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 intracellular 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 extracellular 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 oue12 ubr5 Number 142, Volume 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 — al. et Pedrazzani 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. Surgery November 2007

in 15 families that fulﬁlled the IGCLC criteria. Three truncating and 1 splice site mutation were 23/89 (25.8) discovered in 10 families with the newly proposed Missense Mutations criteria 1A, and a missense mutation was characterized in one family with criteria 6.12 Suriano et al analyzed 66 early onset DGC (criteria 3) identifying 2 truncating and 3 missense 66/89 (74.2) Mutations

Truncating CDH1 germline mutations. On this basis, CDH1 mutation screening is recommended for young patients with DGC.56,60 Interestingly enough, More et al61 described a missense and a splice site CDH1 (%) Total (10.8)

89/826 germline mutation in 2 families not belonging to Mutations either IGCLC or modified criteria. Table I reviews all E-cad germline mutations detected in patients belonging to the IGCLC29,30 as well as the modified criteria.12 Considering the (21.6) 179/826 IGCLC criteria, 164 families fulfilled the proposed condition; among these, 51 (31%) were carriers of a CDH1 germline mutation. Taking into account the modified criteria, the number of families in- (4.5) mutations discovered in patients with diagnosed colon cancer and lobular breast 37/826 creased to 192, whereas the number of mutation carriers was 21 (11%). Overall, 89 CDH1 germline CDH1 mutations have been detected until now, 66 (74%) were truncating and 23 (26%) were missense (%) FIGC FGC† (6.7) CDH1 variants. To date, no CDH1 germline mutation 17/254 Mutations has been identified in patients with intestinal GC. Table II contains a complete list of all the differ-

51) ent E-cad germline mutations identiﬁed. Ͻ EOGC (30.7)

254/826 CDH1 GERMLINE MISSENSE MUTATION (Age Although the pathogenic role of CDH1 truncating mutations has been demonstrated clearly, the role of missense variants remains controversial. (%) CDH1 (10.9)

21/192 Missense mutations in the E-cad gene were identi- Mutations ﬁed in about 1 out of 4 HDGC patients (Table I). Missense changes span the entire region of the E-cad gene without preferential hot spots.

(23.2) Although the disease-penetrance was estimated 192/826 at about 70% to 80% in germline truncating muta- tions22,63 missense mutations manifested a low-penetrance phenotype.64 To date, the pathogenic role of 35 (%) FDGC CDH1

(31.1) missense mutations has not yet been deﬁned and the 51/164 Mutations identiﬁcation of this variant represents a clinical bur- den in both the genetic counseling and the management of relatives that are CDH1 mutation carriers. To solve this challenging question, Suriano et al (19.9) developed in silico analysis and in vitro functional

) assays to help infer the possible deleterious nature of E-cad germline missense variants.24,65 The au- mutations detected in HDGC, in FDGC, and in Early Onset Gastric Cancer (EOGC) are included. Germline

826 164/826 thors characterized the functional signiﬁcance of Families HDGC

Number of 13 missense mutations; among these, 11 mutations Continued CDH1 ( hampered the ability in vitro of E-cad to mediate cell-to-cell adhesion and to suppress cell invasion, which supports their pathogenic role.64,66 Interest- Reference Total Table I. *All germline §Two families did not fulfill modified clinical criteria and are classified as FDGC. cancer were not considered. †No information on clinical‡Five criteria, of all these were 50 considered families as were FGC. described previously. ingly, the 2 missense mutations that did not show Surgery Pedrazzani et al. 649 Volume 142, Number 5

