Share This Article:

Molecular Analyses of Early-Onset Gastric Cancer in Brazilian Patients: TP53 Mutations, Cadherin-Catenin and Mucins Proteins Expression

Abstract Full-Text HTML Download Download as PDF (Size:275KB) PP. 33-42
DOI: 10.4236/jct.2013.41A005    3,452 Downloads   5,700 Views   Citations

ABSTRACT

Early gastric carcinomas may develop with a molecular profile differing from sporadic carcinomas occurring at a later age. In this study, we analyzed a retrospective series of 88 patients with gastric adenocarcinoma diagnosed before the age of 45 years for the presence of TP53 mutations, clinicopathological features and immunohistochemistry to evaluate the expression of markers considered to be important in gastric carcinogenesis (E-cadherin, β-catenin, MUC1, MUC2, MUC5AC, MUC6 and p53). The majority of proportion of tumors were diffuse-type (70%) and advanced stage (56%). Familial history of cancer was positive in 21% of the cases. There was a significant association between altered expression of E-cadherin and β-catenin, and between p53 expression and perineural invasion. TP53 mutations were detected in 14.5% of evaluated cases, including a germline mutation (p.R337H) in a 12-year old patient. Overall survival analysis showed significant differences in relation with tumor stage and histopathology. The evaluated biomarkers did not present prognostic value in non-exploratory multivariate analyses. The low frequency of TP53 mutations in this series suggests these alterations are not a major molecular event in gastric cancer occurring at early age, although the identification of a case with germline p.R337H mutation is consistent with the hypothesis that a small proportion of early, apparently sporadic gastric cancer, may be associated with widespread Brazilian founder mutations. Further studies are needed to evaluate the prognostic significance of markers for specific groups of patients according to tumor histology and familial history.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

E. Silva, J. Fregnani, G. Martel, W. Costa Jr., F. Coimbra, M. Achatz, P. Hainaut and F. Soares, "Molecular Analyses of Early-Onset Gastric Cancer in Brazilian Patients: TP53 Mutations, Cadherin-Catenin and Mucins Proteins Expression," Journal of Cancer Therapy, Vol. 4 No. 1A, 2013, pp. 33-42. doi: 10.4236/jct.2013.41A005.

