Germline mutations in WNK2 could be associated with serrated polyposis syndrome

被引：2

作者：

Soares de Lima, Yasmin ^{[1
]}

Arnau-Collell, Coral ^{[1
]}

Munoz, Jenifer ^{[1
]}

Herrera-Pariente, Cristina ^{[1
]}

Moreira, Leticia ^{[1
]}

Ocana, Teresa ^{[1
]}

Diaz-Gay, Marcos ^{[1
,2
]}

Franch-Exposito, Sebastia ^{[1
,3
]}

Cuatrecasas, Miriam ^{[4
,5
]}

Carballal, Sabela ^{[1
]}

Lopez-Novo, Anael ^{[6
]}

Moreno, Lorena ^{[1
]}

Fernandez, Guerau ^{[7
,8
]}

Diaz de Bustamante, Aranzazu ^{[9
]}

Peters, Sophia ^{[10
]}

Sommer, Anna K. ^{[10
]}

Spier, Isabel ^{[10
,11
]}

te Paske, Iris B. A. W. ^{[12
]}

van Herwaarden, Yasmijn J. ^{[13
]}

Castells, Antoni ^{[1
]}

Bujanda, Luis ^{[14
]}

Capella, Gabriel ^{[15
]}

Steinke-Lange, Verena ^{[16
,17
]}

Mahmood, Khalid ^{[18
,19
,20
]}

Joo, JiHoon Eric ^{[18
,19
]}

Arnold, Julie ^{[21
]}

Parry, Susan ^{[21
]}

Macrae, Finlay A. ^{[22
,23
,24
]}

Winship, Ingrid M. ^{[23
,24
]}

Rosty, Christophe ^{[18
,19
,25
,26
]}

Cubiella, Joaquin ^{[27
]}

Rodriguez-Alcalde, Daniel ^{[28
]}

Holinski-Feder, Elke ^{[16
,17
]}

de Voer, Richarda ^{[12
]}

Buchanan, Daniel D. ^{[18
,19
,23
]}

Aretz, Stefan ^{[10
,11
]}

Ruiz-Ponte, Clara ^{[6
]}

Valle, Laura ^{[15
]}

Balaguer, Francesc ^{[1
]}

Bonjoch, Laia ^{[1
]}

Castellvi-Bel, Sergi ^{[1
]}

机构：

[1] Hosp Clin Barcelona, Dept Gastroenterol, Inst Invest Biomed August Pi i Sunyer IDIBAPS, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Barcelona, Spain

[2] Univ Calif San Diego UCSD, Dept Cellular & Mol Med, San Diego, CA USA

[3] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[4] Hosp Clin Barcelona, Dept Pathol, Inst Invest Biomed August Pi i Sunyer IDIBAPS, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Barcelona, Spain

[5] Tumor Bank Biobank, Barcelona, Spain

[6] Fdn Publ Galega Med Xenom FPGMX, Grp Med Xenom USC, Inst Invest Sanitaria Santiago IDIS, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Santiago De Compostela, Spain

[7] Hosp St Joan de Deu, Dept Genet & Mol Med IPER, Barcelona, Spain

[8] Inst Recerca St Joan de Deu, Ctr Biomed Res Network Rare Dis CIBERER, Barcelona, Spain

[9] Hosp Univ Mostoles, Dept Genet, Mostoles, Spain

[10] Univ Bonn, Med Fac, Inst Human Genet, Bonn, Germany

[11] Univ Hosp Bonn, Natl Ctr Hereditary Tumor Syndromes, Bonn, Germany

[12] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Human Genet, Med Ctr, Nijmegen, Netherlands

[13] Radboud Univ Nijmegen, Dept Gastroenterol & Hepatol, Med Ctr, Nijmegen, Netherlands

[14] Basque Country Univ UPV EHU, Gastroenterol Dept, Hosp Donostia Inst Biodonostia, Ctr Invest Biomed Red Enfermedades Hepat & Digest, San Sebastian, Spain

[15] Inst Invest Biomed Bellvitge IDIBELL, Hereditary Canc Program, Inst Oncol, Oncobell,Ctr Invest Biomed Red Canc CIBERONC, Barcelona, Spain

[16] Klinikum Univ Munchen, Med Klin & Poliklin 4, Campus Innenstadt, Munich, Germany

[17] MGZ Ctr Med Genet Ctr, Munich, Germany

[18] Univ Melbourne, Colorectal Oncogen Grp, Dept Clin Pathol, Melbourne Med Sch, Parkville, Vic, Australia

[19] Univ Melbourne, Ctr Canc Res, Parkville, Vic, Australia

[20] Univ Melbourne, Melbourne Bioinformat, Carlton, Vic, Australia

[21] New Zealand Familial Gastrointestinal Canc Serv, Auckland, New Zealand

[22] Royal Melbourne Hosp, Colorectal Med & Genet, Parkville, Vic, Australia

[23] Royal Melbourne Hosp, Genom Med & Family Canc Clin, Parkville, Vic, Australia

[24] Univ Melbourne, Dept Med, Parkville, Vic, Australia

[25] Envoi Specialist Pathologists, Brisbane, Qld, Australia

[26] Univ Queensland, Brisbane, Qld, Australia

[27] Complexo Hosp Univ Ourense, Gastroenterol Dept, Inst Invest Sanitaria Galicia Sur, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Orense, Spain

[28] Hosp Univ Mostoles, Digest Dis Sect, Mostoles, Spain

来源：

JOURNAL OF MEDICAL GENETICS | 2023年 / 60卷 / 06期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

Genetic Predisposition to Disease; Gene Editing; Gastroenterology; Loss of Function Mutation; Digestive System Disease; SIGNALING PATHWAYS; RNF43; MUTATIONS; KINASE; EXPRESSION;

D O I：

10.1136/jmg-2022-108684

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Background Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts. Methods After a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. The WNK2 gene was disrupted in HT-29 cells by gene editing, and WNK2 variants were transfected using a lentiviral delivery system. Cells were analysed by immunoblots, real-time PCR and functional assays monitoring the mitogen-activated protein kinase (MAPK) pathway, cell cycle progression, survival and adhesion. Results We identified 2 rare germline variants in the WNK2 gene in the discovery cohort, 3 additional variants in the validation cohort and 10 other variants in the external cohorts. Variants c.2105C>T (p.Pro702Leu), c.4820C>T (p.Ala1607Val) and c.6157G>A (p.Val2053Ile) were functionally characterised, displaying higher levels of phospho-PAK1/2, phospho-ERK1/2, CCND1, clonogenic capacity and MMP2. Conclusion After whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in the WNK2 gene. Functional studies suggested germline WNK2 variants affect protein function in the context of the MAPK pathway, a molecular hallmark in this disease.

引用

页码：557 / 567

页数：11

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