Familial Cancer

, Volume 15, Issue 2, pp 215–219 | Cite as

CDH1 germline mutations and hereditary lobular breast cancer

  • Giovanni CorsoEmail author
  • Mattia Intra
  • Chiara Trentin
  • Paolo Veronesi
  • Viviana Galimberti


Hereditary diffuse gastric cancer is an autosomal dominant inherited disease associated of CDH1 germline mutations (that encodes for the E-cadherin protein), and lobular breast cancer is the second most frequent type of neoplasia. Recently, novel E-cadherin constitutional alterations have been identified in pedigree clustering only for lobular breast carcinoma without evidence of diffuse gastric tumors and in absence of BRCA1/2 mutations. This first evidence opens novel questions about the inherited correlation between diffuse gastric and lobular breast cancers. In this brief review we revise the literature data about the CDH1 mutation frequency affecting exclusively lobular breast cancer, providing clinical recommendation for asymptomatic mutation carriers.


Lobular breast cancer E-cadherin germline mutation Hereditary breast cancer 



This manuscript was support by AIRC 5 × 1000 grant.

Compliance with ethical standards

Conflict of interest

All other authors declare that they have no conflicts of interest.


  1. 1.
    Berx G, Cleton-Jansen AM, Nollet F et al (1995) E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J 14:6107–6115PubMedPubMedCentralGoogle Scholar
  2. 2.
    Takeichi M (1991) Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251:1451–1455CrossRefPubMedGoogle Scholar
  3. 3.
    Takeichi M, Hirano S, Matsuyoshi N, Fujimori T (1992) Cytoplasmic control of cadherin-mediated cell–cell adhesion. Cold Spring Harb Symp Quant Biol 57:327–334CrossRefPubMedGoogle Scholar
  4. 4.
    Christofori G, Semb H (1999) The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci 24:73–76. doi: 10.1016/S0968-0004(98)01343-7 CrossRefPubMedGoogle Scholar
  5. 5.
    Corso G, Carvalho J, Marrelli D et al (2013) Somatic mutations and deletions of the E-cadherin gene predict poor survival of patients with gastric cancer. J Clin Oncol 31:868–875. doi: 10.1200/JCO.2012.44.4612 CrossRefPubMedGoogle Scholar
  6. 6.
    Caldas C, Carneiro F, Lynch HT et al (1999) Familial gastric cancer: overview and guidelines for management. J Med Genet 36:873–880. doi: 10.1136/jmg.36.12.873 PubMedPubMedCentralGoogle Scholar
  7. 7.
    Guilford P, Hopkins J, Harraway J et al (1998) E-cadherin germline mutations in familial gastric cancer. Nature 392:402–405CrossRefPubMedGoogle Scholar
  8. 8.
    Corso G, Marrelli D, Pascale V, Vindigni C, 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. doi: 10.1186/1471-2407-12-8 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Keller G, Vogelsang H, Becker I et al (1999) Diffuse type gastric and lobular breast carcinoma in a familial gastric cancer patient with an E-cadherin germline mutation. Am J Pathol 155:337–342. doi: 10.1016/S0002-9440(10)65129-2 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Benusiglio PR, Malka D, Rouleau E et al (2013) CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study. J Med Genet 50:486–489. doi: 10.1136/jmedgenet-2012-101472 CrossRefPubMedGoogle Scholar
  11. 11.
    Petridis C, Shinomiya I, Kohut K et al (2014) Germline CDH1 mutations in bilateral lobular carcinoma in situ. Br J Cancer 110:1053–1057. doi: 10.1038/bjc.2013.792 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Silva R, Susy C, Carneiro F, Amendoeira I (2014) Genetic profile and morphological features of breast cancers in the setting of Hereditary Breast Cancer (HBC) syndrome. Virchows Arch 465(Suppl 1):S111–S112Google Scholar
  13. 13.
    Rahman N, Stone JG, Coleman G et al (2000) Lobular carcinoma in situ of the breast is not caused by constitutional mutations in the E-cadherin gene. Br J Cancer 82:568–570. doi: 10.1054/bjoc.1999.0965 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Masciari S, Larsson N, Senz J et al (2007) Germline E-cadherin mutations in familial lobular breast cancer. J Med Genet 44:726–731. doi: 10.1136/jmg.2007.051268 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Schrader KA, Masciari S, Boyd N et al (2011) Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet 48:64–68. doi: 10.1136/jmg.2010.079814 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Xie ZM, Li LS, Laquet C et al (2011) Germline mutations of the E-cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer. Cancer 117:3112–3117. doi: 10.1002/cncr.25876 CrossRefPubMedGoogle Scholar
  17. 17.
    Lei H, Sjöberg-Margolin S, Salahshor S et al (2002) CDH1 mutations are present in both ductal and lobular breast cancer, but promoter allelic variants show no detectable breast cancer risk. Int J Cancer 98:199–204. doi: 10.1002/ijc.10176 CrossRefPubMedGoogle Scholar
  18. 18.
