The genomic landscape of small intestine neuroendocrine tumors

被引：249

作者：

Banck, Michaela S. ^{[1
,2
]}

Kanwar, Rahul ^{[1
]}

Kulkarni, Amit A. ^{[1
]}

Boora, Ganesh K. ^{[1
]}

Metge, Franziska ^{[1
]}

Kipp, Benjamin R. ^{[3
]}

Zhang, Lizhi ^{[3
]}

Thorland, Erik C. ^{[3
]}

Minn, Kay T. ^{[1
]}

Tentu, Ramesh ^{[1
]}

Eckloff, Bruce W. ^{[4
]}

Wieben, Eric D. ^{[4
]}

Wu, Yanhong ^{[4
]}

Cunningham, Julie M. ^{[4
]}

Nagorney, David M. ^{[5
]}

Gilbert, Judith A. ^{[6
]}

Ames, Matthew M. ^{[6
]}

Beutler, Andreas S. ^{[1
,2
]}

机构：

[1] Mayo Clin, Div Med Oncol, Rochester, MN 55905 USA

[2] Mayo Clin, Ctr Canc, Rochester, MN 55905 USA

[3] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA

[4] Mayo Clin, Med Genome Facil, Rochester, MN 55905 USA

[5] Mayo Clin, Dept Surg, Rochester, MN 55905 USA

[6] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2013年 / 123卷 / 06期

关键词：

CARCINOID-TUMORS; CANCER GENOMES; PATHWAY GENES; CELLS; INHIBITION; MUTATIONS; LEUKEMIA;

D O I：

10.1172/JCI67963

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

Small intestine neuroenclocrine tumors (SI-NETs) are the most common malignancy of the small bowel. Several clinical trials target PI3K/Akt/mTOR signaling; however, it is unknown whether these or other genes are genetically altered in these tumors. To address the underlying genetics, we analyzed 48 SI-NETs by massively parallel exome sequencing. We detected an average of 0.1 somatic single nucleotide variants (SNVs) per 10(6) nucleotides (range, 0-0.59), mostly transitions (C>T and A>G), which suggests that SI-NETs are stable cancers. 197 protein-altering somatic SNVs affected a preponderance of cancer genes, including FGFR2, MEN1, HOOK3, EZH2, MLF1, CARD11, VHL, NONO, and SMAD1. Integrative analysis of SNVs and somatic copy number variations identified recurrently altered mechanisms of carcinogenesis: chromatin remodeling, DNA damage, apoptosis, RAS signaling, and axon guidance. Candidate therapeutically relevant alterations were found in 35 patients, including SRC, SMAD family genes, AURKA, EGFR, HSP90, and PDGFR. Mutually exclusive amplification of AKT1 or AKT2 was the most common event in the 16 patients with alterations of PI3K/Akt/mTOR signaling. We conclude that sequencing-based analysis may provide provisional grouping of SI-NETs by therapeutic targets or deregulated pathways.

引用

页码：2502 / 2508

页数：7

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