Table II. CDH1 germline mutations detected to date Reference CDH1 Mutation Exon/Intron Mutation Type Ethnicity 60 5=UTR(-117)GϾA Promoter Missense American 60 5=UTR(-71)CϾG Promoter Missense American 60 41delT Exon 1 Deletion European 43 45insT Exon 1 Insertion European 60 48ϩ5GϾC Intron 1 Splice Site American 60 48ϩ15CϾG Intron 1 Splice Site American 31, 55, 61* 49-2AϾG Intron 1 Splice Site European 42 53delC Exon 2 Deletion European 31 59GϾA Exon 2 Non sense European 29 70GϾT Exon 2 Non sense European/USA 32 185GϾT Exon 3 Missense Japanese 28 187CϾT Exon 3 Non sense European/USA 29 190CϾT Exon 3 Non sense Maori/NZ 41 283CϾT Exon 3 Non sense European 61 353CϾG Exon 3 Missense European 35 372delC Exon 3 Deletion European 12 382delC Exon 3 Deletion European 60 388ϩ26CϾT Intron 3 Splice Site American 39 525 CϾG Exon 4 Missense European 24 532-18CϾT Intron 4 Splice site European 29 586GϾT Exon 5 Non sense European 12 531ϩ1GϾA Intron 5 Splice site European 57 531ϩ2TϾA Intron 5 Splice site European 61 715GϾA Exon 6 Missense European 33 731AϾG Exon 6 Missense Korean 43 832GϾA Exon 6 Splice site Pakistan 12 892GϾA Exon 7 Missense European 49, 56* 1003CϾT Exon 7 Non sense European, American 22 1008GϾT Exon 7 Splice site Maori/NZ 43, 59* 1018AϾG Exon 8 Missense European, Chinese 56 1063del Exon 8 Deletion American 12 1064insT Exon 8 Insertion European 61 1107delC Exon 8 Deletion European 62 1118CϾT Exon 8 Missense European 12, 46* 1135del8ins5 Exon 8 Deletion/Insertion European 57, 61* 1137GϾA Exon 8 Splice site European 29 1137ϩ1GϾA Intron 8 Splice site African/USA 12 1212delC Exon 9 Deletion European 12 1226TϾC Exon 9 Missense European 45 1243AϾC Exon 9 Missense Japanese 56 1285CϾT Exon 9 Missense American 61 1391-1392delTC Exon 10 Deletion European 33 1460TϾC Exon 10 Missense Korean 43 1472insA Exon 10 Insertion European 12 1476delAG Exon 10 Deletion European 29 1487del7 Exon 10 Deletion European/NZ 53 1507CϾT Exon 10 Non sense Chinese 42 1565ϩ1GϾT Intron 10 Splice site Arabic/NZ 29 1588insC Exon 11 Insertion European/USA 58 1610delC Exon 11 Deletion European 52 1619insG Exon 11 Insertion European 42 1710delT Exon 11 Deletion African/USA 28 1711insG Exon 11 Insertion European/USA 12 1711ϩ5GϾA Intron 11 Splice site European 40 1774 GϾA Exon 12 Missense European 12 1779insC Exon 12 Insertion European 650 Pedrazzani et al. Surgery November 2007

Table II. (Continued) Reference CDH1 Mutation Exon/Intron Mutation Type Ethnicity 28, 42, 56* 1792CϾT Exon 12 Non sense Maori/NZ, European/Canada 24 1849GϾA Exon 12 Missense African/USA 24, 51, 61* 1901CϾT Exon 12 Missense European, Maori 60 1937-13TϾC Intron 12 Splice Site American 12 2061delTG Exon 13 Deletion European 22, 61* 2095CϾT Exon 13 Non sense Maori/NZ, Chinese 56 2161CϾG Exon 13 Splice site American 12 2195GϾA Exon 14 Missense European 56 2276delG Exon 14 Deletion American 42 2295ϩ5GϾA Intron 14 Splice site European 12 2310delC Exon 15 Deletion European 22 2381insC Exon 15 Insertion Maori/NZ 52 2396CϾG Exon 15 Missense European 60 2439ϩ31GϾA Intron 15 Splice site American 61 2440-6CϾG Intron 15 Splice site European 44 2494GϾA Exon 16 Missense Japanese