    van der Post RS, Vogelaar IP, Carneiro F et al (2015) Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet 52:361–374. doi: 10.1136/jmedgenet-2015-103094 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Corso G, Figueiredo J, Biffi R et al (2014) E-cadherin germline mutation carriers: clinical management and genetic implications. Cancer Metastasis Rev 33:1081–1094. doi: 10.1007/s10555-014-9528-y CrossRefPubMedGoogle Scholar
  20. 20.
    Cataliotti L, Galimberti V, Mano MP (2010) The nipple sparing mastectomy (NSM). Attualità Senologia 59:11–20Google Scholar
  21. 21.
    Petit JY, Veronesi U, Lohsiriwat V et al (2011) Nipple-sparing mastectomy-is it worth the risk? Nat Rev Clin Oncol 8:742–747. doi: 10.1038/nrclinonc.2011.159 CrossRefPubMedGoogle Scholar
  22. 22.
    Porter AJ, Evans EB, Foxcroft LM, Simpson PT, Lakhani SR (2014) Mammographic and ultrasound features of invasive lobular carcinoma of the breast. J Med Imaging Radiat Oncol 58:1–10. doi: 10.1111/1754-9485.12080 CrossRefPubMedGoogle Scholar
  23. 23.
    Moll R, Mitze M, Frixen UH, Birchmeier W (1993) Differential loss of E-cadherin expression in infiltrating ductal and lobular breast carcinomas. Am J Pathol 143:1731–1742PubMedPubMedCentralGoogle Scholar
  24. 24.
    Yeatman TJ, Cantor AB, Smith TJ et al (1995) Tumor biology of infiltrating lobular carcinoma. Implications for management. Ann Surg 222:549–559 (discussion 559–561) CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Le Gal M, Ollivier L, Asselain B et al (1992) Mammographic features of 455 invasive lobular carcinomas. Radiology 185:705–708CrossRefPubMedGoogle Scholar
  26. 26.
    Brem RF, Ioffe M, Rapelyea JA et al (2009) Invasive lobular carcinoma: detection with mammography, sonography, MRI, and breast-specific gamma imaging. AJR Am J Roentgenol 192:379–383. doi: 10.2214/AJR.07.3827 CrossRefPubMedGoogle Scholar
  27. 27.
    Mann RM, Hoogeveen YL, Blickman JG, Boetes C (2008) MRI compared to conventional diagnostic work-up in the detection and evaluation of invasive lobular carcinoma of the breast: a review of existing literature. Breast Cancer Res Treat 107:1–14. doi: 10.1007/s10549-007-9528-5 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Selinko VL, Middleton LP, Dempsey PJ (2004) Role of sonography in diagnosing and staging invasive lobular carcinoma. J Clin Ultrasound 32:323–332. doi: 10.1002/jcu.20052 CrossRefPubMedGoogle Scholar
  29. 29.
    Krecke KN, Gisvold JJ (1993) Invasive lobular carcinoma of the breast: mammographic findings and extent of disease at diagnosis in 184 patients. AJR Am J Roentgenol 161:957–960CrossRefPubMedGoogle Scholar
  30. 30.
    Berg WA, Gutierrez L, NessAiver MS et al (2004) Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Radiology 233:830–849. doi: 10.1148/radiol.2333031484 CrossRefPubMedGoogle Scholar
  31. 31.
    Tan SM, Behranwala KA, Trott PA et al (2002) A retrospective study comparing the individual modalities of triple assessment in the pre-operative diagnosis of invasive lobular breast carcinoma. Eur J Surg Oncol 28:203–208. doi: 10.1053/ejso.2001.1236 CrossRefPubMedGoogle Scholar
  32. 32.
    Watermann DO, Tempfer C, Hefler LA, Parat C, Stickeler E (2005) Ultrasound morphology of invasive lobular breast cancer is different compared with other types of breast cancer. Ultrasound Med Biol 31:167–174. doi: 10.1016/j.ultrasmedbio.2004.11.005 CrossRefPubMedGoogle Scholar
  33. 33.
    Lei J, Yang P, Zhang L, Wang Y, Yang K (2014) Diagnostic accuracy of digital breast tomosynthesis versus digital mammography for benign and malignant lesions in breasts: a meta-analysis. Eur Radiol 24:595–602. doi: 10.1007/s00330-013-3012-x CrossRefPubMedGoogle Scholar
  34. 34.
    Oliveira TM, Elias J Jr, Melo AF et al (2014) Evolving concepts in breast lobular neoplasia and invasive lobular carcinoma, and their impact on imaging methods. Insights Imaging 5:183–194. doi: 10.1007/s13244-014-0324-6 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Muttalib M, Ibrahem R, Khashan AS, Hajaj M (2014) Prospective MRI assessment for invasive lobular breast cancer. Correlation with tumour size at histopathology and influence on surgical management. Clin Radiol 69:23–28. doi: 10.1016/j.crad.2013.07.016 CrossRefPubMedGoogle Scholar
  36. 36.
    Hansford S, Kaurah P, Li-Chang H et al (2015) Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol 1(1):23–32. doi: 10.1001/jamaoncol.2014.168 CrossRefPubMedGoogle Scholar
  37. 37.
    Mateus AR, Seruca R, Machado JC et al (2007) EGFR regulates RhoA-GTP dependent cell motility in E-cadherin mutant cells. Hum Mol Genet 16:1639–1647. doi: 10.1093/hmg/ddm113 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Giovanni Corso
    • 1
    Email author
  • Mattia Intra
    • 1
  • Chiara Trentin
    • 2
  • Paolo Veronesi
    • 1
  • Viviana Galimberti
    • 1
  1. 1.Division of SenologyEuropean Institute of OncologyMilanItaly
  2. 2.Division of Breast ImagingEuropean Institute of OncologyMilanItaly

Personalised recommendations