Advertisement

Familial Cancer

, Volume 13, Issue 1, pp 131–135 | Cite as

Diversity of the clinical presentation of the MMR gene biallelic mutations

  • Gaëlle Bougeard
  • Laurence Olivier-Faivre
  • Stéphanie Baert-Desurmont
  • Julie Tinat
  • Cosette Martin
  • Emilie Bouvignies
  • Stéphanie Vasseur
  • Frédéric Huet
  • Gérard Couillault
  • Pierre Vabres
  • Florence Le Pessot
  • Caroline Chapusot
  • David Malka
  • Brigitte Bressac-de Paillerets
  • Mario Tosi
  • Thierry FrebourgEmail author
Short Communication

Abstract

Constitutional mismatch repair-deficiency, due to biallelic mutations of MMR genes, results in a tumour spectrum characterized by leukaemias, lymphomas, brain tumours and adenocarcinomas of the gastro-intestinal tract, occurring mostly in childhood. We report here two families illustrating the phenotypic diversity associated with biallelic MMR mutations. In the first family, two siblings developed six malignancies including glioblastoma, lymphoblastic T cell lymphoma, rectal and small bowel adenocarcinoma with onset as early as 6 years of age. We showed that this dramatic clinical presentation was due to the presence of two complex genomic PMS2 deletions in each patient predicted to result into complete PMS2 inactivation. In the second family, the index case presented with an early form of Lynch syndrome with colorectal adenocarcinomas at ages 17 and 20 years, and urinary tract tumours at the age of 25 years. We identified in this patient two MSH6 mutations corresponding to a frameshift deletion and an in frame deletion. The latter was not predicted to result into complete inactivation of MSH6. These reports show that the clinical expression of biallelic MMR mutations depends on the biological impact of the second MMR mutation and that, in clinical practice, the presence of a second MMR mutation located in trans should also be considered in patients suspected to present a Lynch syndrome with an unusual early-onset of tumours.

Keywords

MMR Mutation Tumour 

Notes

Acknowledgments

This work was supported by the INCa, the French National Cancer Institute.

Conflict of interest

The authors declared that they have no conflict of interest.

