TY - JOUR
T1 - Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing
AU - Vogelaar, Ingrid P.
AU - van der Post, Rachel S.
AU - Van Krieken, J. Han J M
AU - Spruijt, Liesbeth
AU - van Zelst-Stams, Wendy A. G.
AU - Kets, C. Marleen
AU - Lubinski, Jan
AU - Jakubowska, Anna
AU - Teodorczyk, Urszula
AU - Aalfs, Cora M.
AU - Van Hest, Liselotte P.
AU - Pinheiro, Hugo
AU - Oliveira, Carla
AU - Jhangiani, Shalini N.
AU - Muzny, Donna M.
AU - Gibbs, Richard A.
AU - Lupski, James R
AU - De Ligt, Joep
AU - Vissers, Lisenka E L M
AU - Hoischen, Alexander
AU - Gilissen, Christian
AU - Van De Vorst, Maartje
AU - Goeman, Jelle J.
AU - Schackert, Hans K
AU - Ranzani, Guglielmina N.
AU - Molinaro, Valeria
AU - García, Encarna B.Gómez
AU - Hes, Frederik J.
AU - Holinski-Feder, Elke
AU - Genuardi, Maurizio
AU - Ausems, Margreet G.E.M.
AU - Sijmons, Rolf H.
AU - Wagner, Anja
AU - Van Der Kolk, Lizet E.
AU - Bjørnevoll, Inga
AU - Høberg Vetti, Hildegunn
AU - van Kessel, Ad Geurts
AU - Kuiper, Roland P.
AU - Ligtenberg, Marjolijn J. L.
AU - Hoogerbrugge, Nicoline
N1 - Funding Information:
We thank Lilian Vreede, Hanna Feunekes, Eveline Kamping and Neeltje Arts from the Radboud university medical center for excellent technical assistance. This work was supported by the Radboud university medical center for Oncology, granted in 2010, the Dutch Cancer Society (KUN 2013-5876, RSvdP), ZONMW (917-10-358), the Deutsche Krebshilfe Grant 70-2371, FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, by Portuguese funds through the Portuguese Foundation for Science and Technology (FCT)/Ministério da Ciência, Tecnologia e Inovação, in the framework of the projects: (1) 'Institute for Research and Innovation in Health Sciences' (POCI-01-0145-FEDER-007274); (2) FCOMP-01-0124-FEDER-015779 (ref. FCT PTDC/SAU-GMG/110785/2009), a Post-doc grant to HP (ref. SFRH/BPD/79499/2011), by the US National Human Genome Research Institute (NHGRI) National Heart Lung and Blood Institute (NHBLI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, NINDS grant RO1 NS058529 to JRL and NHGRI 5U54HG003273 to RAG.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.
AB - Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.
UR - http://www.scopus.com/inward/record.url?scp=85031288768&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2017.138
DO - 10.1038/ejhg.2017.138
M3 - Article
C2 - 28875981
AN - SCOPUS:85031288768
SN - 1018-4813
VL - 25
SP - 1246
EP - 1252
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 11
ER -