- Research article
- Open Access
Frequency of CDH1 germline mutations in gastric carcinoma coming from high- and low-risk areas: metanalysis and systematic review of the literature
BMC Cancer volume 12, Article number: 8 (2012)
The frequency of E-cadherin germline mutations in countries with different incidence rates for gastric carcinoma has not been well established. The goal of this study was to assess the worldwide frequency of CDH1 germline mutations in gastric cancers coming from low- and high-risk areas.
English articles using MEDLINE access (from 1998 to 2011). Search terms included CDH1, E-cadherin, germline mutation, gastric cancer, hereditary, familial and diffuse histotype.
The study included all E-cadherin germline mutations identified in gastric cancer patients; somatic mutations and germline mutations reported in other tumors were excluded.
The method of this study was scheduled in accordance with the "PRISMA statement for reporting systematic reviews and meta-analyses". Countries were classified as low- or middle/high risk-areas for gastric carcinoma incidence. Statistical analysis was performed to correlate the CDH1 mutation frequency with gastric cancer incidence areas.
A total of 122 E-cadherin germline mutations have been identified; the majority (87.5%) occurred in gastric cancers coming from low-risk areas. In high-risk areas, we identified 16 mutations in which missense mutations were predominant. (68.8%). We verified a significant association between the mutation frequency and the gastric cancer risk area (p < 0.001: overall identified mutations in low- vs. middle/high-risk areas).
E-cadherin genetic screenings performed in low-risk areas for gastric cancer identified a higher frequency of CDH1 germline mutations. This data could open new approaches in the gastric cancer prevention test; before proposing a proband candidate for the CDH1 genetic screening, geographic variability, alongside the family history should be considered.
CDH1 germline mutations are associated with the development of the autosomal cancer syndrome namely Hereditary Diffuse Gastric Cancer (HDGC) [1, 2]; about 25-30% of families fulfilling the clinical criteria for HDGC established by the International Gastric Cancer Linkage Consortium (IGCLC) have constitutional alterations of the CDH1 gene . CDH1 germline mutations can also be identified in sporadic early onset GC (EOGC) in less than 4% of patients 35 years of age at the time of diagnosis, presenting as de novo mutations .
Different patterns of CDH1 germline mutations have been described as truncating, deletion, insertion, splice site, non sense, silence, and at last, missense alterations .; for CDH1 non-missense mutations, the penetrance rate is high, with an estimated risk of > 80% ., in missense mutation carriers, the estimated cancer-risk is unknown. CDH1 missense mutations are rather frequently detected in HDGC and in EOGC, and they can be classified as neutral or pathogenic variants .
The worldwide incidence of gastric carcinoma is extremely heterogeneous and the causes of these differences are still unclear; it has been reported that GC presents different characteristics considering tumors coming from low- and high-risk area . In GC patients coming from high-risk areas environmental factors, as specific foods, are more probably associated with the gastric carcinogenesis [8, 9] in which genetic factors, as CDH1 or TP53 germline mutations, are very rarely identified [10–15]. To assess the CDH1 germline mutation frequency in low- and high-risk areas for GC, we reviewed all E-cadherin constitutional alterations identified from 1998 to date, considering the worldwide geographic distribution. We focused on low- and high-risk areas of gastric carcinoma in particular.
Study accuracy and approach
The accuracy of this systematic review and meta-analysis was assessed using the checklist of items in accordance with the "Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement" .
In particular, we scheduled this systematic review and meta-analysis as follows: a) Identification: to assess the CDH1 germline mutation frequency in different risk areas for GC; b) Screening: to search all identified CDH1 germline mutations, as well as in patients with DGC as in asymptomatic carriers; c) Eligibility: to include all data reported in an accessible source bank (the National Library of Medicine's MEDLINE database); d) Included: to analyse the obtained results with statistical analysis (Figure 1).
In this study we considered all countries in which an independent CDH1 genetic screening has been performed, aiming for germline mutation search.
We subdivided the world areas in two groups: low (group A) and middle-high incidence (group B) areas, considering the GC incidence data reported by Ferlay J. and Colleagues . Among group A, we identified these countries: USA, Spain, France, Ireland, Canada, United Kingdom, New Zealand, Germany, Finland, Pakistan, Sweden, the Netherlands, Austria and Iran. This group also included some cases defined only as "European" and without specific ancestry. We excluded that this part is comes from the European area with middle-high GC risk (as North of Portugal, Central Italy, and Eastern Europe). Group B includes these zones: Italy (Tuscany), Portugal (North), Japan, China, Korea, South America, Lithuania and Poland.
