Whole-genome reconstruction and mutational signatures in gastric cancer

Niranjan Nagarajan, Denis Bertrand, Axel M. Hillmer, Zhi Jiang Zang, Fei Yao, Pierre Etienne Jacques, Audrey S M Teo, Ioanna Cutcutache, Zhenshui Zhang, Wah Heng Lee, Yee Yen Sia, Song Gao, Pramila N. Ariyaratne, Andrea Ho, Xing Yi Woo, Lavanya Veeravali, Choon Kiat Ong, Niantao Deng, Kartiki V. Desai, Chiea Chuen KhorMartin L. Hibberd, Atif Shahab, Jaideepraj Rao, Mengchu Wu, Ming Teh, Feng Zhu, Sze Yung Chin, Brendan Pang, Jimmy B Y So, Guillaume Bourque, Richie Soong, Wing Kin Sung, Bin Tean Teh, Steven Rozen, Xiaoan Ruan, Khay Guan Yeoh, Patrick B O Tan, Yijun Ruan

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

BACKGROUND: Gastric cancer is the second highest cause of global cancer mortality. To explore the complete repertoire of somatic alterations in gastric cancer, we combined massively parallel short read and DNA paired-end tag sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability.

RESULTS: Integrative analysis and de novo assemblies revealed the architecture of a wild-type KRAS amplification, a common driver event in gastric cancer. We discovered three distinct mutational signatures in gastric cancer--against a genome-wide backdrop of oxidative and microsatellite instability-related mutational signatures, we identified the first exome-specific mutational signature. Further characterization of the impact of these signatures by combining sequencing data from 40 complete gastric cancer exomes and targeted screening of an additional 94 independent gastric tumors uncovered ACVR2A, RPL22 and LMAN1 as recurrently mutated genes in microsatellite instability-positive gastric cancer and PAPPA as a recurrently mutated gene in TP53 wild-type gastric cancer.

CONCLUSIONS: These results highlight how whole-genome cancer sequencing can uncover information relevant to tissue-specific carcinogenesis that would otherwise be missed from exome-sequencing data.

Original languageEnglish
Pages (from-to)R115
JournalGenome biology
Volume13
Issue number12
DOIs
Publication statusPublished - 1 Jan 2012
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Cite this

Nagarajan, N., Bertrand, D., Hillmer, A. M., Zang, Z. J., Yao, F., Jacques, P. E., ... Ruan, Y. (2012). Whole-genome reconstruction and mutational signatures in gastric cancer. Genome biology, 13(12), R115. https://doi.org/10.1186/gb-2012-13-12-r115