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Journal of Cancer Research and Clinical Oncology

Erschienen in:

18.09.2021 | Original Article – Clinical Oncology

CDH1 germline mutations in a Chinese cohort with hereditary diffuse gastric cancer

verfasst von: Zhiwen Pan, Zhixuan Fu, Cong Luo, Yejiang Bao, Mingli Wang, Wenming Cao, Xiaohong Xu

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 8/2022

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Abstract

Purpose

Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer (HDGC) and have been identified in multiple ethnicities. However, CDH1 germline mutations have seldom been documented in Chinese patients with HDGC, and their frequency remains unclear. Here, we aimed to examine the frequency of CDH1 germline mutations in Chinese patients with HDGC. In total, 285 patients who met the International Gastric Cancer Linkage Consortium 2015 testing criteria of HDGC for CDH1 germline mutations were recruited.

Methods

All 16 CDH1 exons, including neighboring intronic sequences, were amplified using polymerase chain reaction and screened using Sanger sequencing. Variants were analyzed using Mutation Surveyor V4.0, SIFT, and PolyPhen-2 software.

Results

Three nonsense and nine missense CDH1 germline mutations were identified in 21 of 285 index cases (7.4%). Two CDH1 germline mutations, N405Y (Asn405Tyr) and W409X (Trp409Ter), were identified as new variants. In addition, up to 28.6% of CDH1 mutations in the 21 indicated patients were identified as c.1775G>C (E551Q). The frequency of CDH1 mutations was 6.5% (7/108) in HDGC and 7.9% (14/177) in early onset diffuse gastric cancer (EODGC). The mutation detection rates of CDH1 in males and females were 6.7% (4/60) and 8.5% (10/117) in EODGC and 4.6% (3/65) and 9.3% (4/43) in HDGC, respectively.

Conclusion

These data reveal, for the first time, the type and frequency of CDH1 germline mutations in Chinese HDGC and demonstrate that germline CDH1 mutations are a noteworthy contributor to the high frequency of HDGC in Chinese.

Adzhubei IA, Schmidt S, Peshkin L et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249. https://doi.org/10.1038/nmeth0410-248CrossRefPubMedPubMedCentral

Barber ME, Save V, Carneiro F et al (2008) Histopathological and molecular analysis of gastrectomy specimens from hereditary diffuse gastric cancer patients has implications for endoscopic surveillance of individuals at risk. J Pathol 216:286–294. https://doi.org/10.1002/path.2415CrossRefPubMed

Benusiglio PR, Malka D, Rouleau E et al (2013) CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study. J Med Genet 50:486–489. https://doi.org/10.1136/jmedgenet-2012-101472CrossRefPubMed

Benusiglio PR, Colas C, Rouleau E et al (2015) Hereditary diffuse gastric cancer syndrome: improved performances of the 2015 testing criteria for the identification of probands with a CDH1 germline mutation. J Med Genet 52(8):563–565. https://doi.org/10.1136/jmedgenet-2015-103153CrossRefPubMed

Brenner H, Bode G, Boeing H (2000) Helicobacter pylori infection among offspring of patients with stomach cancer. Gastroenterology 118:31–35. https://doi.org/10.1016/S0016-5085(00)70411-2CrossRefPubMed

Caldas C, Carneiro HT, Lynch F et al (1999) Familial gastric cancer: overview and guidelines for management. J Med Genet 36:873–880PubMedPubMedCentral

Chen W, Zheng R, Baade P et al (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66:115–132. https://doi.org/10.3322/caac.21338CrossRefPubMed

Choi H, Ki C, Suh S, Kim J (2014) Presymptomatic identification of CDH1 germline mutation in a healthy Korean individual with family history of gastric cancer. Ann Lab Med 34:386–389. https://doi.org/10.3343/alm.2014.34.5.386CrossRefPubMedPubMedCentral

