Molecular Pathology of Hereditary Diffuse Gastric Cancer


Hereditary diffuse gastric cancer is a rare, autosomal dominant hereditary cancer syndrome associated with germline mutations in CDH1 in which 60% - 80% of affected individuals develop advanced diffuse gastric cancer, many as young adults. At clinical presentation, ~90% of these malignancies represent advanced, surgically incurable disease. As such, presymptomatic identification of germline CDH1 mutation carriers followed by early prophylactic total gastrictomy is the sole effective management strategy available. DNA sequence analysis of the CDH1 gene to identify the affected germline allele is the diagnostic standard of care; however, CDH1s relatively high frequency of polymorphisms and the limited amount of experience available regarding them dictate that many identified variants are, as yet, of unknown clinical significance. Given the dramatic consequences of inappropriately offered or withheld treatment, careful clinical selection of at-risk individuals is critical. To facilitate this, multiple groups have published screening criteria recommendations, and while there is disagreement regarding the optimal diagnostic approach, the most widely-used overlap to a considerable degree.

Share and Cite:

J. Odegaard and I. Schrijver, "Molecular Pathology of Hereditary Diffuse Gastric Cancer," Journal of Cancer Therapy, Vol. 4 No. 2, 2013, pp. 554-561. doi: 10.4236/jct.2013.42070.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] N. Chun and J. M. Ford, “Genetic Testing by Cancer Site,” The Cancer Journal, Vol. 18, No. 4, 2012, pp. 355-363. doi:10.1097/PPO.0b013e31826246dc
[2] H. Wu, J. A. Rusiecki, K. Zhu, J. Potter and S. S. Devesa, “Stomach Carcinoma Incidence Patterns in the United States by Histologic Type and Anatomic Site,” Cancer Epidemiology, Biomarkers, and Prevention, Vol. 18, No. 7, 2009, pp. 1945-1952. doi:10.1158/1055-9965.EPI-09-0250
[3] J. Stone, S. Bevan, D. Cunningham, A. Hill, N. Rahman, J. Peto, A. Marossy and R. S. Houlston, “Low Frequency of Germline E-Cadherin Mutations in Familial and Nonfamilial Gastric Cancer,” British Journal of Cancer, Vol. 79, No. 11-12, 1999, pp. 1935-1937. doi:10.1038/sj.bjc.6690308
[4] P. Guilford, J. Hopkins, J. Harraway, N. McLeod, P. Harawira, H. Taite, R. Scoular, A. Miller and A. E. Reeve, “E-Cadherin Germline Mutations in Familial Gastric Cancer,” Nature, Vol. 392, No. 6674, 1998, pp. 402-405. doi:10.1038/32918
[5] P. D. Pharoah, P. Guilford and C. Caldas, “Incidence of Gastric Cancer and Breast Cancer in CDH1 (E-Cadherin) Mutation Carriers from Hereditary Diffuse Gastric Cancer Families,” Gastroenterology, Vol. 121, No. 6, 2001, pp. 1348-1353. doi:10.1053/gast.2001.29611
[6] R. C. Fitzgerald, R. Hardwick, D. Huntsman, F. Carneiro, P. Guilford, V. Blair, D. C. Chung, J. Norton, K. Ragunath, J. H. Van Krieken, S. Dwerryhouse and C. Caldas, “Hereditary Diffuse Gastric Cancer: Updated Consensus Guidelines for Clinical Management and Directions for Future Research,” Journal of Medical Genetics, Vol. 47, No. 7, 2010, pp. 436-444. doi:10.1136/jmg.2009.074237