References

[1] J. A. G. da Silva, “Estimate/2012—Cancer Incidence in Brazil,” National Cancer Institute, Rio de Janeiro, 2011. http://www.inca.gov.br/estimativa/2012
[2] A. N. Milne, R. Sitarz, R. Carvalho, et al., “Early Onset Gastric Cancer: On the Road to Unraveling Gastric Carcinogenesis,” Current Molecular Medicine, Vol. 7, No. 1, 2007, pp. 15-28. doi:10.2174/156652407779940503
[3] A. N. Milne, R. Carvalho, F. M. Morsink, et al., “Early-Onset Gastric Cancers Have a Different Molecular Expression Profile than Conventional Gastric Cancers,” Modern Pathology, Vol. 19, No. 4, 2006, pp. 564-572. doi:10.1038/modpathol.3800563
[4] R. Carvalho, A. N. Milne, B. P. van Rees, et al., “Early-Onset Gastric Carcinomas Display Molecular Characteristics Distinct from Gastric Carcinomas Occurring at a Later Age,” The Journal of Pathology, Vol. 204, No. 1, 2004, pp. 75-83. doi:10.1002/path.1602
[5] R. Santoro, F. Carboni, P. Lepiane, et al., “Clinicopathological Features and Prognosis of Gastric Cancer in Young European Adults,” British Journal of Surgery, Vol. 94, No. 6, pp. 737-742. doi:10.1002/bjs.5600
[6] A. Jawhari, S. Jordan, S. Poole, et al., “Abnormal Immunoreactivity of the E-Cadherin-Catenin Complex in Gastric Carcinoma: Relationship with Patient Survival,” Gastroenterology, Vol. 112, No. 1, 1997, pp. 46-54. doi:10.1016/S0016-5085(97)70218-X
[7] M. Tanaka, Y. Kitajima, G. Edakuni, et al., “Abnormal Expression of E-Cadherin and Beta-Catenin May Be a Molecular Marker of Submucosal Invasion and Lymph Node Metastasis in Early Gastric Cancer,” British Journal of Surgery, Vol. 89, No. 2, 2002, pp. 236-244.
[8] P. Guilford, J. Hopkins, J. Harraway, et al., “E-Cadherin Germline Mutations in Familial Gastric Cancer,” Nature, Vol. 392, No. 6674, 1998, pp. 402-405. doi:10.1038/32918
[9] C. Carrato, C. Balague, C. De Bolos, et al., “Differential Apomucin Expression in Normal and Neoplastic Human Gastrointestinal Tissues,” Gastroenterology, Vol. 107, No. 1, 1994, pp. 160-172.
[10] S. B. Ho, L. L. Shekels, N. W. Toribara, et al., “Mucin Gene Expression in Normal, Pre-Neoplastic, and Neoplastic Human Gastric Epithelium,” Cancer Research, Vol. 55, No. 12, 1995, pp. 2681-2690.
[11] E. M. Silva, M. D. Begnami, J. H. Fregnani, et al., “Cadherin-Catenin Adhesion System and Mucin Expression: A Comparison between Young and Older Patients with Gastric Carcinoma,” Gastric Cancer, Vol. 11, No. 3, 2008, pp. 149-159. doi:10.1007/s10120-008-0468-5
[12] D. Malkin, F. P. Li, L. C. Strong, et al., “Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms,” Science, Vol. 250, No. 4985, 1990, pp. 1233-1238. doi:10.1126/science.1978757
[13] J. M. Varley, “Germline TP53 Mutations and Li-Fraumeni Syndrome,” Human Mutation, Vol. 21, No. 3, 2003, pp. 313-320. doi:10.1002/humu.10185
[14] F. Lalloo, J. Varley, D. Ellis, A. Moran, L. O’Dair, P. Pharoah and D. G. Evans, “Early Onset Breast Cancer Study Group. Prediction of Pathogenic Mutations in Patients with Early-Onset Breast Cancer by Family History,” Lancet, Vol. 361, No. 9363, 2003 pp. 1101-1102. doi:10.1016/S0140-6736(03)12856-5
[15] M. I. Achatz, M. Olivier, C. F. Le, et al., “The TP53 Mutation, R337H, Is Associated with Li-Fraumeni and Li-Fraumeni-Like Syndromes in Brazilian Families,” Cancer Letters, Vol. 245, No. 1-2, 2007, pp. 96-102. doi:10.1016/j.canlet.2005.12.039
[16] E. I. Palmero, L. Schüler-Faccini, M. Caleffi, M. I. Achatz, M. Olivier, G. Martel-Planche, V. Marcel, E. Aguiar, J. Giacomazzi, I. P. Ewald, R. Giugliani, P. Hainaut, P. Ashton-Prolla, “Detection of R337H, a Germline TP53 Mutation Predisposing to Multiple Cancers, in Asymptomatic Women Participating in a Breast Cancer Screening Program in Southern Brazil,” Cancer Letters, Vol. 261, No. 1, 2008, pp. 21-25. doi:10.1016/j.canlet.2007.10.044