CDH1 germline mutation search and selected articles
We revised all CDH1 germline mutations reported in MEDLINE from March 1998 to November 2010, through analysis of original reports and reviews of the literature edited in the English language. Moreover, we also included data from two international workshops of the IGCLC (in 1999 and in 2010) [2, 3]. Whenever sufficient, we also considered information obtained from abstract in the English language with the main text edited in other languages; a total of 156 papers were selected for this study. The reported CDH1 constitutional alterations are defined as truncating, deletion, insertion, splice site, non-sense, and missense mutations (Table 1); we grouped these mutations as non-missense (truncating, deletion, insertion, splice site and non sense) or missense mutations. This study excluded all CDH1 somatic mutations identified in gastric carcinoma, and the germline alterations found in primary lobular breast carcinoma as well as in mucinous colon cancer. We considered also mutations namely in review papers as "unpublished results" [5, 18].
We used the following search terms to search all reports, reviews and databases: E-cadherin; CDH1 gene; germline mutation, and genetic screening; HDGC, and IGCLC; familial GC; diffuse histotype; Maori kindred, prophylactic gastrectomy.
Assessment of risk bias
We also evaluated the possibility that the available data is biased; in particular, we considered two kinds of possible bias: a) in case selection, specifically by the literature reviewer and b) from literature data. Point a) was attacked considering two reviewers that performed eligibility assessment independently and disagreements between those were resolved by consensus; all participants confirmed the process for data acquisitions. For point b), we examined results from the available studies for clues that suggest there may be missing studies (namely publication bias) or missing data from the included studies (namely selective reporting bias).
All CDH1 germline mutations were stored in a database, considering the respective geographical origins. Qualitative data in the 2 groups were expressed as frequencies, organized into contingency tables, and evaluated with the [chi]2 test (Pearson [chi]2 test or Fisher exact test) to investigate potential differences. The results were considered statistically significant for p < 0.05. Statistical analysis was conducted by using SPSS statistical package (version 15.0) (SPSS, Chicago, IL).
The majority of selected studies were original reports
We analysed a total of 212 studies; in detail 156 were excluded because they comprised somatic mutations, germline mutations in breast or colon cancers, molecular analyses, prophylactic gastrectomy descriptions and outdated reviews. Instead, the other 56 studies were included and classified as shown in the flow diagram (Figure 1). The majority of the studies were original reports (71.4%), and only the three (5.4%) latest updated reviews were considered for this study [4, 5, 54]. Two studies (3.6%) were the results of International Workshop Consensus Conferences (namely IGCLC), which delineated the clinical criteria selecting proband for the CDH1 genetic screening [2, 3].
For each included study, we considered the number and the pattern of the identified CDH1 germline mutations; moreover, we carefully evaluated the ancestry of mutation carriers.
Selection of countries with different risk area for gastric carcinoma
Far and Middle Western, European and American countries performed almost an independent genetic screening aiming for CDH1 germline mutation search (Figure 2). The countries that identified at least one germline CDH1 alteration were the following, a) Far East: China, Korea, Japan and New Zealand; b) Middle East: Iran and Pakistan; c) Europe: Italy, Spain, Ireland, the United Kingdom, Lithuania, Germany, Finland, the Netherlands, Sweden, Portugal and Austria; d) America: USA, Canada and Colombia.
We assembled these countries considering the incidence rates of gastric carcinoma spread and were classified as: a) low- (group A) and b) middle/high-risk (group B) area (details are described in method section).
Frequency of CDH1 mutation is associated with specific gastric cancer risk area
All genetic screenings identified at least 122 CDH1 germline mutations (Table 1); 72.1% of these were non-missense and 27.9% missense alterations (Table 2). Non-missense mutations occurred with a frequency of 87.5% and 5.7%, respectively in groups A and B and missense alterations were 50% in group A and 32.4% in group B (Figure 3). Twelve CDH1 mutations, six non-missense and six missense, were reported without ancestry. 93 CDH1 germline mutations were identified in group A; 17 (18.3%) were missense and 77 (82.7%) non-missense. In group B, a total of 16 germline mutations have been reported, from which 11 (68.7%) were missense and 5 (31.3%) non-missense. The overall CDH1 germline mutation frequency was significantly higher in group A as well as the rate of non-missense alterations (group A vs. group B: Fisher exact test χ2 15,872; p < 0.001).
Minimization of risk bias
Point a) Two independent reviewers confirmed the results crosschecking all data, as well as the number and the ethnicity of CDH1 germline mutations; results were routinely discussed in scientific meetings and seminars. To facilitate the common consultation, all identified CDH1 alterations were recorded in Table 1. Point b) The heterogeneity of publications could be a risk bias; we considered only original reports that were the large majority of the analysed paper (71.4%), and reviews as other papers were considered only to confirm the results from those original reports. In particular, the last review  and one original paper  reported some CDH1 germline mutations namely as "unpublished results", this could reduce the risk bias related with the "missing studies". Considering the "selective reporting bias" as the missing data from the included studies, we assessed that the CDH1 mutations overlapped with the latest review  and with the selected original papers.