*Different families with the same mutation. any pathogenic nature were described in normal inactivated only in the tumor tissue. Also in HDGC, populations at polymorphic frequency and can be both alleles must be inactivated for the protein considered as neutral variants.24,52 A statistical function to be lost and for cancer to develop. The model has been proposed recently to implement impairment of gene function of the wild-type allele the above-mentioned assays. A multivariate ap- is known as the “second inactivating hit,” and it is proach to infer the significance of CDH1 missense caused by 1 of the following mechanisms: somatic mutations was built through the analysis of the mutation, loss of heterozygosity (LOH), or pro- cosegregation of the mutation within pedigrees, moter hypermethylation. frequency in a healthy population of controls, re- Very little is known about inactivation of the currence in independent families, and functional wild-type allele in carriers of the CDH1 gene muta- in vitro and in silico data. In silico characterization tion, and for this reason, we will refer to sporadic of the missense variants is a theoretic approach that GC to describe the different underlying mecha- attempts to predicts whether an amino acid substi- nisms. Grady et al68 and Oliveira et al46 studied 6 tution affects protein function by using the Sorting and 4 HDGC patients, respectively. Hypermethyl- Intolerant From Tolerant (SIFT) software available at ation of the CDH1 gene promoter, somatic CDH1 http://blocks.fhcrc.org/sift/SIFT.html. The neigh- mutation, and CDH1 intragenic deletion were con- bor-joining method to group mutations according to firmed as possible causes of inactivation of the the collected information was used as a statistical wild-type allele. analysis using the MEGA 3.1 software (http://www. Somatic mutations. Somatic mutations of CDH1, expasy.ch/spdbv/), and the robustness of mutation clusters with a bootstrap test was assessed (considered which is a common event in sporadic DGC, has been demonstrated in about 50% of DGC but not as “statistically significant” with a bootstrap value of 25,69-71 26 95% or higher). CDH1 germline missense variants in the intestinal histotype. Berx et al re- were classified according to the parameters defined ported that the most frequently observed changes in the multivariate analysis. This analysis allowed the in DGC are splice site variants that cause skipping distribution of the variants into 2 distinct groups: in exon 8 or 9 and account for in-frame deletions. neutral variant versus mutation.67 Conversely, missense and truncating mutations are 69 Second inactivating hit of E-cadherin. The E-cad seldom observed. Machado et al searched for the gene is regarded as a classic tumor suppressor gene CDH1 gene somatic mutation in 23 GC patients. that occurs early in GC carcinogenesis; it is hence Among these patients, somatic mutations were expected to undergo inactivation of both alleles to identified in 9 (39%) affected by DGC. The authors be suppressed. Patients with autosomal-dominant concluded that the E-cad mutation represents fre- inherited neoplasms have a mutated allele in the quently the second inactivating hit in DGC but not germline, whereas the other (wild-type) allele is in intestinal GC. Surgery Pedrazzani et al. 651 Volume 142, Number 5

