Skip to main content

Advertisement

SpringerLink
Log in

Cleft lip/palate and hereditary diffuse gastric cancer: report of a family harboring a CDH1 c.687 + 1G > A germline mutation and review of the literature

  • Original Article
  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominantly inherited cancer syndrome associated with a high risk for diffuse gastric and lobular breast cancer, caused by heterozygous CDH1 germline mutations. Of note, also cleft lip/palate (CLP) has been described in few HDGC families. Here we report on an extensive pedigree presenting with HDGC, CLP and a CDH1 splice site mutation (c.687 + 1G > A) and review the literature for families with CDH1 mutations, HDGC and CLP. Transcript analysis showed that the c.687 + 1G > A mutation leads to loss of the last 42 bp of exon 5 and is consequently predicted to cause loss of 14 amino acids in the first extracellular cadherin repeat (EC) domain. Five mutation carriers developed diffuse gastric cancer and four individuals presented with CLP. Wild type CDH1 expression levels did not differ between CDH1 mutation carriers with CLP compared to those without CLP. Beside this extensive pedigree, we outline another previously unreported HDGC/CLP family with a CDH1 (c.1711 + 1G > C) germline mutation in this study. Review of the literature revealed a significant enrichment of CDH1 mutations within the EC domains in CLP/HDGC families (Fisher’s exact test, p = 0.007) in comparison to CDH1 mutations associated with HDGC only. Report of further CLP/HDGC associated mutations is necessary to confirm this observation. This study highlights that CLP represents an important phenotypic feature of CDH1 germline mutation carriers and emphasizes the inclusion of CLP in the HDGC testing criteria. The underlying causes for the appearance of variable phenotypes in CDH1 mutation carriers could include genetic variation, epigenetic changes and environmental factors and should be investigated in future studies.

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

Similar content being viewed by others

References

  1. Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, Schrader KA, Schaeffer DF, Shumansky K, Zogopoulos G, Santos TA, Claro I, Carvalho J, Nielsen C, Padilla S, Lum A, Talhouk A, Baker-Lange K, Richardson S, Lewis I, Lindor NM, Pennell E, MacMillan A, Fernandez B, Keller G, Lynch H, Shah SP, Guilford P, Gallinger S, Corso G, Roviello F, Caldas C, Oliveira C, Pharoah PD, Huntsman DG (2015) Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol 1(1):23–32. https://doi.org/10.1001/jamaoncol.2014.168

    Article  PubMed  Google Scholar 

  2. Frebourg T, Oliveira C, Hochain P, Karam R, Manouvrier S, Graziadio C, Vekemans M, Hartmann A, Baert-Desurmont S, Alexandre C, Lejeune Dumoulin S, Marroni C, Martin C, Castedo S, Lovett M, Winston J, Machado JC, Attie T, Jabs EW, Cai J, Pellerin P, Triboulet JP, Scotte M, Le Pessot F, Hedouin A, Carneiro F, Blayau M, Seruca R (2006) Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer. J Med Genet 43(2):138–142. https://doi.org/10.1136/jmg.2005.031385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kluijt I, Siemerink EJ, Ausems MG, van Os TA, de Jong D, Simoes-Correia J, van Krieken JH, Ligtenberg MJ, Figueiredo J, van Riel E, Sijmons RH, Plukker JT, van Hillegersberg R, Dekker E, Oliveira C, Cats A, Hoogerbrugge N, Dutch Working Group on Hereditary Gastric C (2012) CDH1-related hereditary diffuse gastric cancer syndrome: clinical variations and implications for counseling. Int J Cancer 131(2):367–376. https://doi.org/10.1002/ijc.26398

    Article  CAS  PubMed  Google Scholar 

  4. Benusiglio PR, Caron O, Consolino E, Duvillard P, Coulet F, Blayau M, Malka D (2013) Cleft lip, cleft palate, hereditary diffuse gastric cancer and germline mutations in CDH1. Int J Cancer 132(10):2470. https://doi.org/10.1002/ijc.27923

    Article  CAS  PubMed  Google Scholar 

  5. Vogelaar IP, Figueiredo J, van Rooij IA, Simoes-Correia J, van der Post RS, Melo S, Seruca R, Carels CE, Ligtenberg MJ, Hoogerbrugge N (2013) Identification of germline mutations in the cancer predisposing gene CDH1 in patients with orofacial clefts. Hum Mol Genet 22(5):919–926. https://doi.org/10.1093/hmg/dds497