[7] P. Carneiro, M. S. Fernandes, J. Figueiredo, J. Caldeira, J. Carvalho, H. Pinheiro, M. Leite, S. Melo, P. Oliveira, J. Simoes-Correia, M. J. Oliveira, F. Carneiro, C. Figueiredo, J. Paredes, C. Oliveira and R. Seruca, “E-Cadherin Dysfunction in Gastric Cancer—Cellular Consequences, Clinical Applications, and Open Questions,” FEBS Letters, Vol. 586, No. 18, 2012, pp. 2981-2989. doi:10.1016/j.febslet. 2012.07.045
[8] M. Al-Hajj and M. F. Clarke, “Self-Renewal and Solid Tumor Stem Cells,” Oncogene, Vol. 23, No. 43, 2004, pp. 7274-7282. doi:10.1038/sj.onc.1207947
[9] B. Humar and P. Guilford, “Hereditary Diffuse Gastric Cancer: A Manifestation of Lost Cell Polarity,” Cancer Science, Vol. 100, No. 7, 2009, pp. 1151-1157. doi:10.1111/j.1349-7006.2009.01163.x
[10] N. den Elzen, C. V. Buttery, M. P. Maddugoda, G. Ren and A. S. Yap, “Cadherin Adhesion Receptors Orient the Mitotic Spindle during Symmetric Cell Division in Mammalian Epithelia,” Molecular Biology of the Cell, Vol. 20, No. 16, 2009, pp. 3740-3750. doi:10.1091/mbc.E09-01-0023
[11] C. D’Souza-Schorey, “Diassembling Adherens Junctions: Breaking up Is Hard to Do,” Trends in Cellular Biology, Vol. 15, No. 1, 2005, pp. 19-26. doi:10.1016/j.tcb.2004.11.002
[12] P. Guilford, V. Blair, H. More and B. Humar, “A Short Guide to Hereditary Diffuse Gastric Cancer,” Hereditary Cancer in Clinical Practice, Vol. 5, No. 4, 2007, pp. 183-194. doi:10.1186/1897-4287-5-4-183
[13] B. Humar, R. Fukuzawa, V. Blair, A. Dunbier, H. More, A. Charlton, H. K. Yang, W. H. Kim, A. E. Reeve, I. Martin and P. Guilford, “Destabilized Adhesion in the Gastric Proliferative Zone and c-Src Kinase Activation Mark the Development of Early Diffuse Gastric Cancer,” Cancer Research, Vol. 67, No. 6, 2007, pp. 2480-2489. doi:10.1158/0008-5472.CAN-06-3021
[14] Y. Chen, K. Kingham, J. M. Ford, J. Rosing, J. Van Dam, R. B. Jeffrey, T. A. Longacre, N. Chun, A. Kurian and J. A. Norton, “A Prospective Study of Total Gastrectomy for CDH1-Positive Hereditary Diffuse Gastric Cancer,” Annals of Surgical Oncology, Vol. 18, No. 9, 2011, pp. 2594-2598. doi:10.1245/s10434-011-1648-9
[15] V. Blair, I. Martin, D. Shaw, I. Winship, D. Kerr, J. Arnold, P. Harawira, M. McLeod, S. Parry, A. Charlton, M. Findlay, B. Cox, B. Humar, H. More and P. Guilford, “Hereditary Diffuse Gastric Cancer: Diagnosis and Management,” Clinical Gastroenterology and Hepatology, Vol. 4, No. 3, 2006, pp. 262-275. doi:10.1016/j.cgh.2005.12.003
[16] A. Charlton, V. Blair, D. Shaw, S. Parry, P. Guilford and I. G. Martin, “Hereditary Diffuse Gastric Cancer: Predominance of Multiple Foci of Signet Ring Carcinoma in Distal Stomach and Transition Zone,” Gut, Vol. 53, No. 6, 2004, pp. 814-820. doi:10.1136/gut.2002.010447
[17] F. Carneiro, D. G. Huntsman, T. C. Smyrk, D. A. Owen, R. Seruca, P. Pharoah, C. Caldas and M. Sobrinho-Simoes, “Model of the Early Development of Diffuse Gastric Cancer in E-Cadherin Mutation Carriers and Its Implications for Patient Screening,” Journal of Pathology, Vol. 203, No. 2, 2004, pp. 681-687. doi:10.1002/path.1564
