Oncotarget

Research Papers:

Whole-exome sequencing identified mutational profiles of high-grade colon adenomas

Sung Hak Lee _, Seung Hyun Jung, Tae-Min Kim, Je-Keun Rhee, Hyeon-Chun Park, Min Sung Kim, Sung Soo Kim, Sug Hyung Lee, Chang Hyeok An, Sug Hyung Lee and Yeun-Jun Chung

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Oncotarget. 2017; 8:6579-6588. https://doi.org/10.18632/oncotarget.14172

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Abstract

Sung Hak Lee1,*, Seung Hyun Jung4,6,*, Tae-Min Kim2, Je-Keun Rhee2, Hyeon-Chun Park3,4, Min Sung Kim5,6, Sung Soo Kim7, Chang Hyeok An8, Sug Hyung Lee5,6, Yeun-Jun Chung3,4,5

1Departments of Hospital Pathology, The Catholic University of Korea, Seoul, Korea

2Departments of Medical Informatics, The Catholic University of Korea, Seoul, Korea

3Departments of Microbiology, The Catholic University of Korea, Seoul, Korea

4Departments of Integrated Research Center for Genome Polymorphism, The Catholic University of Korea, Seoul, Korea

5Departments of Pathology, The Catholic University of Korea, Seoul, Korea

6Departments of Cancer Evolution Research Center, The Catholic University of Korea, Seoul, Korea

7Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea

8Departments of General Surgery The Catholic University of Korea, Seoul, Korea

*These two authors contributed equally to this work

Correspondence to:

Yeun-Jun Chung, email: yejun@catholic.ac.kr

Sug Hyung Lee, email: suhulee@catholic.ac.kr

Chang Hyeok An, email: achcolo@catholic.ac.kr

Keywords: colon, adenoma, high grade adenoma, mutation, whole-exome sequencing

Received: November 14, 2016     Accepted: December 02, 2016     Published: December 25, 2016

ABSTRACT

Although gene-to-gene analyses identified genetic alterations such as APC, KRAS and TP53 mutations in colon adenomas, it is largely unknown whether there are any others in them. Mutational profiling of high-grade colon adenoma (HGCA) that just precedes colon carcinoma might identify not only novel adenoma-specific genes but also critical genes for its progression to carcinoma. For this, we performed whole-exome sequencing (WES) of 12 HGCAs and identified 11 non-hypermutated and one hypermutated (POLE-mutated) cases. We identified 22 genes including APC, KRAS, TP53, GNAS, NRAS, SMAD4, ARID2, and PIK3CA with non-silent mutations in the cancer Census Genes. Bi-allelic and mono-allelic APC alterations were found in nine and one HGCAs, respectively, while the other two harbored wild-type APC. Five HGCAs harbored either mono-allelic (four HGCAs) or bi-allelic (one HGCA) SMAD4 mutation or 18q loss that had been known as early carcinoma-specific changes. We identified MTOR, ACVR1B, GNAQ, ATM, CNOT1, EP300, ARID2, RET and MAP2K4 mutations for the first time in colon adenomas. Our WES data is largely matched with the earlier ‘adenoma-carcinoma model’ (APC, KRAS, NRAS and GNAS mutations), but there are newly identified SMAD4, MTOR, ACVR1B, GNAQ, ATM, CNOT1, EP300, ARID2, RET and MAP2K4 mutations in this study. Our findings provide resource for understanding colon premalignant lesions and for identifying genomic clues for differential diagnosis and therapy options for colon adenomas and carcinomas.


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