Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes

Zhi Jiang Zang; Ioana Cutcutache; Song Ling Poon; Shen Li Zhang; John R. Mcpherson; Jiong Tao; Vikneswari Rajasegaran; Hong Lee Heng; Niantao Deng; Anna Gan; Kiat Hon Lim; Choon Kiat Ong; Da Chuan Huang; Sze Yung Chin; Iain Beehuat Tan; Cedric Chuan Young Ng; Willie Yu; Yingting Wu; Minghui Lee; Jeanie Wu; Dianne Poh; Wei Keat Wan; Sun Young Rha; Jimmy So; Manuel Salto-Tellez; Khay Guan Yeoh; Wai Keong Wong; Yi Jun Zhu; P. Andrew Futreal; Brendan Pang; Yijun Ruan; Axel M. Hillmer; Denis Bertrand; Niranjan Nagarajan; Steve Rozen; Bin Tean Teh; Patrick Tan

doi:10.1038/ng.2246

Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes

Zhi Jiang Zang, Ioana Cutcutache, Song Ling Poon, Shen Li Zhang, John R. Mcpherson, Jiong Tao, Vikneswari Rajasegaran, Hong Lee Heng, Niantao Deng, Anna Gan, Kiat Hon Lim, Choon Kiat Ong, Da Chuan Huang, Sze Yung Chin, Iain Beehuat Tan, Cedric Chuan Young Ng, Willie Yu, Yingting Wu, Minghui Lee, Jeanie WuDianne Poh, Wei Keat Wan, Sun Young Rha, Jimmy So, Manuel Salto-Tellez, Khay Guan Yeoh, Wai Keong Wong, Yi Jun Zhu, P. Andrew Futreal, Brendan Pang, Yijun Ruan, Axel M. Hillmer, Denis Bertrand, Niranjan Nagarajan, Steve Rozen, Bin Tean Teh, Patrick Tan^*

^*Corresponding author for this work

Pathology

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Abstract

Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.

Original language	English (US)
Pages (from-to)	570-574
Number of pages	5
Journal	Nature Genetics
Volume	44
Issue number	5
DOIs	https://doi.org/10.1038/ng.2246
State	Published - May 2012

Funding

We thank S.T. Tay, K. Ramnarayanan, A. Pandey, Z. Lei, Y. Liu, Y. Suzuki, S. Ramgopal and the Duke–NUS Genome Biology Facility for technical assistance. We also thank AITbiotech for sequencing services. N.D., I.B.T. and W.Y. are recipients of the NUS Graduate School for Integrative Sciences and Engineering Scholarship. This work was supported by funding from the National Medical Research Council (NMRC/ TCR/001/2007 and NMRC/STAR/0006/2009), the Cancer Science Institute of Singapore, the Genome Institute of Singapore, Duke–NUS Graduate Medical School Singapore and The Lee Foundation.

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Genetics

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Zang, Z. J., Cutcutache, I., Poon, S. L., Zhang, S. L., Mcpherson, J. R., Tao, J., Rajasegaran, V., Heng, H. L., Deng, N., Gan, A., Lim, K. H., Ong, C. K., Huang, D. C., Chin, S. Y., Tan, I. B., Ng, C. C. Y., Yu, W., Wu, Y., Lee, M., ... Tan, P. (2012). Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nature Genetics, 44(5), 570-574. https://doi.org/10.1038/ng.2246

@article{08b87bd7c1c1466db8a363f43cb4464a,

title = "Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes",

abstract = "Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.",

author = "Zang, {Zhi Jiang} and Ioana Cutcutache and Poon, {Song Ling} and Zhang, {Shen Li} and Mcpherson, {John R.} and Jiong Tao and Vikneswari Rajasegaran and Heng, {Hong Lee} and Niantao Deng and Anna Gan and Lim, {Kiat Hon} and Ong, {Choon Kiat} and Huang, {Da Chuan} and Chin, {Sze Yung} and Tan, {Iain Beehuat} and Ng, {Cedric Chuan Young} and Willie Yu and Yingting Wu and Minghui Lee and Jeanie Wu and Dianne Poh and Wan, {Wei Keat} and Rha, {Sun Young} and Jimmy So and Manuel Salto-Tellez and Yeoh, {Khay Guan} and Wong, {Wai Keong} and Zhu, {Yi Jun} and Futreal, {P. Andrew} and Brendan Pang and Yijun Ruan and Hillmer, {Axel M.} and Denis Bertrand and Niranjan Nagarajan and Steve Rozen and Teh, {Bin Tean} and Patrick Tan",