[18] M. E. Barber, V. Save, F. Carneiro, S. Dwerryhouse, P. Lao-Sirieix, R. H. Hardwick, C. Caldas and R. C. Ritzgerald, “Histopathological and Molecular Analysis of Gastrectomy Specimens from Hereditary Diffuse Gastric Cancer Patients Has Implications for Endoscopic Surveillance of Individuals at Risk,” Journal of Pathology, Vol. 216, No. 3, 2008, pp. 286-294. doi:10.1002/path.2415
[19] D. G. Huntsman, F. Carneiro, F. R. Lewis, P. M. MacLeod, A. Hayashi, K. G. Monaghan, R. Maung, R. Seruca, C. E. Jackson and C. Caldas, “Early Gastric Cancer in Young Asymptomatic Carriers of Germ-Line E-Cadherin Mutations,” New England Journal of Medicine, Vol. 344, No. 25, 2001, pp. 1904-1909. doi:10.1056/NEJM200106213442504
[20] M. D. Crabtree, I. P. Tomlinson, I. C. Talbot and R. K. Phillips, “Variability in the Severity of Colonic Disease in Familial Adenomatous Polyposis Results from Differences in Tumor Initiation Rather than Progression and Depends Relatively Little on Patient Age,” Gut, Vol. 49, 2001, pp. 540-543. doi:10.1136/gut.49.4.540
[21] S. M. Everett and A. T. Axon, “Early Gastric Cancer in Europe,” Gut, Vol. 41, No. 2, 1997, pp. 142-150. doi:10.1136/gut.41.2.142
[22] P. Guilford, B. Humar and V. Blair, “Hereditary Diffuse Gastric Cancer: Translation of CDH1 Germline Mutations into Clinical Practice,” Gastric Cancer, Vol. 13, No. 1, 2010, pp. 1-10. doi:10.1007/s10120-009-0531-x
[23] P. Kaurah, A. MacMillan, N. Boyd, J. Senz, A. De Luca, N. Chun, et al., “Founder and Recurrent CDH1 Mutations in Families with Hereditary Diffuse Gastric Cancer,” Journal of the American Medical Association, Vol. 297, No. 21, 2007, pp. 2360-2372. doi:10.1001/jama.297.21.2360
[24] H. More, B. Humar, W. Weber, R. Ward, A. Christian, C. Lintott, F. Graziano, A. M. Ruzzo, E. Acosta, B. Boman, M. Harlan, P. Ferreira, R. Seruca, G. Suriano and P. Guilford, “Identification of Seven Novel Germline Mutations in the Human E-Cadherin Gene,” Human Mutation, Vol. 28, No. 2, 2007. p. 203. doi:10.1002/humu.9473
[25] G. Suriano, S. Yew, P. Ferreira, J. Senz, P. Kaurah, J. M. Ford, et al., “Characterization of a Recurrent Germ Line Mutation of the E-Cadherin Gene: Implications for Genetic Testing and Clinical Management,” Clinical Cancer Research, Vol. 11, No. 15, 2005. pp. 5401-5409. doi:10.1158/1078-0432.CCR-05-0247
[26] G. Berx, K.-F. Becker, H. Hoflier and F. Roy, “Mutations of the Human E-Cadherin (CDH1) Gene,” Human Mutation, Vol. 12, No. 4, 1998, pp. 226-237. doi:10.1002/(SICI)1098-1004(1998)12:4<226:: AID-HUMU2>3.0.CO;2-D
[27] C. Oliveira, J. Senz, P. Kaurah, H. Pinheiro, R. Sanges, A. Haegert, et al., “Germline CDH1 Deletions in Hereditary Diffuse Gastric Cancer Families,” Human Molecular Genetics, Vol. 18, No. 9, 2009, pp. 1545-1555. doi:10.1093/hmg/ddp046
[28] R. Karam, J. Carvalho, I. Bruno, C. Graziado, J. Senz, D. Huntsman, F. Carneiro, R. Seruca, M. F. Wilkinson and C. Olveira, “The NMD mRNA Surveillance Pathway Downregulates Aberrant E-Cadherin Transcripts in Gastric Cancer Cells and in CDH1 Mutation Carriers,” Oncogene, Vol. 27, No. 30, 2008, pp. 4255-4260. doi:10.1038/onc.2008.62
