Skip to main content
SpringerLink
Log in

A homozygote splice site PMS2 mutation as cause of Turcot syndrome gives rise to two different abnormal transcripts

  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

Turcot syndrome is a rare, inherited disease predisposing of tumours in the central nerve system and in the colorectal system. This report describes a Turcot patient with an extraordinary clinical history. The patient is still alive at the age of 43. She was operated at the age of 10 by brain tumour and at the age of 16 by colorectal cancer. She has since then been treated for multiple cancers (gastrointestinal, endometrial, basal cell carcinomas), and removal of adenomatous polyps at several occasions. The aim of this work was to investigate if there was any specific genotype that explains her remarkable clinical history. Microsatellite instability and immunohistochemistry analysis for four DNA mismatch repair proteins were performed. DNA mutation analysis was done for genes involved in polyposis and mismatch repair by denaturing high performance liquid chromatography and sequencing. cDNA analysis was carried out for the mismatch repair gene PMS2. The patients genotype was found to be a homozygous splice site mutation in the PMS2 gene, c.989-1G<T, which resulted in two abnormal transcripts, not one as expected. The patient’s long time survival may in part be explained by meticulous follow up by health care professionals. The other importing factor is probably the nature of here genotype. cDNA analysis showed that the homozygous mutation led to two abnormal transcripts, of which one is perhaps less detrimental. Thus cDNA analysis is of prime importance for the full evaluation of the effect of putative splicing mutations.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

APC:

Adenomatous polyposis coli

CNS:

Central nerve system

HNPCC:

Hereditary nonpolyposis colorectal cancer

MUTYH:

MutY E. coli homologue

References

  1. Turcot J, Despres JP, St Pierre F (1959) Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases. Dis Colon Rectum 2:465–468. doi:10.1007/BF02616938

    Article  PubMed  CAS  Google Scholar 

  2. Hamilton SR, Liu B, Parsons RE et al (1995) The molecular basis of Turcot’s syndrome. N Engl J Med 332:839–847. doi:10.1056/NEJM199503303321302

    Article  PubMed  CAS  Google Scholar 

  3. Paraf F, Jothy S, Van Meir EG (1997) Brain tumor-polyposis syndrome: two genetic diseases? J Clin Oncol 15:2744–2758

    PubMed  CAS  Google Scholar 

  4. Trimbath JD, Petersen GM, Erdman SH et al (2001) Cafe-au-lait spots and early onset colorectal neoplasia: a variant of HNPCC? Fam Cancer 1:101–105. doi:10.1023/A:1013881832014

    Article  PubMed  CAS  Google Scholar 

  5. Loukola A, Eklin K, Laiho P et al (2001) Microsatellite marker analysis in screening for hereditary nonpolyposis colorectal cancer (HNPCC). Cancer Res 61:4545–4549

    PubMed  CAS  Google Scholar 

  6. Aaltonen LA, Salovaara R, Kristo P et al (1998) Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 338:1481–1487. doi:10.1056/NEJM199805213382101

    Article  PubMed  CAS  Google Scholar 

  7. Groden J, Thliveris A, Samowitz W et al (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600. doi:10.1016/0092-8674(81)90021-0

    Article  PubMed  CAS  Google Scholar 

  8. Jones S, Emmerson P, Maynard J et al (2002) Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C–>T:A mutations. Hum Mol Genet 11:2961–2967. doi:10.1093/hmg/11.23.2961

    Article  PubMed  CAS  Google Scholar 

  9. Weber TK, Conlon W, Petrelli NJ et al (1997) Genomic DNA-based hMSH2 and hMLH1 mutation screening in 32 Eastern United States hereditary nonpolyposis colorectal cancer pedigrees. Cancer Res 57:3798–3803

    PubMed  CAS  Google Scholar 

  10. Nicolaides NC, Carter KC, Shell BK et al (1995) Genomic organization of the human PMS2 gene family. Genomics 30:195–206. doi:10.1006/geno.1995.9885

    Article  PubMed  CAS  Google Scholar 

  11. De Vos M, Hayward BE, Picton S et al (2004) Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 74:954–964. doi:10.1086/420796

    Article  PubMed  Google Scholar 

  12. Al-Tassan N, Chmiel NH, Maynard J et al (2002) Inherited variants of MYH associated with somatic G:C–>T:A mutations in colorectal tumors. Nat Genet 30:227–232. doi:10.1038/ng828

    Article  PubMed  CAS  Google Scholar 

  13. De Rosa M, Fasano C, Panariello L et al (2000) Evidence for a recessive inheritance of Turcot’s syndrome caused by compound heterozygous mutations within the PMS2 gene. Oncogene 19:1719–1723. doi:10.1038/sj.onc.1203447

    Article  PubMed  CAS  Google Scholar 

  14. Nakagawa H, Lockman JC, Frankel WL et al (2004) Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res 64:4721–4727. doi:10.1158/0008-5472.CAN-03-2879

    Article  PubMed  CAS  Google Scholar 

  15. Agostini M, Tibiletti MG, Lucci-Cordisco E et al (2005) Two PMS2 mutations in a Turcot syndrome family with small bowel cancers. Am J Gastroenterol 100:1886–1891. doi:10.1111/j.1572-0241.2005.50441.x

    Article  PubMed  CAS  Google Scholar 

  16. Gottschling S, Reinhard H, Pagenstecher C et al (2008) Hypothesis: possible role of retinoic acid therapy in patients with biallelic mismatch repair gene defects. Eur J Pediatr 167(2):225–229. doi:10.1007/s00431-007-0474-3