Incidence of gastric carcinoma
Until recently, gastric carcinoma was the second most common cancer worldwide, but now, with an estimated 934,000 new cases per year in 2002 (8.6% of new cases), it is in fourth place behind cancers of lung, breast and colon and rectum. It is the second most common cause of cancer death (700,000 deaths annually). Almost two-thirds of cases occur in developing countries and 42% in China alone. The geographic distribution of GC is characterized by wide international variations; high-risk areas include East Asia (China, Japan and Korea), Eastern Europe, and parts of Central and South America. Incidence rates are low (< 10 per 100,000 in men) in Southern Asia, North and East Africa, North America, Australia, New Zealand and Africa [17, 55].
In Europe, GC represents the fifth most common cancer, after colon and rectum, breast, lung and prostate, with an incidence of 149,000 per year and mortality rate of 116,000. The highest European risk area for GC is the Eastern zone with an incidence of 70,000 per year (Belarus area). Portugal and Italy represent one of the most high-risk European areas for stomach cancer, in particular, respectively, with incidence in 2008 of 41,100 and in Italy with incidence of 33,400 per year . In Italy, Tuscany and central regions present a GC mortality rate of 4,2/10,000 inhabitants (2002 ISTAT-The Italian National Institute of Statistics).
E-cadherin and diffuse gastric cancer
The CDH1 gene maps to chromosome 16q22.1 and consists of 16 exons that encode a 120-kDa protein called E-cadherin, which is a member of the transmembrane glycoproteins family. E-cadherin is expressed on epithelial tissues and is responsible for calcium-dependent cell-cell adhesion. Functionally, it is critical for establishing and maintaining polarized and differentiated epithelia through intercellular adhesion complexes. Human E-cadherin is considered an invasion suppressor, and under-expression of E-cadherin is correlated with the infiltrative and metastatic ability of the tumor .
In 1998 in New Zealand, a country that represents a low GC risk-area, Guilford and Colleagues identified firstly in Maori kindred the first CDH1 germline truncating mutation in cases with family history for diffuse gastric carcinoma . Subsequently, several international countries reported other CDH1 germline mutations in HDGC or in sporadic EODGC with different ethnicities [4, 54].
The definition of the HDGC syndrome was established in 1999 by the IGCLC that also delineated the criteria for the CDH1 genetic screening, as follows: 1) two or more documented cases of diffuse gastric cancer in 1st/2nd degree relatives, with at least one diagnosed before the age of 50, or 2) three or more cases of documented diffuse gastric cancer in 1st/2nd degree relatives, independently of age of onset . Subsequently, the last consensus conference of Cambridge in 2010 , modified the criteria as: a) two GC cases in family, one confirmed DGC < 50; b) three confirmed DGC cases in 1st or 2nd degree relatives independent of age; c) age < 40; Corso and Colleagues recently proposed the cut-off age of onset at ≤ 35 in sporadic EODGC ; d) personal or family history of DGC and lobular breast cancer, one < 50.
In this study, we reported a total of 122 CDH1 germline mutations, respectively 94 (77%) in group A (low-risk area) and 16 (13.1%) in group B (middle/high-risk area) (12-9.9% mutations were without ethnicity information).
Revising these 122 CDH1 mutations, we observed some main findings: 1) the overall mutation rate is lower in group B rather than in group A (13.1% vs. 77%; p < 0.001); 2) group A shows a higher frequency of non-missense mutations; moreover, CDH1 non-missense mutations are extremely lower in group B (5.7%), in which missense variants are predominant (32.4%) (Figure 2).
Considering the first point, we stated that CDH1 germline mutations in GC middle/high-risk area are rather rarely identified respecting to low-risk area; as reported, in middle/high-risk area the probability to perform a CDH1 genetic screening with negative result is high enough [10–12], in which maybe operates environmental factors.
Summary of evidence: CDH1 mutations and geographic variability
The abovementioned clinical criteria represents an important approach in selecting probands for the CDH1 genetic screening. Currently, different modifications have been appointed at these criteria [2, 4, 32], evaluating clinical and molecular results along the international consensus conferences; so far, the risk area vs. incidence of gastric carcinoma has never been discussed in these scientific meetings. We stated that "GC risk area and incidence" can represent an important emerging factor that relates strongly to the prognosis and other important behaviors of GC patients; ethnicity of GC patients coming from low- or high-risk areas could be considered in these criteria in order to identify cases with high or low-risk mutation carriers in hereditary syndromes. Information about the ancestry, can improve the accuracy of proband selection for the CDH1 genetic screening; in particular, we can consider GC patients as high or low-risk mutation carriers respectively in low or high-risk GC areas whenever the abovementioned criteria is fulfilled. This data verifies that in high-risk areas, clinical criteria should be applied strictly to cases with a strong family history for GC in particular when it has identified very young members.
It is important to stress that geographical variability represents a novel risk factor for gastric carcinoma, clinico-pathological features and some molecular results can confirm it. These acknowledgments, like the GC risk-area, provide important information and can propose different approaches in clinical practice for GC prevention and treatment.