[29] B. Humar, V. Blair, A. Charlton, H. More, I. Martin and P. Guilford, “E-Cadherin Deficiency Initiates Gastric Signet-Ring Carcinoma in Mice and Man,” Cancer Research, Vol. 69, No. 5, 2009, pp. 2050-2056. doi:10.1158/0008-5472.CAN-08-2457
[30] C. Olveira, J. de Bruin, S. Nabais, M. Ligtenberg, C. Moutinho, F. M. Nagengast, R. Seruca, H. van Krieken and F. Carneiro, “Intragenic Deletion of CDH1 as the Inactivating Mechanism of the Wild-Type Allele in an HDGC Tumour,” Oncogene, Vol. 23, No. 12, 2004. pp. 2236-2240. doi:10.1038/sj.onc.1207335
[31] W. M. Grady, J. Willis, P. J. Guilford, A. K. Dunbier, T. T. Toro, H. Lynch, G. Wiesner, K. Ferguson, C. Eng, J. G. Park, S. J. Kim and S. Markowitz, “Methylation of the CDH1 Promoter as the Second Genetic Hit in Hereditary Diffuse Gastric Cancer,” Nature Genetics, Vol. 26, No. 1, 2000, pp. 16-17. doi:10.1038/79120
[32] P. W. Derksen, X. Liu, F. Saridin, H. van der Gulden, J. Zevenhoven, B. Evers, J. R. van Beijnum, A. W. Griffioen, J. Vink, P. Krimpenfort, J. L. Peterse, R. D. Cardiff, A. Berns and J. Jonkers, “Somatic Inactivation of E-Cadherin and p53 in Mice Leads to Metastatic Lobular Mammary Carcinoma through Induction of Anoikis Resistance,” Cancer Cell, Vol. 10, No. 5, 2006. pp. 437-449. doi:10.1016/j.ccr.2006.09.013
[33] F. M. Mullins, L. Dietz, M. Lay, J. L. Zehnder, J. Ford, N. Chun and I. Schrijver, “Identification of an Intronic SNP Leading to Allele Dropout during Validation of a CDH1 Sequencing Assay: Implications for Designing PCR-Based Assays,” Genetics in Medicine, Vol. 9, No. 11, 2007, pp. 752-760. doi:10.1097/GIM.0b013e318159a369
[34] M. Dixon, et al., “A RAND/UCLA Appropriateness Study of the Management of Familial Gastric Cancer,” Annals of Surgical Oncology, Vol. 20, No. 2, 2012, pp. 533-541. doi:10.1245/s10434-012-2584-z
[35] C. Caldas, et al., “Familial Gastric Cancer: Overview and Guidelines for Management,” Journal of Medical Genetics, Vol. 36, No. 12, 1999, pp. 873-880.
[36] A. R. Brooks-Wilson, P. Kaurah, G. Suriano, S. Leach, J. Senz, N. Grehan, et al., “Germline E-Cadherin in Hereditary Diffuse Gastric Cancer: Assessment of 42 New Families and Review of Genetic Screening Criteria,” Journal of Medical Genetics, Vol. 41, No. 7, 2004, pp. 508-517. doi:10.1136/jmg.2004.018275
[37] R. M. Cisco, J. M. Ford and J. A. Norton, “Hereditary Diffuse Gastric Cancer: Implications of Genetic Testing for Screening and Prophylactic Surgery,” Cancer, Vol. 113, No. 7, 2008, pp. 1850-1856. doi:10.1002/cncr.23650
[38] R. M. Cisco and J. A. Norton, “Hereditary Diffuse Gastric Cancer: Surgery, Surveillance, and Unanswered Questions,” Future Oncology, Vol. 4, No. 4, 2008. pp. 553-559. doi:10.2217/1479 6694.4.4.553
[39] F. Roviello, G. Corso, C. Pedrazzani, D. Marrelli, G. De Falco, A. Berardi, et al., “Hereditary Diffuse Gastric Cancer and E-Cadherin: Description of the First Germline Mutation in an Italian Family,” European Journal of Surgical Oncology, Vol. 33, No. 4, 2007, pp. 448-451. doi:10.1016/j.ejso.2006.10.028