Loss of heterozygosity (LOH). In sporadic GC foci of diffuse-type, signet-ring cell carcinoma con- (diffuse as well as intestinal), LOH is reported with fined to the superficial gastric mucosa.78 Huntsman a wide range of frequency (3% to 60%).25,69-71 Liu et al23 reported that most neoplastic foci in the et al72 found a high frequency (38%) of LOH of resected specimen after prophylactic gastrectomy CDH1 genes for intestinal and diffuse GCs and are less than 1 mm in diameter, and all occur in concluded that LOH is a major mechanism of otherwise apparently normal-appearing surface ep- E-cad inactivation. In contrast, Machado et al69 ithelium. found LOH to be responsible for CDH1 gene im- Carneiro et al79 proposed a histologic model for pairment in only 1 of 9 patients with sporadic DGC. GC development in E-cad mutation carriers: At the Promoter hypermethylation. Hypermethylation beginning, histopathologic analysis shows a pattern of the CDH1 gene promoter is the most frequent of in situ signet-ring cell carcinoma with early Page- event underlying the second genetic hit in toid spread. Subsequently, early invasion is fol- 46,68,69,73 GC. DNA is methylated (addition of –CH3 lowed by overt Pagetoid proliferation of signet-ring groups) at cytosine located 5= to guanosine in the cells, and lastly, invasive signet-ring cell carcinoma CpG island;74 this mechanism has an important is evident. The discrepancy between the numerous regulatory effect on gene expression, especially invasive foci of carcinoma and the low number when the promoter region of the gene that con- of in situ carcinomas suggests that invasion of the trols the transcription process is involved.75 Aber- lamina propria by signet-ring cells may occur with- rant promoter methylation and the associated loss of out a morphologically detectable in situ carcinoma. gene expression occur commonly in several types of Oliveira et al80 described a family with HDGC in human cancer.76 which a germline CDH1 mutation was detected Tamura et al73 suggested that hypermethylation after morphologic identification of multifocal, dif- of the CDH1 promoter may play a major role in fuse, signet-ring cell carcinoma and in situ carci- causing the inactivation of the E-cad gene in GC noma lesions with Pagetoid spread. and especially in DGC. At immunohistochemical Pathologic mapping of the entire gastric mucosa analysis, hypermethylation of the promoter region has been performed in 29 stomachs from 13 differ- was associated with a decreased expression of E-cad ent HDGC kindred. Among the 29 described cases, in tumor tissue. Considering the experience re- none revealed H pylori infection, and none showed ported by Machado et al,69 CDH1 promoter hyper- lymph node metastasis or lymphovascular inva- methylation was reported in 56% and 29% of DGC sion. Among these cases, 15 patients underwent and intestinal GC, respectively. Liu et al72 reported prophylactic gastrectomy for a truncating muta- promoter hypermethylation in 76% of DGC and in tion.23,78,81-86 50% of intestinal GC. Graziano et al77 investigated the relationship be- CLINICAL MANAGEMENT tween the epigenetic changes of CDH1 and the Among patients with GC, about 20% belong to a outcome of 73 patients with resected DGC. This family that fulfills the IGCLC criteria, and among experience showed CDH1 promoter hypermethyl- these, 1 of 3 is found to be a carrier of a CDH1 ation in 40 patients (54%); a significant adverse germline mutation (Table I). Given the high pos- association was found between the neoplasms with sibility, clinicians must be concerned with missing hypermethylation and the distribution of disease- an E-cad gene mutation carrier when they are deal- free and relapsed patients. ing with a patient affected by DGC and 1) at least 1 Grady et al68 demonstrated that the hypermeth- documented case of GC in first-degree or second- ylation of the CDH1 promoter region is the most degree relatives diagnosed before the age of 50 important mechanism underlying the second ge- years; 2) 2 or more documented cases of DGC in netic hit in HDGC. In this study, the authors pos- first-degree or second-degree relatives (indepen- tulated that promoter methylation was reversible dent of age of onset); and 3) age less than 45-50 and may be an attractive target for the develop- years.12,30 When these criteria are present, the ment of new anti-cancer therapies. search for a CDH1 germline mutation should be considered strongly, and if any changes in the PATHOLOGY OF HDGC E-cad gene are demonstrated, genetic counseling DGC with signet-ring cells is the predominant should be offered to other family members. histologic type in carriers of CDH1 germline muta- The American Society of Clinical Oncology rec- tions. In advanced stages, HDGC is indistinguish- ommends that an individual should not be tested able from sporadic DGC; conversely, “early” stage for a cancer predisposition gene unless there is a HDGC is characterized by the presence of multiple reasonably high likelihood of detecting a disease- 652 Pedrazzani et al. Surgery November 2007 causing mutation, and the result is intended to after other genetic or epigenetic changes, as it has influence medical management.87 Oliveira et al16 been postulated by several authors.88 Pharoah et al suggest reserving genetic screening until the pa- computed the risk for GC in CDH1 truncating mu- tient can make informed consent. Recently, the tation carriers to be 1% by the age of 20 years and New Zealand HDGC Group88 proposed a flow 4% by the age of 30 years. On this basis, most chart with recommended procedures for diagnosis authors recommend prophylactic gastrectomy for and management of HDGC in which they suggest HDGC to be performed during the second decade that all family members should be offered testing at of life. Once again, in this study, more than one the age of 16 years. third of the cases belong to the above-mentioned Management of CDH1 carriers requires consid- Maori family. The authors themselves stated that, erations about screening for other-site neoplasms, even though the provided information could be such as breast and colon cancers. For women, the useful for genetic counseling in multiple-case fam- estimated cumulative risk of breast cancer by age 80 ilies, the limitations of the data should be consid- years is 39% (95% CI, 12-84)81; in these patients, ered when they are used as an aid in clinical the penetrance of other-site neoplasms is much decision making. These trends may not apply to lower and the possibility of developing GC is almost individuals with a minimal family history in whom 5 times greater.84 Regarding colon cancer, avail- the risk is likely to be less, either because of the risk able data do not clearly support the role of CDH1 of variation between mutations or because modify- germline mutation in the development of this neo- ing genes or other risk factors influence strongly plasia.40 penetrance. Hence, an estimated 4% risk of ad- Prophylactic gastrectomy. Prophylactic total gas- vanced GC is probably overestimated in other fam- trectomy has been suggested as the treatment of ilies, and consequently, the risk of postoperative choice for carriers of CDH1 mutations, and even mortality would overweigh the risk of advanced GC. though the age at which it should be performed Fifth, it is important to highlight that no prophy- has not yet been determined definitely, it is pro- lactic gastrectomy has been performed in carriers posed by most authors during the second decade of of missense mutations until now, even though life.22,23,35,82,88 Nonetheless, several considerations a pathologic behavior has been demonstrated by must be pointed out. First, estimated disease pen- in silico and in vitro analyses in the majority.65 etrance in germline truncating mutations is only Consistently, we described recently a missense mu- 70% to 80%,22,63,81 and hence a universal policy of tation in a patient affected by GC at the age of 79 prophylactic gastrectomy would result in 20% to years and in her brother in whom no evidence of 30% incidence of unnecessary operations.81 Sec- GC was observed at the age of 73 years.62,66 ond, the number of procedures (prophylactic gas- Surveillance endoscopy. In CDH1 mutation car- trectomy) carried out up to now is still limited, and riers, surveillance endoscopy should have the role strong evidence-based conclusions cannot be con- of preserving the stomach or delaying the opera- sidered as definitive (Table III89). Third, about tion, although some concerns remain about the 40% of total gastrectomies have been performed in possibility of missing the presence of small in situ members of the same family, such us the Maori neoplasms. To be safe, surveillance endoscopy family firstly described by Guilford et al.22 Notewor- should be able to detect signet-ring cell carcinoma thy, the mean age of this group (mean, 28 years; at an early stage (pT1) and before submucosal range, 15-49) is less with respect to other families invasion (pT1m). The major concern with surveil- members (mean, 36 years; range, 22-57) (P ϭ .03); lance endoscopy relates to the fact that in HDGC, conversely, the average number of neoplastic foci most neoplastic foci lie within an apparently nor- (mean, 137; range, 15-487) was greater (mean, 15; mal-appearing epithelium.23 No official guidelines range, 0-65) (P ϭ .002). Furthermore, the percent exist for the surveillance of E-cad germline muta- of individuals with GC was greater for the Maori tion carriers; however, the 2003 consensus of the family (26%) with respect to other reported fami- IGCLC for surveillance recommended a 30-min lies (14%) (P ϭ .002).81 It seems that the risk of endoscopy every 6 months by a team experienced developing DGC is greater and at an earlier age in at diagnosing early GC.88 Based on the experience this family in comparison with other described fam- of Japanese mass endoscopic screening programs, ilies. Fourth, with regard to the timing of the op- chromoendoscopy has been proposed by some au- eration, most cases described showed microscopic thors. Clinical practice in New Zealand suggests the foci of in situ carcinoma frequently less than 1 mm use of the Congo red-methylene blue method with in diameter. After an early, prolonged phase of in the aim of improving the sensitivity of detection of situ carcinoma, invasive carcinoma would develop early HDGC.90 Shaw et al reported the results of oue12 ubr5 Number 142, Volume Surgery