note = "Funding Information: We thank S.T. Tay, K. Ramnarayanan, A. Pandey, Z. Lei, Y. Liu, Y. Suzuki, S. Ramgopal and the Duke–NUS Genome Biology Facility for technical assistance. We also thank AITbiotech for sequencing services. N.D., I.B.T. and W.Y. are recipients of the NUS Graduate School for Integrative Sciences and Engineering Scholarship. This work was supported by funding from the National Medical Research Council (NMRC/ TCR/001/2007 and NMRC/STAR/0006/2009), the Cancer Science Institute of Singapore, the Genome Institute of Singapore, Duke–NUS Graduate Medical School Singapore and The Lee Foundation.",

year = "2012",

month = may,

doi = "10.1038/ng.2246",

language = "English (US)",

volume = "44",

pages = "570--574",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "5",

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Zang, ZJ, Cutcutache, I, Poon, SL, Zhang, SL, Mcpherson, JR, Tao, J, Rajasegaran, V, Heng, HL, Deng, N, Gan, A, Lim, KH, Ong, CK, Huang, DC, Chin, SY, Tan, IB, Ng, CCY, Yu, W, Wu, Y, Lee, M, Wu, J, Poh, D, Wan, WK, Rha, SY, So, J, Salto-Tellez, M, Yeoh, KG, Wong, WK, Zhu, YJ, Futreal, PA, Pang, B, Ruan, Y, Hillmer, AM, Bertrand, D, Nagarajan, N, Rozen, S, Teh, BT & Tan, P 2012, 'Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes', Nature Genetics, vol. 44, no. 5, pp. 570-574. https://doi.org/10.1038/ng.2246

TY - JOUR

T1 - Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes

AU - Zang, Zhi Jiang

AU - Cutcutache, Ioana

AU - Poon, Song Ling

AU - Zhang, Shen Li

AU - Mcpherson, John R.

AU - Tao, Jiong

AU - Rajasegaran, Vikneswari

AU - Heng, Hong Lee

AU - Deng, Niantao

AU - Gan, Anna

AU - Lim, Kiat Hon

AU - Ong, Choon Kiat

AU - Huang, Da Chuan

AU - Chin, Sze Yung

AU - Tan, Iain Beehuat

AU - Ng, Cedric Chuan Young

AU - Yu, Willie

AU - Wu, Yingting

AU - Lee, Minghui

AU - Wu, Jeanie

AU - Poh, Dianne

AU - Wan, Wei Keat

AU - Rha, Sun Young

AU - So, Jimmy

AU - Salto-Tellez, Manuel

AU - Yeoh, Khay Guan

AU - Wong, Wai Keong

AU - Zhu, Yi Jun

AU - Futreal, P. Andrew

AU - Pang, Brendan

AU - Ruan, Yijun

AU - Hillmer, Axel M.

AU - Bertrand, Denis

AU - Nagarajan, Niranjan

AU - Rozen, Steve

AU - Teh, Bin Tean

AU - Tan, Patrick

N1 - Funding Information: We thank S.T. Tay, K. Ramnarayanan, A. Pandey, Z. Lei, Y. Liu, Y. Suzuki, S. Ramgopal and the Duke–NUS Genome Biology Facility for technical assistance. We also thank AITbiotech for sequencing services. N.D., I.B.T. and W.Y. are recipients of the NUS Graduate School for Integrative Sciences and Engineering Scholarship. This work was supported by funding from the National Medical Research Council (NMRC/ TCR/001/2007 and NMRC/STAR/0006/2009), the Cancer Science Institute of Singapore, the Genome Institute of Singapore, Duke–NUS Graduate Medical School Singapore and The Lee Foundation.

PY - 2012/5

Y1 - 2012/5

N2 - Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.

AB - Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.

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ER -

Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes

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UN SDGs

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