Molecular features and pathogenicity of E-cadherin missense mutations
The second consideration of this study is that GC high-risk area shows a higher frequency of CDH1 missense mutations; identification of a CDH1 missense alteration also implicated its functional assessment, because in vitro and in silico analysis with study of control population demonstrates that this mutation can be a novel polymorphic variant without pathogenic impact. We also revised the frequencies of CDH1 germline missense mutations with a pathogenic role that was assessed in 21 CDH1 missense alterations [4, 56]; 17 of these showed a deleterious impact and respectively 5 (29.4%) were coming from middle/high risk-areas and 12 (70.6%) from low risk-areas. The pathogenicity of the remaining 13 mutations is unknown. As reported, the probability of finding a novel pathogenic CDH1 missense mutation (including also non-missense mutations) is higher in GC low-risk areas. Very recently, we revised the role of the CDH1 germline mutation in pathogenesis of sporadic EODGC; a total of 19 mutations have been reported to date in this GC group but only six (2.3%) of them did in fact represent variants with a proven potentially deleterious effect. This predicted pathogenicity was based on the type of mutation (frameshift) or on the results obtained from in vitro functional analysis. Five of the six germline pathogenic CDH1 mutations were detected in EOGC patients from low or moderate incidence GC areas, whereas only one arose in a patient from Portugal, a high incidence GC area. Although CDH1 germline mutations have been searched for in EOGC patients from other areas where high incidence rates of GC are verified, namely in countries like China, Korea, Japan, and even Italy, no deleterious CDH1 germline variants have been identified .
These results demonstrated that functional assessment of CDH1 germline missense mutations is mandatory, in particular in GC high-risk cases that show a higher frequency of unpathogenic missense mutations.
Limitations of the current study
Certainly, this study presents some limitations that should be discussed, also for further consideration. First, the CDH1 germline mutation frequency could be affected by research activity, as publication bias or access to medical care, considering that some CDH1 variants could be unpublished in MEDLINE; this factor probably is due to the lack of a CDH1 recorded mutation database. However, MEDLINE is the unique search engine in which we can access easily and freely; unfortunately we do not have access in confidential and in unpublished data. However, this bias should be very small, because we carefully collected all CDH1 mutations recorded in MEDLINE; we also discussed this point in the "result" section. The second point is that we do not know precisely in what proportion of cases CDH1 mutations are identified in low vs. middle/high risk areas, and if the mutation frequency is related to the number of screened subjects; moreover, the accuracy of this study could be affected by the human migrations. The overall CDH1 mutation number identified to date is rather low and we are not able to also include this factor (as ratio between number of mutations vs. number of screened kindred, migration of population, etc.) risking to dissipate the statistical value, in the excess of data stratification. In the specific, we were not able to assess the quantitative genetic analysis due to the lack of information about the impact of environmental factor in DGC development and about migratory behavior. Further, if applicable and also considering that the clinical criteria are rather limited, in a larger family collection, this data could be considered. The third limitation is that we cannot analyse intestinal GC and other risk factors, such as environmental agents (i.e. specific diet habits); however, the aim of this study is only to assess the frequency of CDH1 germline mutation in DGC, in which environmental factors are probably less important than in intestinal hystotype. Moreover, the CDH1 germline or somatic mutations have not reported in intestinal gastric carcinoma, and for this reason, it was excluded from this systematic review.
GC patients coming from high-risk areas show a lower incidence of CDH1 germline mutations when compared with individuals coming from low-risk areas. The finding that CDH1 mutation frequencies are extremely different in high and low-risk GC zones confirms that gastric carcinoma presents various clinico-pathologic and molecular features. This data could also open new different approaches in the GC prevention test; before proposing a proband candidate for the CDH1, genetic screening, geographic variability and family history should be considered.
Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE: E-cadherin germline mutations in familial gastric cancer. Nature. 1998, 392 (6674): 402-405. 10.1038/32918.
Caldas C, Carneiro F, Lynch HT, Yokota J, Wiesner GL, Powell SM, Lewis FR, Huntsman DG, Pharoah PD, Jankowski JA, MacLeod P, Vogelsang H, Keller G, Park KG, Richards FM, Maher ER, Gayther SA, Oliveira C, Grehan N, Wight D, Seruca R, Roviello F, Ponder BA, Jackson CE: Familial gastric cancer: overview and guidelines for management. J Med Genet. 1999, 36 (12): 873-880.
Fitzgerald RC, Hardwick R, Huntsman D, Carneiro F, Guilford P, Blair V, Chung DC, Norton J, Ragunath K, Van Krieken JH, Dwerryhouse S, Caldas C, International Gastric Cancer Linkage Consortium: Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010, 47 (7): 436-444. 10.1136/jmg.2009.074237.
Corso G, Pedrazzani C, Pinheiro H, Fernandes E, Marrelli D, Rinnovati A, Pascale V, Seruca R, Oliveira C, Roviello F: E-cadherin genetic screening and clinico-pathologic characteristics of early onset gastric cancer. Eur J Cancer. 2011, 47 (4): 631-639. 10.1016/j.ejca.2010.10.011.
