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Clinical Review E-Cadherin and Hereditary Diffuse Gastric Cancer

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Clinical Review E-Cadherin and Hereditary Diffuse Gastric Cancer Clinical review E-cadherin and hereditary diffuse gastric cancer Corrado Pedrazzani, MD,* Giovanni Corso, MD,* Daniele Marrelli, MD, and Franco Roviello, MD, Siena, Italy From the Department of Human Pathology and Oncology, Unit of Surgical Oncology, University of Siena, Italy Gastric cancer (GC) remains a leading cause of CDH1 GENE AND E-CADHERIN PROTEIN 1 cancer-related deaths worldwide, even though a The CDH1 gene maps to chromosome 16q22.1 decrease in its incidence and mortality rate has and consists of 16 exons occupying about 100 kb of been observed in recent decades.2 Although the genomic DNA. The CDH1 gene is transcribed into incidence of intestinal GC has declined gradually, a 4.5-kb mRNA13 that encodes for the 120-kDa the incidence of diffuse gastric cancer (DGC) has protein E-cadherin (E-cad). E-cad is a member of remained stable. Most GCs are sporadic and seem the transmembrane glycoprotein family expressed to result from the cumulative effects of different on epithelial tissue and is responsible for calcium- environmental risk factors; smoking, alcohol con- dependent, cell-to-cell adhesion.14 Other well-known sumption, and dietary habits have been ad- components of this family are N-cadherin (neuro- dressed as important risk factors.3-5 Helicobacter nal) and P-cadherin (placental). pylori (H pylori) infection and gene polymorphisms E-cad is critical for establishing and maintaining of proinflammatory cytokines represent other fea- polarized and differentiated epithelia through in- tures of this process that leads to the development of tercellular adhesion complexes. The E-cad protein GC.6,7 has 3 major components: “signal peptide” consist- Although the influence of genetic predisposi- ing of 27 amino acids encoded by exons 1 and 2, tion to GC has not yet been determined fully, fa- “precursor peptide” consisting of 154 amino acids milial clustering has been reported in 10% to encoded by exons 2 to 4, and “mature protein” con- 30%.2,8-11 Genetic factors play a fundamental role taining 728 amino acids encoded by exons 4 to 16. in the genesis of the well-defined autosomal dom- The “mature protein” segment has an intracel- lular domain, a transmembrane domain, and an inant familial syndrome termed Hereditary Diffuse extracellular domain. The latter is formed by 5 Gastric Cancer (HDGC) associated with the diffuse tandem cadherin repeats known as “cadherin do- histotype and caused by germline mutations in mains” (EC1-EC5) each containing about 110 the E-cadherin gene (CDH1) that accounts for 1% ϩ amino acid residues and involved in Ca2 -depen- of all GC cases.12 dent homophilic interaction (Fig). The large ex- tracellular domain (N-terminal) includes exons 4 to 13 and interacts with adherens junctions that *C.P. and G.C. contributed equally to this article. cluster on the surface of homotypic neighboring 15-17 Supported by Grant PAR 2004 to the University of Siena and by cells. The smaller transmembrane domain Grant MIUR 2005 to the Unit of Surgical Oncology, University includes exons 13 and 14, whereas the cytoplasmic of Siena, Italy. domain (C-terminal) comprises exons 14 to 16 and Accepted for publication June 1, 2007. interacts with cytoskeleton actin filaments through Reprint requests: Franco Roviello, MD, Via De Gasperi 5, 53100 catenins (␣-, ␤-, and ␥-catenins and p120ctn)in Siena, Italy. E-mail: [email protected]. regulating the intracellular signaling pathways. Surgery 2007;142:645-57. ␤-catenin attaches to the C-terminal region of E- 0039-6060/$ - see front matter cad and then to ␣-catenin, through which the com- © 2007 Mosby, Inc. All rights reserved. plex is linked to the actin cytoskeleton; p120ctn doi:10.1016/j.surg.2007.06.006 binds to a juxtamembrane site of E-cad cytoplasmic SURGERY 645 646 Pedrazzani et al. Surgery November 2007 Figure. Structure of CDH1 gene and of E-cadherin protein. tail.17 The cadherin–catenins complex is involved for the management of patients with DGC. The in intracellular signaling and promotes tumor proposed criteria were as follows: 1) 2 or more doc- growth through the Wnt-signaling pathway.18 umented cases of DGC in first-degree or second-de- Human E-cad is considered an invasion suppres- gree relatives with at least 1 diagnosed before the age sor, and its deregulation is often found in advanced of 50 years, and 2) 3 or more documented cases of cases of sporadic GC. Underexpression of E-cad is DGC in first-degree or second-degree relatives inde- also correlated with the infiltrative and metastatic pendent