[17] S. Garritano, F. Gemignani, E. I. Palmero, et al., “Detailed Haplotype Analysis at the TP53 Locus in p.R337H Mutation Carriers in the Population of Southern Brazil: Evidence for a Founder Effect,” Human Mutation, Vol. 31, No. 2, 2010, pp. 143-150. doi:10.1002/humu.21151
[18] E. M. da Silva, M. I. Achatz, G. Martel-Planche, et al., “TP53 mutation p.R337H in Gastric Cancer Tissues of a 12-Year-Old Male Child: Evidence for Chimerism Involving a Common Mutant Founder Haplotype: Case Report,” BMC Cancer, Vol. 11, 2011, p. 449. doi:10.1186/1471-2407-11-449
[19] L. H. Sobin, M. K. Gospodarowicz and C. Wittekind, “International Union against Cancer (UICC) TNM Classification of Malignant Tumours,” 7th edition, Wiley-Liss, New York, 2010, pp. 73-76.
[20] P. Lauren, “The Two Histological Main Types of Gastric Carcinoma: Diffuse and So-Called Intestinal-Type Carcinoma. An Attempt at a Histo-Clinical Classification,” Acta Pathologica Microbiologica Scandinavica, Vol. 64, 1965, pp. 46-49.
[21] C. P. Theuer, C. de Virgilio, G. Keese, et al., “Gastric Adenocarcinoma in Patients 40 Years of Age or Younger,” The American Journal of Surgery, Vol. 172, No. 5, 1996, pp. 473-476. doi:10.1016/S0002-9610(96)00223-1
[22] H. Medina-Franco, M. J. Heslin and R. Cortes-Gonzalez, “Clinico Pathological Characteristics of Gastric Carcinoma in Young and Elderly Patients: A Comparative Study,” Annals of Surgical Oncology, Vol. 7, No. 7, 2000, pp. 515-519. doi:10.1007/s10434-000-0515-x
[23] A. Ramos-De la Medina, N. Salgado-Nesme, G. Torres-Villalobos, et al., “Clinicopathologic Characteristics of Gastric Cancer in a Young Patient Population,” Journal of Gastrointestinal Surgery, Vol. 8, No. 3, 2004, pp. 240-244. doi:10.1016/j.gassur.2003.12.009
[24] T. Yokota, N. Takahashi, S. Teshima, et al., “Early Gastric Cancer in the Young: Clinicopathological Study,” Australian and New Zealand Journal of Surgery, Vol. 69, No. 6, 1999, pp. 443-446. doi:10.1046/j.1440-1622.1999.01553.x
[25] J. H. van Krieken, M. Sasako and C. J. van de Vele, “Gastric Cancer,” In: M. K. Gospodarowicz, D. E. Henson and R. V. P. Hutter, B. O’Sullivan, L. H. Sobin and C. Wittekind, Eds., Prognostic Factors in Cancer, Wiley-Liss, New York, 2001, pp. 251-265.
[26] T. C. Windham, P. M. Termuhlen, J. Ajani, et al., “Adenocarcinoma of the Stomach in Patients Age 35 Years and Younger: No Impact of Early Diagnosis on Survival Outcome,” Journal of Surgical Oncology, Vol. 81, No 3, 2002, pp. 118-124. doi:10.1002/jso.10157
[27] H. Katai, M. Sasako, T. Sano, et al., “Gastric Carcinoma in Young Adults,” Japanese Journal of Clinical Oncology, Vol. 26, No. 3, 1996, pp. 139-143. doi:10.1093/oxfordjournals.jjco.a023197
[28] T. Eguchi, Y. Takahashi, M. Yamagata, et al., “Gastric Cancer in Young Patients,” Journal of the American College of Surgeons, Vol. 188, No. 1, 1999, pp. 22-26. doi:10.1016/S1072-7515(98)00268-3
[29] B. R. Smith and B. E. Stabile, “Extreme Aggressiveness and Lethality of Gastric Adenocarcinoma in the very Young,” Archives of Surgery, Vol. 144, No. 6, 2009, pp. 506-510. doi:10.1001/archsurg.2009.77
[30] M. Rugge, Y. H. Shiao, G. Busatto, et al., “The p53 Gene in Patients under the Age of 40 with Gastric Cancer: Mutation Rates Are Low but Are Associated with a Cardiac Location,” Molecular Pathology, Vol. 53, No. 4, 2000, pp. 207-210. doi:10.1136/mp.53.4.207
[31] A. M. Bunt, P. C. Hogendoorn, C. J. van de Velde, et al., “Lymph Node Staging Standards in Gastric Cancer,” Journal of Clinical Oncology, Vol. 13, No. 9, 1995, pp. 2309-2316.