Guilford P, Humar B, Blair V: Hereditary diffuse gastric cancer: translation of CDH1 germline mutations into clinical practice. Gastric Cancer. 2010, 13 (1): 1-10. 10.1007/s10120-009-0531-x.
Suriano G, Oliveira MJ, Huntsman D, Mateus AR, Ferreira P, Casares F, Oliveira C, Carneiro F, Machado JC, Mareel M, Seruca R: E-cadherin germline missense mutations and cell phenotype: evidence for the independence of cell invasion on the motile capabilities of the cells. Hum Mol Genet. 2003, 12 (22): 3007-3016. 10.1093/hmg/ddg316.
Marrelli D, Pedrazzani C, Corso G, Neri A, Di Martino M, Pinto E, Roviello F: Different pathological features and prognosis in gastric cancer patients coming from high-risk and low-risk areas of Italy. Ann Surg. 2009, 250 (1): 43-50. 10.1097/SLA.0b013e3181ad6487.
Palli D, Russo A, Decarli A: Dietary patterns, nutrient intake and gastric cancer in a high-risk area of Italy. Cancer Causes Control. 2001, 12 (2): 163-172. 10.1023/A:1008970310963.
González CA, Jakszyn P, Pera G, Agudo A, Bingham S, Palli D, Ferrari P, Boeing H, del Giudice G, Plebani M, Carneiro F, Nesi G, Berrino F, Sacerdote C, Tumino R, Panico S, Berglund G, Simán H, Nyrén O, Hallmans G, Martinez C, Dorronsoro M, Barricarte A, Navarro C, Quirós JR, Allen N, Key TJ, Day NE, Linseisen J, Nagel G, Bergmann MM, Overvad K, Jensen MK, Tjonneland A, Olsen A, Bueno-de-Mesquita HB, Ocke M, Peeters PH, Numans ME, Clavel-Chapelon F, Boutron-Ruault MC, Trichopoulou A, Psaltopoulou T, Roukos D, Lund E, Hemon B, Kaaks R, Norat T, Riboli E: Meat intake and risk of stomach and esophageal adenocarcinoma within the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst. 2006, 98 (5): 345-354. 10.1093/jnci/djj071.
Zhu ZG, Yu YY, Zhang Y, Ji J, Zhang J, Liu BY, Chen XH, Lu Y, Jiang HS, Bu L, Hu LD, Kong XY: Germline mutational analysis of CDH1 and pathologic features in familial cancer syndrome with diffuse gastric cancer/breast cancer proband in a Chinese family. Eur J Surg Oncol. 2004, 30 (5): 531-535. 10.1016/j.ejso.2004.03.004.
Jakubowska A, Lawniczak M, Wojnarska B, Cybulski C, Huzarski T, Byrski T, Tołoczko-Grabarek A, Jaworska K, Durda K, Starzyńska T, Lubiński J: CDH1 gene mutations do not contribute in hereditary diffuse gastric cancer in Poland. Fam Cancer. 2010, 9 (4): 605-608. 10.1007/s10689-010-9381-2.
Song W, He YL, Zhang CH, Cai SR, Zhou XF, Peng JJ, Wang Z, Yang DJ, Zhan WH: Associations of E-cadherin gene (CDH1) and hereditary gastric cancer in China. Zhonghua Wai Ke Za Zhi. 2009, 47 (16): 1204-1208.
Graziano F, Ruzzo AM, Bearzi I, Testa E, Lai V, Magnani M: Screening E-cadherin germline mutations in Italian patients with familial diffuse gastric cancer: an analysis in the District of Urbino, Region Marche, Central Italy. Tumori. 2003, 89 (3): 255-258.
Corso G, Pedrazzani C, Marrelli D, Pinto E, Roviello F: Familial gastric cancer and Li-Fraumeni syndrome. Eur J Cancer Care. 2010, 19 (3): 377-381. 10.1111/j.1365-2354.2008.01066.x.
Corso G, Roviello F, Paredes J, Pedrazzani C, Novais M, Correia J, Marrelli D, Cirnes L, Seruca R, Oliveira C, Suriano G: Characterization of the P373L E-cadherin germline missense mutation and implication for clinical management. Eur J Surg Oncol. 2007, 33 (9): 1061-1067. 10.1016/j.ejso.2007.03.001.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PlosMedicine. 2009, 6 (7): e1000100-
Ferlay J, Parkin DM, Steliarova-Foucher E: Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010, 46 (4): 765-781. 10.1016/j.ejca.2009.12.014.