Table III. Pathologic mapping of total gastrectomy specimens for HDGC performed to date CDH1 Age/ Macroscopic Histological Lamina propria Muscolaris propria No. of Mean diameter Reference mutation Family Gender Endoscopy appearance type invasion invasion foci (range) Lϩ/Vϩ 83 1588insC A 47/F Normal Normal SRCs No No 15 1-4 No 41/F 13 40/M 45 37/F 5 39/M 2 23† 2095CϾT B 27/F Normal Normal SRCs Yes No 65 Յ1No 35/F 55 23† 1711insG C 22/M Normal Normal SRCs Yes No 2 Յ1No 28/F 1 40/M 3 78 1008GϾT D 40/M SRCs Normal SRCs No No 45 0.1-14 No 28/M 214 15/F 318 34/F 111 16/M* 15 45/F* 487 27/F* 51 20/F* 238 19/F* 115 49/F* 18 19/F* 19 18/F* Yes Yes 15 78 1792CϾT E 43/F Normal Normal SRCs No No 4 1-4.5 No 78 2287GϾT F 33/F SRCs Normal SRCs No No 32 1-4.5 No 86 45insT G 57/M Normal Normal Normal — — — — — 34/M SRCs Yes No 5 Յ1No 89 1135del8ins5 H 28/F SRCs Normal SRCs No No 2 NS No erzaie al. et Pedrazzani 85 1212delC I 28/F Normal Normal Normal — — — — — 35/M

