title: Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing.
abstract: Gastric cancer (GC) is the second most common cause of cancer-related deaths. It is known to be a heterogeneous disease with several molecular and histological subtypes. Here we perform whole-genome sequencing of 49 GCs with diffuse (N=31) and intestinal (N=18) histological subtypes and identify three mutational signatures, impacting TpT, CpG and TpCp[A/T] nucleotides. The diffuse-type GCs show significantly lower clonality and smaller numbers of somatic and structural variants compared with intestinal subtype. We further divide the diffuse subtype into one with infrequent genetic changes/low clonality and another with relatively higher clonality and mutations impacting TpT dinucleotide. Notably, we discover frequent and exclusive mutations in Ephrins and SLIT/ROBO signalling pathway genes. Overall, this study delivers new insights into the mutational heterogeneity underlying distinct histologic subtypes of GC that could have important implications for future research in the diagnosis and treatment of GC.
authors.affiliation: Lilly Research Labs, Eli Lilly and Co, Indianapolis, Indiana 46285, USA.
authors.forename: Swee Seong
authors.initials: SS
authors.lastname: Wong
authors.affiliation: Department of Pathology &Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, South Korea.
authors.forename: Kyoung-Mee
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Lilly Research Labs, Eli Lilly and Co, Indianapolis, Indiana 46285, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Ting
authors.affiliation: Lilly Research Labs, Eli Lilly and Co, Indianapolis, Indiana 46285, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Yu
authors.affiliation: Shanghai Biocorp, Shanghai 201203, China.
authors.forename: Jake
authors.initials: J
authors.lastname: Fu
authors.affiliation: BGI Techsolutions, Hong Kong, China.
authors.forename: Shawn
authors.initials: S
authors.lastname: Liu
authors.affiliation: Merck Research Labs, Merck Sharpe &Dohme, Boston, Massachusetts 02115, USA.
authors.forename: Razvan
authors.initials: R
authors.lastname: Cristescu
authors.affiliation: Merck Research Labs, Merck Sharpe &Dohme, Boston, Massachusetts 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Nebozhyn
authors.affiliation: BGI Techsolutions, Hong Kong, China.
authors.forename: Lara
authors.initials: L
authors.lastname: Gong
authors.affiliation: Lilly Research Labs, Eli Lilly and Co, Indianapolis, Indiana 46285, USA.
authors.forename: Yong Gang
authors.initials: YG
authors.lastname: Yue
authors.affiliation: Lilly Research Labs, Eli Lilly and Co, Indianapolis, Indiana 46285, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Merck Research Labs, Merck Sharpe &Dohme, Boston, Massachusetts 02115, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Ronghua
authors.affiliation: Merck Research Labs, Merck Sharpe &Dohme, Boston, Massachusetts 02115, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Loboda
authors.affiliation: Merck Research Labs, Merck Sharpe &Dohme, Boston, Massachusetts 02115, USA.
authors.forename: James
authors.initials: J
authors.lastname: Hardwick
authors.affiliation: Merck Research Labs, Merck Sharpe &Dohme, Boston, Massachusetts 02115, USA.
authors.forename: Xiaoqiao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Merck Research Labs, Merck Sharpe &Dohme, Boston, Massachusetts 02115, USA.
authors.forename: Hongyue
authors.initials: H
authors.lastname: Dai
authors.affiliation: Shanghai Biocorp, Shanghai 201203, China.
authors.forename: Jason Gang
authors.initials: JG
authors.lastname: Jin
authors.affiliation: Lilly Research Labs, Eli Lilly and Co, Indianapolis, Indiana 46285, USA.
authors.forename: Xiang S
authors.initials: XS
authors.lastname: Ye
authors.affiliation: Department of Pathology &Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, South Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Kang
authors.affiliation: Department of Pathology &Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, South Korea.
authors.forename: In Gu
authors.initials: IG
authors.lastname: Do
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, South Korea.
authors.forename: Joon Oh
authors.initials: JO
authors.lastname: Park
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, South Korea.
authors.forename: Tae Sung
authors.initials: TS
authors.lastname: Sohn
authors.affiliation: Lilly Research Labs, Eli Lilly and Co, Indianapolis, Indiana 46285, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reinhard
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, South Korea.
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, South Korea.
authors.forename: Sung
authors.initials: S
authors.lastname: Kim
authors.affiliation: Lilly Research Labs, Eli Lilly and Co, Indianapolis, Indiana 46285, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Aggarwal
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D005260:Female; D018740:Genetic Heterogeneity; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D017422:Sequence Analysis, DNA; D013274:Stomach Neoplasms / Q000235:genetics*; D055815:Young Adult