Corso G, Pedrazzani C, Pinheiro H et al (2011) E-cadherin genetic screening and clinico-pathologic characteristics of early onset gastric cancer. Eur J Cancer 47:631–639. https://doi.org/10.1016/j.ejca.2010.10.011CrossRefPubMed

Corso G, Marrelli D, Pascale V et al (2012) Frequency of CDH1 germline mutations in gastric carcinoma coming from high- and low-risk areas: metanalysis and systematic review of the literature. BMC Cancer 12:1–10. https://doi.org/10.1186/1471-2407-12-8CrossRef

Corso G, Figueiredo J, Biffi R et al (2014) E-cadherin germline mutation carriers: clinical management and genetic implications. Cancer Metastasis Rev 33:1081–1094. https://doi.org/10.1007/s10555-014-9528-yCrossRefPubMed

Ferlay F, Parkin D, Steliarova-Foucher E (2010) Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 46:765–781. https://doi.org/10.1016/j.ejca.2009.12.014CrossRefPubMed

Ferlay F, Ervik M, Dikshit R et al (2013) GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No.11, International Agency for Research on Cancer

Fitzgerald RC, Hardwick R, Huntsman D et al (2010) Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet 47:436–444. https://doi.org/10.1136/jmg.2009.074237CrossRefPubMed

Guilford P, Hopkins J, Harraway J et al (1998) E-cadherin germline mutations in familial gastric cancer. Nature 392:402–405. https://doi.org/10.1038/32918CrossRefPubMed

Hansford S, Kaurah P, Li-Chang H et al (2015) Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol 1:23–32. https://doi.org/10.1001/jamaoncol.2014.168CrossRefPubMed

Humar B, Guilford P (2009) Hereditary diffuse gastric cancer: a manifestation of lost cell polarity. Cancer Sci 100:1151–1157. https://doi.org/10.1111/j.1349-7006.2009.01163.xCrossRefPubMed

Jiang Y, Wan YL, Wang ZJ et al (2004) Germline E-cadherin gene mutation screening in familial gastric cancer kindreds. Chinese J Surg 42:914–917

Kaurah P, MacMillan A, Boyd N et al (2007) Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 297:2360–2372. https://doi.org/10.1001/jama.297.21.2360CrossRefPubMed

Kim HC, Wheeler JMD, Kim JC et al (2000) The E-cadherin gene (CDH1) variants T340A and L599V in gastric and colorectal cancer patients in Korea. Gut 47:262–267. https://doi.org/10.1136/gut.47.2.262CrossRefPubMedPubMedCentral

Kim S, Chung JW, Jeong TD et al (2013) Searching for E-cadherin gene mutations in early onset diffuse gastric cancer and hereditary diffuse gastric cancer in Korean patients. Fam Cancer 12:503. https://doi.org/10.1007/s10689-012-9595-6CrossRefPubMed

Kluijt I, Siemerink E, Ausems M et al (2012) CDH1-related hereditary diffuse gastric cancer syndrome: clinical variations and implications for counseling. Int J Cancer 131:367–376. https://doi.org/10.1002/ijc.26398CrossRefPubMed

Kumar P, Henikoff S, Ng P (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081. https://doi.org/10.1038/nprot.2009.86CrossRefPubMed

Laurén P (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scandinavica 64:31–49. https://doi.org/10.1111/apm.1965.64.1.31CrossRef

Lim S, Lee HS, Kim HS et al (2003) Alteration of E-cadherin-mediated adhesion protein is common, but microsatellite instability is uncommon in young age gastric cancers. Histopathology 42:128–136. https://doi.org/10.1046/j.1365-2559.2003.01546.xCrossRefPubMed

Lynch HT, Grady W, Suriano G, Huntsman D (2005) Gastric cancer: new genetic developments. J Surg Oncol 90:114–133. https://doi.org/10.1002/jso.20214CrossRefPubMed