SRC, signet-ring carcinoma. *Unpublished date.88 †Same data were published by Lewis et al.82 653 654 Pedrazzani et al. Surgery November 2007 the first 5 years of chromoendoscopic surveillance tioned repeatedly because of resolution with a de- in 33 members (99 endoscopies) of the HDGC tectable FDG uptake of less than 50%.93 family described by Guilford et al.22 Two DGCs Prophylactic gastrectomy or surveillance gas- were diagnosed at white-light endoscopy because of troscopy? Currently, asymptomatic carriers of the presence of macroscopic lesions; further 11 CDH1 germline mutations and their physicians DGCs were detected after chromo-dye. Correlation must cope with a hard choice where no solid evi- of chromoendoscopic and gastrectomy findings dence-based recommendations can be offered. Pro- showed that the Congo red-methylene blue method phylactic gastrectomy is an option, although the allows the detection of neoplastic foci of 4-10 mm risk of unnecessary resection exists, and the opti- in diameter but not foci less than 4 mm. The mal timing is still to be clearly defined. Endoscopic authors concluded that addition of chromoen- surveillance should be carried out, preferably with doscopy after white-light gastroscopy seems to chromoendoscopy, even if the possibility of missing improve the detection of early HDGC. If the pos- a neoplasm is present. The current uncertainties of tulated theory that small microfoci of in situ HDGC endoscopic surveillance as well as the postoperative are present in all CDH1 mutation carriers at adult risks and long-term morbidity related to prophylac- age is correct, chromoendoscopic surveillance should tic gastrectomy must be explained to the patient so have the role of detecting disease progression with that an informed choice of management can be the principal aim of delaying, if not avoiding, gas- made. trectomy and its side effects. Although a site-predilection for disease has been This work has been supported by grant PAR 2004, described in the transitional zone by Charlton University of Siena and by grant MIUR 2005 to Unit of et al78 in 6 cases of HDGC, a more scattered loca- Surgical Oncology, University of Siena, Italy. tion of neoplastic foci throughout the gastric mu- REFERENCES cosa has been described by Carneiro et al in 9 cases. 1. Parkin DM, Bray F, Ferlay J, Pisani P. 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