Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing

Swee Seong Wong, Kyoung-Mee Kim, Jason C. Ting, Kun Yu, Jake Fu, Shawn Liu, Razvan Cristescu, Michael Nebozhyn, Lara Gong, Yong Gang Yue, Jian Wang, Chen Ronghua, Andrey Loboda, James Hardwick, Xiaoqiao Liu, Hongyue Dai, Jason Gang Jin, Xiang S. Ye, So Young Kang, In Gu Do, Joon Oh Park, Tae Sung Sohn, Christoph Reinhard, Jeeyun Lee, Sung Kim () and Amit Aggarwal ()
Additional contact information
Swee Seong Wong: Lilly Research Labs, Eli Lilly and Co
Kyoung-Mee Kim: Samsung Medical Center, Sungkyunkwan University School of Medicine
Jason C. Ting: Lilly Research Labs, Eli Lilly and Co
Kun Yu: Lilly Research Labs, Eli Lilly and Co
Jake Fu: Shanghai Biocorp
Shawn Liu: BGI Techsolutions
Razvan Cristescu: Merck Research Labs, Merck Sharpe & Dohme
Michael Nebozhyn: Merck Research Labs, Merck Sharpe & Dohme
Lara Gong: BGI Techsolutions
Yong Gang Yue: Lilly Research Labs, Eli Lilly and Co
Jian Wang: Lilly Research Labs, Eli Lilly and Co
Chen Ronghua: Merck Research Labs, Merck Sharpe & Dohme
Andrey Loboda: Merck Research Labs, Merck Sharpe & Dohme
James Hardwick: Merck Research Labs, Merck Sharpe & Dohme
Xiaoqiao Liu: Merck Research Labs, Merck Sharpe & Dohme
Hongyue Dai: Merck Research Labs, Merck Sharpe & Dohme
Jason Gang Jin: Shanghai Biocorp
Xiang S. Ye: Lilly Research Labs, Eli Lilly and Co
So Young Kang: Samsung Medical Center, Sungkyunkwan University School of Medicine
In Gu Do: Samsung Medical Center, Sungkyunkwan University School of Medicine
Joon Oh Park: Samsung Medical Center, Sungkyunkwan University School of Medicine
Tae Sung Sohn: Samsung Medical Center, Sungkyunkwan University School of Medicine
Christoph Reinhard: Lilly Research Labs, Eli Lilly and Co
Jeeyun Lee: Samsung Medical Center, Sungkyunkwan University School of Medicine
Sung Kim: Samsung Medical Center, Sungkyunkwan University School of Medicine
Amit Aggarwal: Lilly Research Labs, Eli Lilly and Co

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6477

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