[32] M. Bjelovic, P. Pesko, M. Micev, et al., “The Significance of Lymphonodal Micrometastasis in the Patients with Gastric Adenocarcinoma,” Acta Chirurgica Iugoslavica, Vol. 52, No. 3, 2005, pp. 21-24. doi:10.2298/ACI0503021B
[33] S. Lim, H. S. Lee, H. S. Kim, et al., “Alteration of E-Cadherin-Mediated Adhesion Protein Is Common, but Microsatellite Instability Is Uncommon in Young Age Gastric Cancers,” Histopathology, Vol. 42, No. 2, 2003, pp. 128-136. doi:10.1046/j.1365-2559.2003.01546.x
[34] C. M. Fenoglio-Preiser, J. Wang, et al., “TP53 and Gastric Carcinoma: A Review,” Human Mutation, Vol. 21, No. 3, 2003, pp. 258-270. doi:10.1002/humu.10180
[35] Y. Yamada, T. Yoshida, K. Hayashi, et al., “p53 Gene Mutations in Gastric Cancer Metastases and in Gastric Cancer Cell Lines Derived from Metastases,” Cancer Research, Vol. 51, No. 21, 1991, pp. 5800-5805.
[36] P. Correa and Y. Shiao, “Phenotypic and Genotypic Events in Gastric Carcinogenesis,” Cancer Research, Vol. 54, No. 7, 1994, pp. 1914s-1943s.
[37] Y. Kakeji, D. Korenaga, S. Tsujitani, et al., “Gastric Cancer with p53 Overexpression Has High Potential for Metastasising to Lymph Nodes,” British Journal of Cancer, Vol. 67, No. 1, 1993, pp. 589-593. doi:10.1038/bjc.1993.108
[38] S. P. Monig, S. Eidt, T. K. Zirbes, et al., “p53 Expression in Gastric Cancer: Clinicopathological Correlation and Prognostic Significance,” Digestive Diseases and Sciences, Vol. 42, No. 12, 1997, pp. 2463-2467. doi:10.1023/A:1018844008068
[39] A. Bilici, M. Seker, B. B. O. Ustaalioglu, et al., “Prognostic Significance of Perineural Invasion in Patients with Gastric Cancer Who Underwent Curative Resection,” Annals of Surgical Oncology, Vol. 17, No. 8, 2010, pp. 2037-2044. doi:10.1245/s10434-010-1027-y
[40] N. Duraker, S. Sisman and G. Can, “The Significance of Perineural Invasion As A Prognostic Factor In Patients With Gastric Carcinoma,” Surgery Today, Vol. 33, No. 2, 2003, pp. 95-100. doi:10.1007/s005950300020?
[41] A. Tanaka, T. Watanabe, K. Okuno, et al., “Perineural Invasion as a Predictor of Recurrence of Gastric Cancer,” Cancer, Vol. 73, No. 3, 1994, pp. 550-555. doi:10.1002/1097-0142(19940201)73:3<550::AID-CNCR2820730309>3.0.CO;2-0
[42] Y. Maehara, M. Tomoda, S. Hasuda, et al., “Prognostic Value of p53 Protein Expression for Patients with Gastric Cancer—A Multivariate Analysis,” British Journal of Cancer, Vol. 79, No. 7-8, 1999, pp. 1255-1261. doi:10.1038/sj.bjc.6690201
[43] S. Kubicka, C. Claas, S. Staab, et al., “p53 Mutation Pattern and Expression of c-erbB2 and c-Met in gastric Cancer: Relation to Histological Subtypes, Helicobacter Pylori Infection, and Prognosis,” Digestive Diseases and Sciences, Vol. 47, No. 1, 2002, pp. 114-121. doi:10.1023/A:1013275706401
[44] H. E. Gabbert, W. Muller, A. Schneiders, et al., “The Relationship of p53 Expression to the Prognosis of 418 Patients with Gastric Carcinoma,” Cancer, Vol. 76, No. 5, 1995, pp. 720-726. doi:10.1002/1097-0142(19950901)76:5<720::AID-CNCR2820760503>3.0.CO;2-E
[45] H. S. Lee, H. K. Lee, H. S. Kim, et al., “Tumour Suppressor Gene Expression Correlates with Gastric Cancer Prognosis,” The Journal of Pathology, Vol. 200, No. 1, 2003, pp. 39-46. doi:10.1002/path.1288
[46] S. E. Baldus, S. P. Monig, V. Arkenau, et al., “Correlation of MUC5AC Immunoreactivity with Histopathological Subtypes and Prognosis of Gastric Carcinoma,” Annals of Surgical Oncology, Vol. 9, No. 9, 2002, pp. 887-893. doi:10.1007/BF02557526
[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

  
comments powered by Disqus

Copyright © 2018 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.