Maeta M, Yamashiro H, Oka A et al (1995) Gastric cancer in the young, with special reference to 14 pregnancy-associated cases: analysis based on 2,325 consecutive cases of gastric cancer. J Surg Oncol 58:191–195. https://doi.org/10.1002/jso.2930580310CrossRefPubMed

More H, Humar B, Weber W et al (2007) Identification of seven novel germline mutations in the human E-cadherin (CDH1) gene. Hum Mutat 28:203. https://doi.org/10.1002/humu.9473CrossRefPubMed

Oliveira C, Bordin M, Grehan N et al (2002) Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred. Hum Mutat 19:510–517. https://doi.org/10.1002/humu.10068CrossRefPubMed

Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. Ca Cancer J Clin 55:74–108. https://doi.org/10.3322/canjclin.55.2.74CrossRefPubMed

Rogers WM, Dobo E, Norton J et al (2008) Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications. Am J Surg Pathol 32:799–809. https://doi.org/10.1097/PAS.0b013e31815e7f1aCrossRefPubMed

Roviello F, Corso G, Pedrazzani C et al (2007) Hereditary diffuse gastric cancer and E-cadherin: description of the first germline mutation in an Italian family. Eur J Surg Oncol 33:448–451. https://doi.org/10.1016/j.ejso.2006.10.028CrossRefPubMed

Suriano G, Oliveira C, Ferreira P et al (2003a) Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands. Hum Mol Gen 12:575–582. https://doi.org/10.1093/hmg/ddg048CrossRefPubMed

Suriano G, Oliveira MJ, Huntsman D et al (2003b) 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 12:3007–3016. https://doi.org/10.1093/hmg/ddg316CrossRefPubMed

Suriano G, Seixas S, Rocha J et al (2006) A model to infer the pathogenic significance of CDH1 germline missense variants. J Mol Med 84:1023–1031. https://doi.org/10.1007/s00109-006-0091-zCrossRefPubMed

Torre LA, Bray F, Siegel RL et al (2015) Global cancer statistics, 2012. Ca A Cancer J Clin 65:69–90. https://doi.org/10.3322/caac.21262CrossRef

van der Post RS, Vogelaar IP, Carneiro F et al (2015a) Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet 52:361–374. https://doi.org/10.1136/jmedgenet-2015-103094CrossRefPubMed

van der Post RS, Vogelaar IP, Manders P et al (2015b) Accuracy of hereditary diffuse gastric cancer testing criteria and outcomes in patients with a germline mutation in CDH1. Gastroenterology 149:897–906. https://doi.org/10.1053/j.gastro.2015.06.003CrossRefPubMed

van Roy F, Berx G (2008) The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci 65:3756–3788. https://doi.org/10.1007/s00018-008-8281-1CrossRefPubMed

Windham TC, Termuhlen PM, Ajani JA et al (2002) Adenocarcinoma of the stomach in patients age 35 years and younger: no impact of early diagnosis on survival outcome. J Surg Oncol 81:118–124. https://doi.org/10.1002/jso.10157CrossRefPubMed

Yamada H, Shinmura K, Ito H et al (2011) Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population. Cancer Sci 102:1782–1788. https://doi.org/10.1111/j.1349-7006.2011.02038.xCrossRefPubMed

Zhang Y, Liu X, Fan Y et al (2006) Germline mutations and polymorphic variants in MMR, E-cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China. Int J Cancer 119:2592–2596. https://doi.org/10.1002/ijc.22206CrossRefPubMed

Titel: CDH1 germline mutations in a Chinese cohort with hereditary diffuse gastric cancer
verfasst von: Zhiwen Pan
Zhixuan Fu
Cong Luo
Yejiang Bao
Mingli Wang
Wenming Cao
Xiaohong Xu
Publikationsdatum: 18.09.2021
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 8/2022
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-021-03775-4

Springer Medizin

CDH1 germline mutations in a Chinese cohort with hereditary diffuse gastric cancer