    Article  CAS  PubMed  Google Scholar 

  6. Brito LA, Yamamoto GL, Melo S, Malcher C, Ferreira SG, Figueiredo J, Alvizi L, Kobayashi GS, Naslavsky MS, Alonso N, Felix TM, Zatz M, Seruca R, Passos-Bueno MR (2015) Rare variants in the epithelial cadherin gene underlying the genetic etiology of nonsyndromic cleft lip with or without cleft palate. Hum Mut 36(11):1029–1033. https://doi.org/10.1002/humu.22827

    Article  CAS  PubMed  Google Scholar 

  7. Ghoumid J, Stichelbout M, Jourdain AS, Frenois F, Lejeune-Dumoulin S, Alex-Cordier MP, Lebrun M, Guerreschi P, Duquennoy-Martinot V, Vinchon M, Ferri J, Jung M, Vicaire S, Vanlerberghe C, Escande F, Petit F, Manouvrier-Hanu S (2017) Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1. Genet Med 19(9):1013–1021. https://doi.org/10.1038/gim.2017.11

    Article  CAS  PubMed  Google Scholar 

  8. Kievit A, Tessadori F, Douben H, Jordens I, Maurice M, Hoogeboom J, Hennekam R, Nampoothiri S, Kayserili H, Castori M, Whiteford M, Motter C, Melver C, Cunningham M, Hing A, Kokitsu-Nakata NM, Vendramini-Pittoli S, Richieri-Costa A, Baas AF, Breugem CC, Duran K, Massink M, Derksen PWB, van IWFJ, van Unen L, Santos-Simarro L, Lapunzina P, Gil-da Silva Lopes VL, Lustosa-Mendes E, Krall M, Slavotinek A, Martinez-Glez V, Bakkers J, van Gassen KLI, de Klein A, van den Boogaard MH, van Haaften G (2018) Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome. Eur J Hum Genet 26(2):210–219. https://doi.org/10.1038/s41431-017-0010-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  10. Brooks-Wilson AR, Kaurah P, Suriano G, Leach S, Senz J, Grehan N, Butterfield YS, Jeyes J, Schinas J, Bacani J, Kelsey M, Ferreira P, MacGillivray B, MacLeod P, Micek M, Ford J, Foulkes W, Australie K, Greenberg C, LaPointe M, Gilpin C, Nikkel S, Gilchrist D, Hughes R, Jackson CE, Monaghan KG, Oliveira MJ, Seruca R, Gallinger S, Caldas C, Huntsman D (2004) Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet 41(7):508–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kluijt I, Sijmons RH, Hoogerbrugge N, Plukker JT, de Jong D, van Krieken JH, van Hillegersberg R, Ligtenberg M, Bleiker E, Cats A (2012) Familial gastric cancer: guidelines for diagnosis, treatment and periodic surveillance. Fam Cancer 11(3):363–369. https://doi.org/10.1007/s10689-012-9521-y

    Article  PubMed  Google Scholar 

  12. Luening C, Rass A, Rozell B, Wroblewski J, Obrink B (1994) Expression of E-cadherin during craniofacial development. J Craniofacial Genet Dev Biol 14(4):207–216

    Google Scholar 

  13. Sun D, Baur S, Hay ED (2000) Epithelial-mesenchymal transformation is the mechanism for fusion of the craniofacial primordia involved in morphogenesis of the chicken lip. Dev Biol 228(2):337–349. https://doi.org/10.1006/dbio.2000.9946

    Article  CAS  PubMed  Google Scholar 

  14. Corso G, Intra M, Trentin C, Veronesi P, Galimberti V (2016) CDH1 germline mutations and hereditary lobular breast cancer. Fam Cancer 15:215–219. https://doi.org/10.1007/s10689-016-9869-5

    Article  CAS  PubMed  Google Scholar 

  15. Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N, Suriano G, Zaor S, Van Manen L, Gilpin C, Nikkel S, Connolly-Wilson M, Weissman S, Rubinstein WS, Sebold C, Greenstein R, Stroop J, Yim D, Panzini B, McKinnon W, Greenblatt M, Wirtzfeld D, Fontaine D, Coit D, Yoon S, Chung D, Lauwers G, Pizzuti A, Vaccaro C, Redal MA, Oliveira C, Tischkowitz M, Olschwang S, Gallinger S, Lynch H, Green J, Ford J, Pharoah P, Fernandez B, Huntsman D (2007) Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 297(21):2360–2372. https://doi.org/10.1001/jama.297.21.2360

    Article  CAS  PubMed  Google Scholar 

  16. Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011) Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet 12(3):167–178. https://doi.org/10.1038/nrg2933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Steinwachs EF, Amos C, Johnston D, Mulliken J, Stal S, Hecht JT (2000) Nonsyndromic cleft lip and palate is not associated with cancer or other birth defects. Am J Med Genet 90(1):17–24