More H, Humar B, Weber W, Ward R, Christian A, Lintott C, Graziano F, Ruzzo AM, Acosta E, Boman B, Harlan M, Ferreira P, Seruca R, Suriano G, Guilford P: Identification of seven novel germline mutations in the human E-cadherin (CDH1) gene. Hum Mutat. 2007, 28 (2): 203-
Bacani JT, Soares M, Zwingerman R, di Nicola N, Senz J, Riddell R, Huntsman DG, Gallinger S: CDH1/E-cadherin germline mutations in early-onset gastric cancer. JMed Genet. 2006, 43 (11): 867-872.
Oliveira C, Senz J, Kaurah P, Pinheiro H, Sanges R, Haegert A, Corso G, Schouten J, Fitzgerald R, Vogelsang H, Keller G, Dwerryhouse S, Grimmer D, Chin SF, Yang HK, Jackson CE, Seruca R, Roviello F, Stupka E, Caldas C, Huntsman D: Germline CDH1 deletions in hereditary diffuse gastric cancer families. Hum Mol Genet. 2009, 18 (9): 1545-1555. 10.1093/hmg/ddp046.
Suriano G, Yew S, Ferreira P, Senz J, Kaurah P, Ford JM, Longacre TA, Norton JA, Chun N, Young S, Oliveira MJ, Macgillivray B, Rao A, Sears D, Jackson CE, Boyd J, Yee C, Deters C, Pai GS, Hammond LS, McGivern BJ, Medgyesy D, Sartz D, Arun B, Oelschlager BK, Upton MP, Neufeld-Kaiser W, Silva OE, Donenberg TR, Kooby DA, Sharma S, Jonsson BA, Gronberg H, Gallinger S, Seruca R, Lynch H, Huntsman DG: Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management. Clin Cancer Res. 2005, 11 (15): 5401-5409. 10.1158/1078-0432.CCR-05-0247.
Oliveira C, Bordin MC, Grehan N, Huntsman D, Suriano G, Machado JC, Kiviluoto T, Aaltonen L, Jackson CE, Seruca R, Caldas C: Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred. Hum Mutat. 2002, 19 (5): 510-517. 10.1002/humu.10068.
Richards FM, McKee SA, Rajpar MH, Cole TR, Evans DG, Jankowski JA, McKeown C, Sanders DS, Maher ER: Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer. Hum Mol Genet. 1999, 8 (4): 607-610. 10.1093/hmg/8.4.607.
Moran CJ, Joyce M, McAnena OJ: CDH1 associated gastric cancer: a report of a family and review of the literature. Eur J Surg Oncol. 2005, 31 (3): 259-264. 10.1016/j.ejso.2004.12.010.
Humar B, Toro T, Graziano F, Müller H, Dobbie Z, Kwang-Yang H, Eng C, Hampel H, Gilbert D, Winship I, Parry S, Ward R, Findlay M, Christian A, Tucker M, Tucker K, Merriman T, Guilford P: Novel germline CDH1 mutations in hereditary diffuse gastric cancer families. Hum Mutat. 2002, 19 (5): 518-525. 10.1002/humu.10067.
Guilford PJ, Hopkins JB, Grady WM, Markowitz SD, Willis J, Lynch H, Rajput A, Wiesner GL, Lindor NM, Burgart LJ, Toro TT, Lee D, Limacher JM, Shaw DW, Findlay MP, Reeve AE: E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum Mutat. 1999, 14 (3): 249-255. 10.1002/(SICI)1098-1004(1999)14:3<249::AID-HUMU8>3.0.CO;2-9.
Shinmura K, Kohno T, Takahashi M, Sasaki A, Ochiai A, Guilford P, Hunter A, Reeve AE, Sugimura H, Yamaguchi N, Yokota J: Familial gastric cancer: clinicopathological characteristics, RER phenotype and germline p53 and E-cadherin mutations. Carcinogenesis. 1999, 20 (6): 1127-1131. 10.1093/carcin/20.6.1127.
Gayther SA, Gorringe KL, Ramus SJ, Huntsman D, Roviello F, Grehan N, Machado JC, Pinto E, Seruca R, Halling K, MacLeod P, Powell SM, Jackson CE, Ponder BA, Caldas C: Identification of germ-line E-cadherin mutations in gastric cancer families of European origin. Cancer Res. 1998, 58 (18): 4086-4089.
Dussaulx-Garin L, Blayau M, Pagenault M, Le Berre-Heresbach N, Raoul JL, Campion JP, David V, Bretagne JF: A new mutation of E-cadherin gene in familial gastric linitis plastica cancer with extra-digestive dissemination. Eur J Gastroenterol Hepatol. 2001, 13 (6): 711-715. 10.1097/00042737-200106000-00016.
Keller G, Vogelsang H, Becker I, Hutter J, Ott K, Candidus S, Grundei T, Becker KF, Mueller J, Siewert JR, Höfler H: Diffuse type gastric and lobular breast carcinoma in a familial gastric cancer patient with an E-cadherin germline mutation. Am J Pathol. 1999, 155 (2): 337-342. 10.1016/S0002-9440(10)65129-2.
Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N, Suriano G, Zaor S, Van Manen L, Gilpin C, Nikkel S, Connolly-Wilson M, Weissman S, Rubinstein WS, Sebold C, Greenstein R, Stroop J, Yim D, Panzini B, McKinnon W, Greenblatt M, Wirtzfeld D, Fontaine D, Coit D, Yoon S, Chung D, Lauwers G, Pizzuti A, Vaccaro C, Redal MA, Oliveira C, Tischkowitz M, Olschwang S, Gallinger S, Lynch H, Green J, Ford J, Pharoah P, Fernandez B, Huntsman D: Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007, 297 (21): 2360-2372. 10.1001/jama.297.21.2360.
Brooks-Wilson AR, Kaurah P, Suriano G, Leach S, Senz J, Grehan N, Butterfield YS, Jeyes J, Schinas J, Bacani J, Kelsey M, Ferreira P, MacGillivray B, MacLeod P, Micek M, Ford J, Foulkes W, Australie K, Greenberg C, LaPointe M, Gilpin C, Nikkel S, Gilchrist D, Hughes R, Jackson CE, Monaghan KG, Oliveira MJ, Seruca R, Gallinger S, Caldas C, Huntsman D: Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet. 2004, 41 (7): 508-517. 10.1136/jmg.2004.018275.
Avizienyte E, Launonen V, Salovaara R, Kiviluoto T, Aaltonen LA: E-cadherin is not frequently mutated in hereditary gastric cancer. J Med Genet. 2001, 38 (1): 49-52. 10.1136/jmg.38.1.49.
Frebourg T, Oliveira C, Hochain P, Karam R, Manouvrier S, Graziadio C, Vekemans M, Hartmann A, Baert-Desurmont S, Alexandre C, Lejeune Dumoulin S, Marroni C, Martin C, Castedo S, Lovett M, Winston J, Machado JC, Attié T, Jabs EW, Cai J, Pellerin P, Triboulet JP, Scotte M, Le Pessot F, Hedouin A, Carneiro F, Blayau M, Seruca R: Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer. J Med Genet. 2006, 43 (2): 138-142.
Mateus AR, Simões-Correia J, Figueiredo J, Heindl S, Alves CC, Suriano G, Luber B, Seruca R: E-cadherin mutations and cell motility: a genotype-phenotype correlation. Exp Cell Res. 2009, 315 (8): 1393-1402. 10.1016/j.yexcr.2009.02.020.
Yoon KA, Ku JL, Yang HK, Kim WH, Park SY, Park JG: Germline mutations of E-cadherin gene in Korean familial gastric cancer patients. J Hum Genet. 1999, 44 (8): 177-180.
Rogers WM, Dobo E, Norton JA, Van Dam J, Jeffrey RB, Huntsman DG, Kingham K, Chun N, Ford JM, Longacre TA: Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications. Am J Surg Pathol. 2008, 32: 799-809. 10.1097/PAS.0b013e31815e7f1a.
Jonsson BA, Bergh A, Stattin P, Emmanuelsson M, Grönberg H: Germline mutations in E-cadherin do not explain association of hereditary prostate cancer, gastric cancer and breast cancer. Int J Cancer. 2002, 98 (6): 838-843. 10.1002/ijc.10258.
Zhang Y, Liu X, Fan Y, Ding J, Xu A, Zhou X, Hu X, Zhu M, Zhang X, Li S, Wu J, Cao H, Li J, Wang Y: Germline mutations and polymorphic variants in MMR, E-cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China. Int J Cancer. 2006, 119 (11): 2592-2596. 10.1002/ijc.22206.
Roviello F, Corso G, Pedrazzani C, Marrelli D, De Falco G, Berardi A, Garosi L, Suriano G, Vindigni C, De Stefano A, Leoncini L, Seruca R, Pinto E: Hereditary diffuse gastric cancer and E-cadherin: description of the first germline mutation in an Italian family. Eur J Surg Oncol. 2007, 33 (4): 448-451. 10.1016/j.ejso.2006.10.028.
Oliveira C, Ferreira P, Nabais S, Campos L, Ferreira A, Cirnes L, Alves CC, Veiga I, Fragoso M, Regateiro F, Dias LM, Moreira H, Suriano G, Machado JC, Lopes C, Castedo S, Carneiro F, Seruca R: E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients. Eur J Cancer. 2004, 40 (12): 1897-1903. 10.1016/j.ejca.2004.04.027.
Wilcox R, Perpich M, Noffsinger A, Posner MC, Cooper K: Hereditary diffuse gastric cancer: multidisciplinary case report with review of the literature. Pathol Res Int. 2011, 2011: 1-5.
Wang Y, Song JP, Ikeda M, Shinmura K, Yokota J, Sugimura H: Ile-Leu substitution (I415L) in germline E-cadherin gene (CDH1) in Japanese familial gastric cancer. Jpn J Clin Oncol. 2003, 33 (1): 17-20. 10.1093/jjco/hyg002.
