Whole-genome reconstruction and mutational signatures in gastric cancer

Whole-genome reconstruction and mutational signatures in gastric cancer

Genome Biology

10.1186/gb-2012-13-12-r115

http://genomebiology.com/2012/13/12/R115

Niranjan Nagarajan, Denis Bertrand, Axel M Hillmer, Zhi Jiang Zang, Fei Yao, Pierre-Étienne Jacques, Audrey SM Teo, Ioana 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 Khor, Martin L Hibberd, Atif Shahab, Yijun Ruan, Jaideepraj Rao, Mengchu Wu, Ming Teh, Feng Zhu, Sze Yung Chin, Brendan Pang, Jimmy BY So, Guillaume Bourque, Richie Soong, Wing-Kin Sung, Bin Tean Teh, Steven Rozen, Xiaoan Ruan, Khay Guan Yeoh, Patrick BO Tan

13 December 2012

Nagarajan et al.: Whole-genome reconstruction and mutational signatures in gastric cancer. Genome Biology 2012 13:R115.

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.

http://creativecommons.org/licenses/by/3.0/

https://oar.a-star.edu.sg/communities-collections/articles/11542

1465-6906

Genome Institute of Singapore