    Article  CAS  PubMed  Google Scholar 

  18. Vieira AR, Khaliq S, Lace B (2012) Risk of cancer in relatives of children born with isolated cleft lip and palate. Am J Med Genet Part A 158A(6):1503–1504. https://doi.org/10.1002/ajmg.a.35359

    Article  PubMed  Google Scholar 

  19. Jindal A, Vieira AR (2012) Family history of cleft lip and palate in subjects diagnosed with leukemia. Am J Med Genet Part A 158A(3):678–679. https://doi.org/10.1002/ajmg.a.34430

    Article  PubMed  Google Scholar 

  20. Bille C, Winther JF, Bautz A, Murray JC, Olsen J, Christensen K (2005) Cancer risk in persons with oral cleft–a population-based study of 8,093 cases. Am J Epidemiol 161(11):1047–1055. https://doi.org/10.1093/aje/kwi132

    Article  PubMed  Google Scholar 

  21. Popoff DAV, Coelho MP, Martelli DRB, Saini R, Coletta RD, Martelli-Júnior H (2013) Non-syndromic oral clefts and risk of cancer: a systematic review. Dentistry 3000(1 (1):12–18. https://doi.org/10.5195/d3000.2013.11

    Article  Google Scholar 

  22. Suriano G, Oliveira C, Ferreira P, Machado JC, Bordin MC, De Wever O, Bruyneel EA, Moguilevsky N, Grehan N, Porter TR, Richards FM, Hruban RH, Roviello F, Huntsman D, Mareel M, Carneiro F, Caldas C, Seruca R (2003) Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands. Hum Mol Genet 12(5):575–582

    Article  CAS  PubMed  Google Scholar 

  23. Schrader KA, Masciari S, Boyd N, Salamanca C, Senz J, Saunders DN, Yorida E, Maines-Bandiera S, Kaurah P, Tung N, Robson ME, Ryan PD, Olopade OI, Domchek SM, Ford J, Isaacs C, Brown P, Balmana J, Razzak AR, Miron P, Coffey K, Terry MB, John EM, Andrulis IL, Knight JA, O’Malley FP, Daly M, Bender P, Moore R, Southey MC, Hopper JL, Garber JE, Huntsman DG (2011) Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet 48(1):64–68. https://doi.org/10.1136/jmg.2010.079814

    Article  CAS  PubMed  Google Scholar 

  24. Corso G, Marrielli D, Pascale V, Roviello F (2012) Frequency of CDH1 germline mutations in gastric carcinoma coming from high- and low-risk areas: metanalysis and systematic review of the literature. BMC Cancer 12(8):10. https://doi.org/10.1186/1471-2407-12-8

    Article  CAS  Google Scholar 

  25. Martelli DR, Coletta RD, Oliveira EA, Swerts MS, Rodrigues LA, Oliveira MC, Martelli Junior H (2015) Association between maternal smoking, gender, and cleft lip and palate. Braz J Otorhinolaryngol 81(5):514–519. https://doi.org/10.1016/j.bjorl.2015.07.011

    Article  PubMed  Google Scholar 

  26. Sabbagh HJ, Hassan MH, Innes NP, Elkodary HM, Little J, Mossey PA (2015) Passive smoking in the etiology of non-syndromic orofacial clefts: a systematic review and meta-analysis. PLoS ONE 10(3):e0116963. https://doi.org/10.1371/journal.pone.0116963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We want to thank the patients who gave consent for sharing their data in this report.

Author information

Authors and Affiliations

  1. Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine I, Ordensklinikum Linz Barmherzige Schwestern, Seilerstätte 4, 4010, Linz, Austria

    Florian Obermair, Melanie Rammer, Jonathan Burghofer, Theodora Malli, Wolfgang Kranewitter & Gerald Webersinke

  2. Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria

    Anna Schossig & Katharina Wimmer

  3. Fourth Department of Internal Medicine, Klinikum Wels-Grieskirchen, Wels, Austria

    Beate Mayrbaeurl

  4. Institute of Medical Genetics, Med Campus IV, Kepler University Hospital, Linz, Austria

    Florian Obermair & Hans-Christoph Duba

Authors
  1. Florian Obermair
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Melanie Rammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonathan Burghofer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Theodora Malli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anna Schossig
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Katharina Wimmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wolfgang Kranewitter
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Beate Mayrbaeurl
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hans-Christoph Duba
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gerald Webersinke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Florian Obermair.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 15 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Obermair, F., Rammer, M., Burghofer, J. et al. Cleft lip/palate and hereditary diffuse gastric cancer: report of a family harboring a CDH1 c.687 + 1G > A germline mutation and review of the literature. Familial Cancer 18, 253–260 (2019). https://doi.org/10.1007/s10689-018-0111-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-018-0111-5

Keywords

Search

Navigation