of age of onset.29,30 ability of the tumor,19 believed to be because of CDH1 germline mutations have been demon- disruption of the cadherin–catenins complex with strated in about 30% of patients with the above-men- the consequent loss of cell adhesion and concom- tioned clinical criteria (Table I31-62); this figure, itant increase in cell motility.20,21 E-cad deregula- however, represents 1% of all GC cases.12 Carriers tion has been identified in early stage tumors in of the E-cad truncating germline mutation have a patients with CDH1 germline mutations suggesting high lifetime risk of developing GC approaching a its involvement as an initial event in HDGC.22-24 cumulative risk by age 80 years of 67% for men (95% CI, 39-99) and 83% for women (95% CI, MUTATIONS OF THE CDH1 GENE AND 58-99) with a mean age of diagnosis at 40 years HEREDITARY DIFFUSE GASTRIC CANCER (range, 14-85).63 Becker et al first demonstrated alterations in After demonstrating the presence of a CDH1 the transcript of the CDH1 gene in 1994; 50% of germline mutation in patients not belonging to the primary DGCs manifested abnormal somatic E-cad IGCLC criteria, Brooks-Wilson et al recommended transcripts, with reduced homophilic cell-to-cell in- their modification considering 1) 2 or more docu- teractions.16,25 Subsequently, mutations of the E- mented cases of DGC in first-degree relatives with cad gene have been identified in 40% to 83% of at least 1 diagnosed before age 50 years; 1A) 2 or sporadic DGCs but not in intestinal GC.26 more cases of GC with at least 1 DGC diagnosed In 1964, Jones27 described a multigenerational before age 50 years; 2) 3 or more documented New Zealand Maori family with an extremely high cases of DGC in first-degree relatives with diagnoses incidence of GC and speculated on a genetic role. at any age; 2A) 3 or more cases of GC, diagnosed at In 1998, Guilford et al22 identified an E-cad any age, with at least 1 documented case of DGC; 3) germline truncating mutation in this family and 2 isolated individual diagnosed with DGC at less than additional Maori families with a predisposition to 45 years of age; 4) isolated individual diagnosed autosomal-dominant DGC. Immediately after this with both DGC and lobular breast cancer (no other report, Gayther et al28 reported other CDH1 germ- criteria met); 5) 1 family member diagnosed with line mutations in 3 families of Northern European DGC and another with lobular breast cancer (no origin. other criteria met); 6) 1 family member diagnosed In 1999, the International Gastric Cancer Link- with DGC and another with signet-ring carcinoma age Consortium (IGCLC) defined a dominantly of the colon (no other criteria met).12 inherited familial cancer syndrome named Hered- Brooks-Wilson et al screened 42 families fulfill- itary Diffuse Gastric Cancer (HDGC), and clinical ing the newly proposed criteria in order to search criteria were established with the aim to develop for CDH1 germline changes. Five truncating, 1 common terminology and to delineate guidelines splice site, and 2 missense mutations were detected Volume 142, Number 5 Surgery Table I. CDH1 germline mutations* CDH1 CDH1 CDH1 Total Number of Mutations Mutations EOGC Mutations Mutations Truncating Missense Reference Families HDGC (%) FDGC (%) (Age Ͻ51) (%) FIGC FGC† (%) Mutations Mutations 22 3 3 3 (100) — — — — — — 3 (100) 3 — 28 18 10 3 (30) — — — — 8 — 3 (16.7) 3 — 31 8 8 2 (25) — — — — — — 2 (25) 2 — 29 6 4 4 (100) 2 2 (100) — — — — 6 (100) 6 — 32 13 3 1 (33.3) — — — — 10 — 1 (7.7) — 1 33 5 5 2 (40) — — — — — — 2 (40) — 2 34 14——6———62——— 35 7 2 1 (50) 5 — — — — — 1 (14.3) 1 — 36 10———— — ——10— — — 37 9———— 9 ———— — — 38 20———— — ——20— — — 39 11 5 1 (20) 4 — — — 1 1 1 (9) — 1 40 48———— — ——48— — — 41 1 1 1 (100) — — — — — — 1 (100) 1 — 42 10 7 4 (5.7) 3 1 (33.3) — — — — 5 (50) 5 — 43 39 11 4 (36.4) 24 — — — 4 — 4 (10.3) 3 1 44 17 2 1 (50) 3 — — — — 12 1 (5.9) — 1 45 78 — — 2 2 (100) — — — 76 2 (2.6) — 2 24 66———— 665(7.6) — — 5 (7.6) 2 3 46 1 1 1 (100) — — — — — — 1 (100) 1 — 47 3 3—————————— 48 40———— 40————— — 49 3 3 1 (33.3) — — — — — — 1 (33.3) 1 — 50 3 3—————————— 51 32 9 1 (11.1) 10 — — — 3 10 1 (3.1) — 1 52 45‡ 4 — 21 1 (4.8) 15 1 (6.6) 5 — 2 (4.4) 1 1 12 38 16 8 (50) 13 4 (30.8) 9 — — — 12 (31.6) 10 2 53 5 5 1 (20) — — — — — — 1 (20) 1 — 54 7 7—————————— 55 1 1 1 (100) — — — — — — 1 (100) 1 — Pedrazzani et al. 56 30 10 3 (30) 10 3 (30) 10 2 (20) — — 8 (26.7) 7 1 57 2 2 2 (100) — — — — — — 2 (100) 2 — 58 1 1 1 (100) — — — — — — 1 (100) 1 — 59 101 — 2 (1.9) 77 2 (2.6) 24 — — — 2 (2.6) — 2 60 81———— 819(11.1) — — 9 (11.1) 7 2 61 36 24 2 (8.3) 12§ 6 (60) — — — — 10 (27.7) 7 3 647 62 14 14 1 (7.1) — — — — — — 1 (7.1) — 1 648 Pedrazzani et al.
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