    Article  PubMed  Google Scholar 

  17. Taylor MD, Perry J, Zlatescu MC et al (1999) The hPMS2 exon 5 mutation and malignant glioma. Case report. J Neurosurg 90:946–950

    Article  PubMed  CAS  Google Scholar 

  18. Clendenning M, Hampel H, LaJeunesse J et al (2006) Long-range PCR facilitates the identification of PMS2-specific mutations. Hum Mutat 27:490–495. doi:10.1002/humu.20318

    Article  PubMed  CAS  Google Scholar 

  19. Hendriks YMC, Jagmohan-Changur S, van der Klift HM et al (2006) Heterozygous mutation in PMS2 cause hereditary nonpolyposis colorectal Carcinoma (Lynch Syndrome). Gastroenterology 130:312–322. doi:10.1053/j.gastro.2005.10.052

    Article  PubMed  CAS  Google Scholar 

  20. Charames GS, Cheng H, Gilpin CA et al (2002) A novel aberrant splice site mutation in the APC gene. J Med Genet 39:754–757. doi:10.1136/jmg.39.10.754

    Article  PubMed  CAS  Google Scholar 

  21. Yu L, Heere-Ress E, Boucher B, et al. (1999) Familial hypercholesterolemia. Acceptor splice site (G–>C) mutation in intron 7 of the LDL-R gene: alternate RNA editing causes exon 8 skipping or a premature stop codon in exon 8. LDL-R(Honduras-1). Atherosclerosis 146:125–131. LDL-R1061(-1) G–>C. doi:10.1016/S0021-9150(99)00109-4

    Google Scholar 

  22. Andreutti-Zaugg C, Scott RJ, Iggo R (1997) Inhibition of nonsense-mediated Messenger RNA decay in clinical samples facilitates detection of human MSH2 mutations with an in vivo fusion protein assay and conventional techniques. Cancer Res 57:3288–3293

    PubMed  CAS  Google Scholar 

  23. Behm-Ansmant I, Kashima I, Rehwinkel J et al (2007) mRNA quality control: an ancient machinery recognizes and degrades mRNAs with nonsense codons. FEBS Lett 15:2845–2853. doi:10.1016/j.febslet.2007.05.027

    Article  CAS  Google Scholar 

  24. Ban C, Junop M, Yang W (1999) Transformation of MutL by ATP binding and hydrolysis: a switch in DNA mismatch repair. Cell 97:85–97. doi:10.1016/S0092-8674(00)80717-5

    Article  PubMed  CAS  Google Scholar 

  25. Guarne A, Junop MS, Yang W (2001) Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase. EMBO J 20:5521–5531. doi:10.1093/emboj/20.19.5521

    Article  PubMed  CAS  Google Scholar 

  26. Truninger K, Menigatti M, Luz J (2005) Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 128:1160–1171. doi:10.1053/j.gastro.2005.01.056

    Article  PubMed  CAS  Google Scholar 

  27. Worthley DL, Walsh MD, Barker M (2005) Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 128:1431–1436. doi:10.1053/j.gastro.2005.04.008

    Article  PubMed  CAS  Google Scholar 

  28. Gryfe R, Gallinger S (2005) Germline PMS2 mutations: one hit or two? Gastroenterology 128:1506–1509. doi:10.1053/j.gastro.2005.03.054

    Article  PubMed  CAS  Google Scholar 

  29. Falkenback D, Johansson J, Halvarsson B, Nilbert M (2005) Defective mismatch-repair as a minor tumorigenic pathway in Barrett esophagus-associated adenocarcinoma. Cancer Genet Cytogenet 157:82–86. doi:10.1016/j.cancergencyto.2004.08.003

    Article  PubMed  CAS  Google Scholar 

  30. Rutz HP, de Tribolet N, Calmes JM, Chapuis G (1991) Long-time survival of a patient with glioblastoma and Turcot’s syndrome. Case report. J Neurosurg 74:813–815

    Google Scholar 

  31. De Vos M, Hayward BE, Charlton R (2006) PMS2 mutations in childhood cancer. J Natl Cancer Inst 98:358–361

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the Cancer Foundation at St Olavs University Hospital. We thank L. A. Lavik, B. Gilde, S. Brathaug, K. Bye and E. Svaasand for technical assistance.

Author information

Authors and Affiliations

  1. Department of Pathology and Medical Genetics, St. Olavs University Hospital, Erling Skjalgssons gt.1, 7006, Trondheim, Norway

    Wenche Sjursen, Inga Bjørnevoll, Kristine Fjelland & Tore Halvorsen

  2. Department of Surgery, St. Olavs University Hospital, Trondheim, Norway

    Helge E. Myrvold

  3. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

    Lars F. Engebretsen

  4. Department of Laboratory Medicine Children’s and Women’s Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway

    Wenche Sjursen

  5. Department of Cancer Research and Molecular Biology, NTNU, Norwegian University of Science and Technology, Trondheim, Norway

    Tore Halvorsen & Helge E. Myrvold

Authors
  1. Wenche Sjursen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Inga Bjørnevoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lars F. Engebretsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kristine Fjelland
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tore Halvorsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Helge E. Myrvold
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wenche Sjursen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sjursen, W., Bjørnevoll, I., Engebretsen, L.F. et al. A homozygote splice site PMS2 mutation as cause of Turcot syndrome gives rise to two different abnormal transcripts. Familial Cancer 8, 179–186 (2009). https://doi.org/10.1007/s10689-008-9225-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-008-9225-5

Keywords

Search

Navigation