Mayrbaeurl B, Keller G, Schauer W, Burgstaller S, Czompo M, Hoebling W, Knoflach P, Duba HC, Hoefler H, Thaler J: Germline mutation of the E-cadherin gene in three sibling cases with advanced gastric cancer: clinical consequences for the other family members. Eur J Gastroenterol Hepatol. 2010, 22 (3): 306-310. 10.1097/MEG.0b013e32832bab9a.
Barber M, Murrell A, Ito Y, Maia AT, Hyland S, Oliveira C, Save V, Carneiro F, Paterson AL, Grehan N, Dwerryhouse S, Lao-Sirieix P, Caldas C, Fitzgerald RC: Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J Pathol. 2008, 16 (3): 295-306.
Jiang Y, Wan YL, Wang ZJ, Zhao B, Zhu J, Huang YT: Germline E-cadherin gene mutation screening in familial gastric cancer kindreds. Zhonghua Wai Ke Za Zhi. 2004, 42 (15): 914-917.
Rodriguez-Sanjuan JC, Fontalba A, Mayorga M, Bordin MC, Hyland SJ, Trugeda S, Garcia RA, Gomez-Fleitas M, Fernandez F, Caldas C, Fernandez-Luna JL: A novel mutation in the E-cadherin gene in the first family with hereditary diffuse gastric cancer reported in Spain. Eur J Surg Oncol. 2006, 32 (10): 1110-1113. 10.1016/j.ejso.2006.06.006.
Keller G, Vogelsang H, Becker I, Plaschke S, Ott K, Suriano G, Mateus AR, Seruca R, Biedermann K, Huntsman D, Döring C, Holinski-Feder E, Neutzling A, Siewert JR, Höfler H: Germline mutations of the E-cadherin (CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients. J Med Genet. 2004, 41 (6): e89-10.1136/jmg.2003.015594.
Salahshor S, Hou H, Diep CB, Loukola A, Zhang H, Liu T, Chen J, Iselius L, Rubio C, Lothe RA, Aaltonen L, Sun XF, Lindmark G, Lindblom A: A germline E-cadherin mutation in a family with gastric and colon cancer. Int J Mol Med. 2001, 8 (4): 439-443.
Simões-Correia J, Figueiredo J, Oliveira C, van Hengel J, Seruca R, van Roy F, Suriano G: Endoplasmic reticulum quality control: a new mechanism of E-cadherin regulation and its implication in cancer. Hum Mol Genet. 2008, 17 (22): 3566-3576. 10.1093/hmg/ddn249.
Ghaffari SR, Dastan J, Rafati M, Sabokbar T: Novel human pathological mutations. Gene symbol: CDH1. Disease: gastric cancer. Hum Genet. 2009, 125 (3): 337-
Caron O, Schielke A, Svrcek M, Fléjou JF, Garzon J, Olschwang S, Sézeur A: Usefulness of prophylactic gastrectomy in a novel large hereditary diffuse gastric cancer (HDGC) family. Am J Gastroenterol. 2008, 103 (8): 2160-2161.
Yabuta T, Shinmura K, Tani M, Yamaguchi S, Yoshimura K, Katai H, Nakajima T, Mochiki E, Tsujinaka T, Takami M, Hirose K, Yamaguchi A, Takenoshita S, Yokota J: E-cadherin gene variants in gastric cancer families whose probands are diagnosed with diffuse gastric cancer. Int J Cancer. 2002, 101 (5): 434-441002E. 10.1002/ijc.10633.
Pedrazzani C, Corso G, Marrelli D, Roviello F: E-cadherin and hereditary diffuse gastric cancer. Surgery. 2007, 142 (5): 645-657. 10.1016/j.surg.2007.06.006.
Holcombe C: Helicobacter pylori: the African enigma. Gut. 1992, 33: 429-431. 10.1136/gut.33.4.429.
Suriano G, Ferreira P, Mateus AR, Correia J, Henriques L, Seruca R: Genetics of hereditary diffuse gastric cancer: progress and future challenges. Future Oncol. 2006, 2 (3): 363-370. 10.2217/147966220.127.116.113.
The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/12/8/prepub
This work was supported by Grants from: Istituto Toscano Tumori ("Gene expression profile and therapeutic implication in gastric cancer. From the clinical overview to the translational research"; Grant ITT-2007) and The Portuguese Foundation for Science and Technology (FCT) (PhD grant numbers SFRH/BD/40090/2007-GC).
The authors declare that they have no competing interests.
GC did CDH1 mutation research in MEDLINE and drafted the manuscript. DM performed statistical analysis. VP collected the overall CDH1 mutation in a database. CV was responsible of the correct histological classification of GC. FR conceived and designed the study, analysed the results and helped to draft the manuscript. All authors read and approved the final manuscript.
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Corso, G., Marrelli, D., Pascale, V. et al. 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 (2012). https://doi.org/10.1186/1471-2407-12-8
- Gastric cancer
- Germline mutation
- Risk area