Skip to main content

Advertisement

SpringerLink
Log in

A de novo pathogenic variant in the MSH6 gene in a 52 years-old woman

  • Short Communication
  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

Lynch syndrome (LS) is a condition which predisposes individuals primarily to early-onset colorectal and endometrial cancer. LS is characterized by a germline pathogenic variant in one of the MMR (MisMatch Repair) gene, inducing a phenotype of microsatellite instability in the tumor, which may be associated with a loss of expression of MMR proteins detected by standard immunohistochemistry on tumor tissue. Most of the time, LS is inherited from a parent in whom the condition may not be known due to incomplete penetrance, but de novo pathogenic variant is a rare occurrence. Here, we describe the case of a 52-year-old woman with no family history of LS, referred to the genetics department for colorectal cancer at the age of 50. Genetic analysis revealed a de novo germline pathogenic variant in the MSH6 gene. To date, this case is only the second report of a de novo pathogenic variant in the MSH6 gene in Lynch syndrome. De novo mutations have been extensively studied over the past years, but little is known about their origin and mechanism of occurrence in MMR genes. However, knowledge of mutation status allows better cancer risk management for the patient and an appropriate genetic testing and counseling for her family.

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

References

  1. Lynch HT, de la Chapelle A (1999) Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 36:801–818

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Hampel H, Frankel WL, Martin E et al (2008) Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol 26:5783–5788. https://doi.org/10.1200/JCO.2008.17.5950

    Article  Google Scholar 

  3. Win AK, Jenkins MA, Dowty JG et al (2017) Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol 26:404–412. https://doi.org/10.1158/1055-9965.EPI-16-0693

    Article  CAS  Google Scholar 

  4. Umar A, Boland CR, Terdiman JP et al (2004) Revised bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268. https://doi.org/10.1093/jnci/djh034

    Article  CAS  PubMed  Google Scholar 

  5. Acuna-Hidalgo R, Veltman JA, Hoischen A (2016) New insights into the generation and role of de novo mutations in health and disease. Genome Biol 17:241. https://doi.org/10.1186/s13059-016-1110-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. McRae Jeremy F, Clayton Stephen (2017) Prevalence and architecture of de novo mutations in developmental disorders. Nature 542:433–438. https://doi.org/10.1038/nature21062

    Article  CAS  Google Scholar 

  7. Win AK, Jenkins MA, Buchanan DD et al (2011) Determining the frequency of de novo germline mutations in DNA mismatch repair genes. J Med Genet 48:530–534. https://doi.org/10.1136/jmedgenet-2011-100082

    Article  CAS  PubMed  Google Scholar 

  8. Tesch VK, IJspeert H, Raicht A et al (2018) No overt clinical immunodeficiency despite immune biological abnormalities in patients with constitutional mismatch repair deficiency. Front Immunol 9:1506. https://doi.org/10.3389/fimmu.2018.01506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hizuka K, Hagiwara S-I, Maeyama T et al (2021) Constitutional mismatch repair deficiency in childhood colorectal cancer harboring a de novo variant in the MSH6 gene: a case report. BMC Gastroenterol 21:60. https://doi.org/10.1186/s12876-021-01646-3

    Article  PubMed  PubMed Central  Google Scholar 

  10. Airaud F, Küry S, Valo I et al (2012) A de novo germline MLH1 mutation in a Lynch syndrome patient with discordant immunohistochemical and molecular biology test results. World J Gastroenterol 18:5635–5639. https://doi.org/10.3748/wjg.v18.i39.5635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Smith L, Tesoriero A, Mead L et al (2006) Large genomic alterations in hMSH2 and hMLH1 in early-onset colorectal cancer: identification of a large complex de novo hMLH1 alteration. Clin Genet 70:250–252. https://doi.org/10.1111/j.1399-0004.2006.00662.x

    Article  CAS  PubMed  Google Scholar 

  12. Stulp RP, Vos YJ, Mol B et al (2006) First report of a de novo germline mutation in the MLH1 gene. World J Gastroenterol 12:809–811. https://doi.org/10.3748/wjg.v12.i5.809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Plasilova M, Zhang J, Okhowat R et al (2006) A de novo MLH1 germ line mutation in a 31-year-old colorectal cancer patient. Genes Chromosomes Cancer 45:1106–1110. https://doi.org/10.1002/gcc.20374

    Article  CAS  PubMed  Google Scholar 

  14. Geurts-Giele WR, Rosenberg EH, Rens A van et al (2019) Somatic mosaicism by a de novo MLH1 mutation as a cause of Lynch syndrome. Mol Genet Genomic Med 7:e00699. https://doi.org/10.1002/mgg3.699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kraus C, Kastl S, Günther K et al (1999) A proven de novo germline mutation in HNPCC. J Med Genet 36:919–921

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Morak M, Laner A, Scholz M et al (2008) Report on de-novo mutation in the MSH2 gene as a rare event in hereditary nonpolyposis colorectal cancer. Eur J Gastroenterol Hepatol 20:1101–1105. https://doi.org/10.1097/MEG.0b013e328305e185

