J Neurosci 25 5584–94 Occurrence Handle15944386 Occurrence Handle1:CAS:528:DC%2BD2MXlsFWhur4%3D Occurrence Handle10.1523/JNEUROSCI.4693-04.2005

    Article  PubMed  CAS  Google Scholar 

  27. P O'Brien L Kapusta I Dardick A Axler J Gnidec (1999) ArticleTitleMultiple familial gastrointestinal nerve tumor and small intestinal neuronal dysplasia Am J Surg Pathol 23 198–204 Occurrence Handle9989847 Occurrence Handle10.1097/00000478-199902000-00009

    Article  PubMed  Google Scholar 

  28. Y Takazawa S Sakurai Y Sakuma T Ikeda J Yamaguchi Y Hashizume et al. (2005) ArticleTitleGastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen' disease) Am J Surg Pathol 29 755–63 Occurrence Handle15897742 Occurrence Handle10.1097/01.pas.0000163359.32734.f9

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, 227-8501, Japan

    Hiroshi Nemoto, Shoji Sasaya, Yasuo Yoshizawa, Takemasa Midorikawa & Yutaka Sanada

  2. Department of Surgical Pathology, Showa University Fujigaoka Hospital, Yokohama, Japan

    Genshu Tate, Takao Suzuki & Toshiyuki Mitsuya

  3. IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel Institute, Department of Experimental Medicine and Pathology, University of Rome “La Sapienza”, Viale Regina Margherita 261, 00198, Rome, Italy

    Annalisa Schirinzi & Bruno Dallapiccola

Authors
  1. Hiroshi Nemoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Genshu Tate
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annalisa Schirinzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takao Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shoji Sasaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasuo Yoshizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takemasa Midorikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Toshiyuki Mitsuya
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bruno Dallapiccola
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yutaka Sanada
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nemoto, H., Tate, G., Schirinzi, A. et al. Novel NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor. J Gastroenterol 41, 378–382 (2006). https://doi.org/10.1007/s00535-006-1772-7

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-006-1772-7

Key words

Search

Navigation