References

  1. 1.
    Ricciardone MD, Ozçelik T, Cevher B, Ozdağ H, Tuncer M, Gürgey A, Uzunalimoğlu O, Centinkaya H, Tanyeli A, Erken E, Oztürk M (1999) Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res 59:290–293PubMedGoogle Scholar
  2. 2.
    Wang Q, Lasset C, Desseigne F, Frappaz D, Bergeron C, Navarro C, Ruano E, Puisieux A (1999) Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res 59:294–297PubMedGoogle Scholar
  3. 3.
    Felton KE, Gilchrist DM, Andrew SE (2007) Constitutive deficiency in DNA mismatch repair. Clin Genet 71:483–498PubMedCrossRefGoogle Scholar
  4. 4.
    Wimmer K, Kratz CP (2010) Constitutional mismatch repair-deficiency syndrome. Haematologica 95:699–701PubMedCrossRefGoogle Scholar
  5. 5.
    Barwell J, Pangon L, Hodgson S, Georgiou A, Kesterton I, Slade T, Taylor M, Payne SJ, Brinkman H, Smythe J, Sebire NJ, Solomon E, Docherty Z, Camplejohn R, Homfray T, Morris JR (2007) Biallelic mutation of MSH2 in primary human cells is associated with sensitivity to irradiation and altered RAD51 foci kinetics. J Med Genet 44:516–520PubMedCrossRefGoogle Scholar
  6. 6.
    Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S (1998) A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248–5257PubMedGoogle Scholar
  7. 7.
    De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT (2004) Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 74:954–964PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Agostini M, Tibiletti MG, Lucci-Cordisco E, Chiaravalli A, Morreau H, Furlan D, Boccuto L, Pucciarelli S, Capella C, Boiocchi M, Viel A (2005) Two PMS2 mutations in a Turcot syndrome family with small bowel cancers. Am J Gastroenterol 100:1886–1891PubMedCrossRefGoogle Scholar
  9. 9.
    Auclair J, Leroux D, Desseigne F, Lasset C, Saurin JC, Joly MO, Pinson S, Xu XL, Montmain G, Ruano E, Navarro C, Puisieux A, Wang Q (2007) Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat 28:1084–1090PubMedCrossRefGoogle Scholar
  10. 10.
    Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, Lindblom A, Lagerstedt K, Thibodeau SN, Lindor NM, Young J, Winship I, Dowty JG, White DM, Hopper JL, Baglietto L, Jenkins MA, de la Chapelle A (2008) The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135:419–428PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Durno CA, Holter S, Sherman PM, Gallinger S (2010) The gastrointestinal phenotype of germline biallelic mismatch repair gene mutations. Am J Gastroenterol 105:2449–2456PubMedCrossRefGoogle Scholar
  12. 12.
    Leenen CH, Geurts-Giele WR, Dubbink HJ, Reddingius R, van den Ouweland AM, Tops CM, van de Klift HM, Kuipers EJ, van Leerdam ME, Dinjens WN, Wagner A (2011) Pitfalls in molecular analysis for mismatch repair deficiency in a family with biallelic pms2 germline mutations. Clin Genet 80:558–565PubMedCrossRefGoogle Scholar
  13. 13.
    Vasovcak P, Krepelova A, Menigatti M, Puchmajerova A, Skapa P, Augustinakova A, Amann G, Wernstedt A, Jiricny J, Marra G, Wimmer K (2012) Unique mutational profile associated with a loss of TDG expression in the rectal cancer of a patient with a constitutional PMS2 deficiency. DNA Repair (Amst) 11:616–623CrossRefGoogle Scholar
  14. 14.
    Yeung JT, Pollack IF, Shah S, Jaffe R, Nikiforova M, Jakacki RI (2013) Optic pathway glioma as part of a constitutional mismatch-repair deficiency syndrome in a patient meeting the criteria for neurofibromatosis type 1. Pediatr Blood Cancer 60:137–139PubMedCrossRefGoogle Scholar
  15. 15.
    Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, Guimbaud R, Buecher B, Bignon YJ, Caron O, Colas C, Noguès C, Lejeune-Dumoulin S, Olivier-Faivre L, Polycarpe-Osaer F, Nguyen TD, Desseigne F, Saurin JC, Berthet P, Leroux D, Duffour J, Manouvrier S, Frébourg T, Sobol H, Lasset C, Bonaïti-Pellié C, French Cancer Genetics Network (2001) Cancer risk associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305:2304–2310CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Gaëlle Bougeard
    • 1
    • 2
  • Laurence Olivier-Faivre
    • 3
  • Stéphanie Baert-Desurmont
    • 1
    • 2
  • Julie Tinat
    • 1
    • 2
  • Cosette Martin
    • 1
    • 2
  • Emilie Bouvignies
    • 1
    • 2
  • Stéphanie Vasseur
    • 1
    • 2
  • Frédéric Huet
    • 3
  • Gérard Couillault
    • 4
  • Pierre Vabres
    • 5
  • Florence Le Pessot
    • 6
  • Caroline Chapusot
    • 7
  • David Malka
    • 8
  • Brigitte Bressac-de Paillerets
    • 8
  • Mario Tosi
    • 1
    • 2
  • Thierry Frebourg
    • 1
    • 2
    Email author
  1. 1.Inserm U1079, Faculty of MedicineUniversity of RouenRouenFrance
  2. 2.Department of Genetics, Institute for Biomedical Research and InnovationUniversity HospitalRouenFrance
  3. 3.Department of GeneticsUniversity HospitalDijonFrance
  4. 4.Department of PaediatricsUniversity HospitalDijonFrance
  5. 5.Department of DermatologyUniversity HospitalDijonFrance
  6. 6.Department of PathologyUniversity HospitalRouenFrance
  7. 7.Department of PathologyUniversity HospitalDijonFrance
  8. 8.Department of GeneticsInstitute Gustave RoussyVillejuifFrance

Personalised recommendations