[40] R. Seevaratnam, N. Coburn, R. Cardoso, M. Dixon, A. Bocicariu and L. Helyer, “A Systematic Review of the Indications for Genetic Testing and Prophylactic Gastrectomy among Patients with Hereditary Diffuse Gastric Cancer,” Gastric Cancer, Vol. 15 Supplement 1, 2012, pp. S153-S163. doi:10.1007/s10120-011-0116-3
[41] H. T. Lynch, E. Silva, D. Wirtzfeld, P. Hebbard, J. Lynch and D. G. Huntsman, “Hereditary Diffuse Gastric Cancer: Prophylactic Surgical Oncology Implications,” Surgical Clinics of North America, Vol. 88, No. 4, 2008, pp. 759-778. doi:10.1016/j.suc.2008.04.006
[42] P. C. Ng and S. Henikoff, “SIFT: Predicting Amino Acid Changes That Affect Protein Function,” Nucleic Acid Research, Vol. 31, No. 13, 2003, pp. 3814-3814. doi:10.1093/nar/gkg509
[43] S. Sunyaev, V. Ramensky, I. Koch, W. Lathe, A. S. Kondrashov and P. Bork, “Prediction of Deleterious Human Alleles,” Human Molecular Genetics, Vol. 10, No. 6, 2001, pp. 591-597. doi:10.1093/hmg/10.6.591
[44] G. Suriano, S. Seixas, J. Rocha and R. Seruca, “A Model to Infer the Pathogenic Significance of CDH1 Germline Missense Variants,” Journal of Molecular Medicine, Vol. 84, No. 12, 2006, pp. 1023-1031. doi:10.1007/s00109-006-0091-z
[45] S. E. Plon, D. M. Eccles, D. Easton, W. D. Foulkes, M. Genuardi, M. S. Greenblatt, et al., “Sequence Variant Classification and Reporting: Recommendations for Improving the Interpretation of Cancer Susceptibility Genetic Test Results,” Human Mutation, Vol. 29, No. 11, 2008, pp. 1282-1291. doi:10.1002/humu.20880
[46] P. D. Pharoah, P. Guilford and C. Caldas, “Incidence of Gastric Cancer and Breast Cancer in CDH1 (E-Cadherin) Mutation Carriers from Hereditary Diffuse Gastric Cancer Families,” Gastroenterology, Vol. 121, No. 6, 2001, pp. 1348-1353. doi:10.1053/gast.2001.29611
[47] J. B. Koea, M. S. Karpeh and M. F. Brennan, “Gastric Cancer in Young Patients: Demographic, Clinicopathological, and Prognostic Factors in 92 Patients,” Annals of Surgical Oncology, Vol. 7, No. 5, 2000, pp. 346-351. doi:10.1007/s10434-000-0346-9
[48] M. Yamashina, “A Variant of Early Gastric Carcinoma. Histologic and Histochemical Studies of Early Signet Ring Cell Carcinomas Discovered Beneath Preserved Surface Epithelium,” Cancer, Vol. 58, No. 6, 1986. pp. 1333-1339. doi:10.1002/1097-0142(19860915)58:6<1333::AID-CNCR28205 80625>3.0.CO;2-B
[49] J. M. Schuetz, S. Leach, P. Kaurah, J. Jeyes, Y. Butterfield, D. Huntsman and A. R. Brooks-Wilson, “Catenin Family Genes Are Not Commonly Mutated in Hereditary Diffuse Gastric Cancer,” Cancer Epidemiology, Biomarkers, and Prevention, Vol. 21, 2012, p. 2272. doi:10.1158/1055-9965.EPI-12-1110
[50] C. Caldas, F. Carneiro, H. T. Lynch, J. Yokota, G. L. Wiesner, S. M. Powell, et al., “Familial Gastric Cancer: Overview and Guidelines for Management,” Journal of Medical Genetics, Vol. 36, No. 12, 1999, pp. 873-880.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.