    Article  PubMed  Google Scholar 

  17. Zajo K, Colace SI, Mouhlas D, Erdman SH (2020) Lynch syndrome-associated colorectal cancer in a 16-year-old girl due to a de novo MSH2 mutation. BMJ Case Rep. https://doi.org/10.1136/bcr-2019-233935

    Article  PubMed  Google Scholar 

  18. Sourrouille I, Coulet F, Lefevre JH et al (2013) Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors. Fam Cancer 12:27–33. https://doi.org/10.1007/s10689-012-9568-9

    Article  CAS  PubMed  Google Scholar 

  19. Guillerm E, Svrcek M, Bardier-Dupas A et al (2020) Molecular tumor testing in patients with Lynch-like syndrome reveals a de novo mosaic variant of a mismatch repair gene transmitted to offspring. Eur J Hum Genet EJHG 28:1624–1628. https://doi.org/10.1038/s41431-020-0689-6

    Article  CAS  PubMed  Google Scholar 

  20. Ryan NAJ, Morris J, Green K et al (2017) Association of mismatch repair mutation with age at cancer onset in lynch syndrome: implications for stratified surveillance strategies. JAMA Oncol 3:1702–1706. https://doi.org/10.1001/jamaoncol.2017.0619

    Article  PubMed  PubMed Central  Google Scholar 

  21. Dominguez-Valentin M, Sampson JR, Seppälä TT et al (2020) Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the prospective lynch syndrome database. Genet Med Off J Am Coll Med Genet 22:15–25. https://doi.org/10.1038/s41436-019-0596-9

    Article  CAS  Google Scholar 

  22. Renaux-Petel M, Charbonnier F, Théry J-C et al (2018) Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome. J Med Genet 55:173–180. https://doi.org/10.1136/jmedgenet-2017-104976

    Article  CAS  PubMed  Google Scholar 

  23. Ripa R, Bisgaard ML, Bülow S, Nielsen FC (2002) De novo mutations in familial adenomatous polyposis (FAP). Eur J Hum Genet EJHG 10:631–637. https://doi.org/10.1038/sj.ejhg.5200853

    Article  CAS  PubMed  Google Scholar 

  24. Kong A, Frigge ML, Masson G et al (2012) Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488:471–475. https://doi.org/10.1038/nature11396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kato MV, Ishizaki K, Shimizu T et al (1994) Parental origin of germ-line and somatic mutations in the retinoblastoma gene. Hum Genet 94:31–38. https://doi.org/10.1007/BF02272838

    Article  CAS  PubMed  Google Scholar 

  26. Carlson KM, Bracamontes J, Jackson CE et al (1994) Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 55:1076–1082

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Goldmann JM, Wong WSW, Pinelli M et al (2016) Parent-of-origin-specific signatures of de novo mutations. Nat Genet 48:935–939. https://doi.org/10.1038/ng.3597

    Article  CAS  PubMed  Google Scholar 

  28. Goriely A, Wilkie AOM (2012) Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am J Hum Genet 90:175–200. https://doi.org/10.1016/j.ajhg.2011.12.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Goriely A (2016) Decoding germline de novo point mutations. Nat Genet 48:823–824. https://doi.org/10.1038/ng.3629

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, 9 quai Moncousu, 44093, Nantes, France

    Elise Pierre-Noël, Fabrice Airaud, Céline Garrec, Ingrid Ricordeau & Stéphane Bezieau

  2. Centre Hospitalier Universitaire de Nantes, Institut des maladies de l’appareil digestif, 1 place Alexis-Ricordeau, 44093, Nantes, France

    Estelle Cauchin

  3. Institut de Cancérologie de l’Ouest, Unité d’Oncogénétique, Boulevard Professeur Jacques Monod, 44800, Saint- Herblain, France

    Estelle Cauchin & Caroline Abadie

  4. Institut de Cancérologie de l’Ouest, laboratoire d’Oncopharmacologie et pharmacogénétique, 15 rue André Boquel, 49055, Angers, France

    Clémence Michon

  5. Département de pathologie tissulaire et moléculaire, Institut de Cancérologie de l’Ouest, Boulevard Professeur Jacques Monod, 44800, Saint-Herblain, France

    Olivier Kerdraon

Authors
  1. Elise Pierre-Noël
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabrice Airaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Estelle Cauchin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Céline Garrec
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ingrid Ricordeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Clémence Michon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Olivier Kerdraon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stéphane Bezieau
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Caroline Abadie
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

EPN involved in concept, manuscript draft, and final approval; FA performed study execution and final approval; EC and CG contributed to study execution, interpretation, manuscript revision, and final approval; IR, CM and OK participated in study execution and final approval; SB and CA took part in concept, manuscript revision, interpretation, and final approval.

Corresponding author

Correspondence to Caroline Abadie.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to disclose.

Consent to participate

Written informed consent for research was obtained from family members.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pierre-Noël, E., Airaud, F., Cauchin, E. et al. A de novo pathogenic variant in the MSH6 gene in a 52 years-old woman. Familial Cancer 21, 319–324 (2022). https://doi.org/10.1007/s10689-021-00274-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-021-00274-w

Keywords

Search

Navigation