Identification of New Genes Involved in Germline Predisposition to Early-Onset Gastric Cancer

The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC...

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Published in:	International journal of molecular sciences Vol. 22; no. 3; p. 1310
Main Authors:	Herrera-Pariente, Cristina, Capó-García, Roser, Díaz-Gay, Marcos, Carballal, Sabela, Muñoz, Jenifer, Llach, Joan, Sánchez, Ariadna, Bonjoch, Laia, Arnau-Collell, Coral, Soares de Lima, Yasmin, Golubicki, Mariano, Jung, Gerhard, Lozano, Juan José, Castells, Antoni, Balaguer, Francesc, Bujanda, Luis, Castellví-Bel, Sergi, Moreira, Leticia
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI 28-01-2021 MDPI AG
Subjects:	early-onset gastric cancer germline predisposition next-generation sequencing somatic profiling whole-exome sequencing early-onset gastric cancer next-generation sequencing somatic profiling whole-exome sequencing germline predisposition
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Abstract	The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC patients without previous germline mutation identified. WES was also performed in nine tumor samples to analyze the somatic profile using SigProfilerExtractor tool. Sequencing germline data were filtered to select those variants with plausible pathogenicity, rare frequency and previously involved in cancer. Then, a manual filtering was performed to prioritize genes according to current knowledge and function. These genetic variants were prevalidated with Integrative Genomics Viewer 2.8.2 (IGV). Subsequently, a further selection step was carried out according to function and information obtained from tumor samples. After IGV and selection step, 58 genetic variants in 52 different candidate genes were validated by Sanger sequencing. Among them, , , and seem to be the most promising genes because of their role in hereditary cancer syndromes, tumor suppression, cell adhesion and recognition, respectively. These encouraging results represent the open door to the identification of new genes involved in GC germline predisposition.
AbstractList	The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC patients without previous germline mutation identified. WES was also performed in nine tumor samples to analyze the somatic profile using SigProfilerExtractor tool. Sequencing germline data were filtered to select those variants with plausible pathogenicity, rare frequency and previously involved in cancer. Then, a manual filtering was performed to prioritize genes according to current knowledge and function. These genetic variants were prevalidated with Integrative Genomics Viewer 2.8.2 (IGV). Subsequently, a further selection step was carried out according to function and information obtained from tumor samples. After IGV and selection step, 58 genetic variants in 52 different candidate genes were validated by Sanger sequencing. Among them, , , and seem to be the most promising genes because of their role in hereditary cancer syndromes, tumor suppression, cell adhesion and recognition, respectively. These encouraging results represent the open door to the identification of new genes involved in GC germline predisposition. The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC patients without previous germline mutation identified. WES was also performed in nine tumor samples to analyze the somatic profile using SigProfilerExtractor tool. Sequencing germline data were filtered to select those variants with plausible pathogenicity, rare frequency and previously involved in cancer. Then, a manual filtering was performed to prioritize genes according to current knowledge and function. These genetic variants were prevalidated with Integrative Genomics Viewer 2.8.2 (IGV). Subsequently, a further selection step was carried out according to function and information obtained from tumor samples. After IGV and selection step, 58 genetic variants in 52 different candidate genes were validated by Sanger sequencing. Among them, APC, FAT4, CTNND1 and TLR2 seem to be the most promising genes because of their role in hereditary cancer syndromes, tumor suppression, cell adhesion and Helicobacter pylori recognition, respectively. These encouraging results represent the open door to the identification of new genes involved in GC germline predisposition. The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC patients without previous germline mutation identified. WES was also performed in nine tumor samples to analyze the somatic profile using SigProfilerExtractor tool. Sequencing germline data were filtered to select those variants with plausible pathogenicity, rare frequency and previously involved in cancer. Then, a manual filtering was performed to prioritize genes according to current knowledge and function. These genetic variants were prevalidated with Integrative Genomics Viewer 2.8.2 (IGV). Subsequently, a further selection step was carried out according to function and information obtained from tumor samples. After IGV and selection step, 58 genetic variants in 52 different candidate genes were validated by Sanger sequencing. Among them, APC , FAT4 , CTNND1 and TLR2 seem to be the most promising genes because of their role in hereditary cancer syndromes, tumor suppression, cell adhesion and Helicobacter pylori recognition, respectively. These encouraging results represent the open door to the identification of new genes involved in GC germline predisposition.
Author	Castells, Antoni Lozano, Juan José Carballal, Sabela Moreira, Leticia Díaz-Gay, Marcos Llach, Joan Bonjoch, Laia Herrera-Pariente, Cristina Capó-García, Roser Arnau-Collell, Coral Castellví-Bel, Sergi Soares de Lima, Yasmin Jung, Gerhard Balaguer, Francesc Golubicki, Mariano Muñoz, Jenifer Sánchez, Ariadna Bujanda, Luis
AuthorAffiliation	4 Molecular Biology Laboratory, Hospital of Gastroenterology “Dr. C. B. Udaondo”, C1264 Buenos Aires, Argentina 3 Oncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, C1264 Buenos Aires, Argentina; mariano.golubicki@gmail.com 6 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Biodonostia Health Research Institute, Basque Country University (UPV/EHU), 20014 San Sebastián, Spain; luis.bujanda@osakidetza.net 5 Bioinformatics Platform, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, 08036 Barcelona, Spain; juanjo.lozano@ciberehd.org 1 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; cristina.herrera@ciberehd.org (C.H.-P.); rosercg95@hotmail.com (R.C.-G.);
AuthorAffiliation_xml	– name: 2 Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA – name: 5 Bioinformatics Platform, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, 08036 Barcelona, Spain; juanjo.lozano@ciberehd.org – name: 6 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Biodonostia Health Research Institute, Basque Country University (UPV/EHU), 20014 San Sebastián, Spain; luis.bujanda@osakidetza.net – name: 1 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; cristina.herrera@ciberehd.org (C.H.-P.); rosercg95@hotmail.com (R.C.-G.); mdiazgay@health.ucsd.edu (M.D.-G.); carballal@clinic.cat (S.C.); jenifer.munoz@ciberehd.org (J.M.); jllachr@clinic.cat (J.L.); asanchezg@clinic.cat (A.S.); bonjoch@clinic.cat (L.B.); arnau@clinic.cat (C.A.-C.); soaresdeli@clinic.cat (Y.S.d.L.); jung@clinic.cat (G.J.); castells@clinic.cat (A.C.); fprunes@clinic.cat (F.B.) – name: 3 Oncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, C1264 Buenos Aires, Argentina; mariano.golubicki@gmail.com – name: 4 Molecular Biology Laboratory, Hospital of Gastroenterology “Dr. C. B. Udaondo”, C1264 Buenos Aires, Argentina
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Keywords	early-onset gastric cancer next-generation sequencing somatic profiling whole-exome sequencing germline predisposition
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Snippet	The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new...
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SubjectTerms	early-onset gastric cancer germline predisposition next-generation sequencing somatic profiling whole-exome sequencing
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Title	Identification of New Genes Involved in Germline Predisposition to Early-Onset Gastric Cancer
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