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Whole-genome reconstruction and mutational signatures in gastric cancer.


ABSTRACT: 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.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.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.

SUBMITTER: Nagarajan N 

PROVIDER: S-EPMC4056366 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Whole-genome reconstruction and mutational signatures in gastric cancer.

Nagarajan Niranjan N   Bertrand Denis D   Hillmer Axel M AM   Zang Zhi Jiang ZJ   Yao Fei F   Jacques Pierre-Étienne PÉ   Teo Audrey S M AS   Cutcutache Ioana I   Zhang Zhenshui Z   Lee Wah Heng WH   Sia Yee Yen YY   Gao Song S   Ariyaratne Pramila N PN   Ho Andrea A   Woo Xing Yi XY   Veeravali Lavanya L   Ong Choon Kiat CK   Deng Niantao N   Desai Kartiki V KV   Khor Chiea Chuen CC   Hibberd Martin L ML   Shahab Atif A   Rao Jaideepraj J   Wu Mengchu M   Teh Ming M   Zhu Feng F   Chin Sze Yung SY   Pang Brendan B   So Jimmy B Y JB   Bourque Guillaume G   Soong Richie R   Sung Wing-Kin WK   Tean Teh Bin B   Rozen Steven S   Ruan Xiaoan X   Yeoh Khay Guan KG   Tan Patrick B O PB   Ruan Yijun Y  

Genome biology 20121213 12


<h4>Background</h4>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.<h4>Results</h4>Integrative analysis and de novo assemblies revealed the architecture of a wild-type KR  ...[more]

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