Oncotarget

Research Papers:

Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma

Tae-Min Kim, Chang Hyeok An, Je-Keun Rhee, Seung-Hyun Jung, Sung Hak Lee, In-Pyo Baek, Min Sung Kim, Sug Hyung Lee and Yeun-Jun Chung _

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Oncotarget. 2015; 6:27725-27735. https://doi.org/10.18632/oncotarget.4834

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Abstract

Tae-Min Kim1,2,*, Chang Hyeok An3,*, Je-Keun Rhee1,2, Seung-Hyun Jung2,4,7, Sung Hak Lee5, In-Pyo Baek4,7, Min Sung Kim2,6, Sug Hyung Lee2,6, Yeun-Jun Chung2,4,7

1Departments of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, South Korea

2Departments of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea

3Departments of Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea

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

5Departments of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea

6Departments of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea

7Departments of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea

*These authors have contributed equally to this work

Correspondence to:

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

Sug Hyung Lee, e-mail: suhulee@catholic.ac.kr

Keywords: colorectal cancer, carcinogenesis, exome sequencing, mutations, evolution

Received: June 10, 2015     Accepted: July 27, 2015     Published: August 07, 2015

ABSTRACT

Although the colorectal adenoma-to-carcinoma sequence represents a classical cancer progression model, the evolution of the mutational landscape underlying this model is not fully understood. In this study, we analyzed eight synchronous pairs of colorectal high-grade adenomas and carcinomas, four microsatellite-unstable (MSU) and four-stable (MSS) pairs, using whole-exome sequencing. In the MSU adenoma-carcinoma pairs, we observed no subclonal mutations in adenomas that became fixed in paired carcinomas, suggesting a ‘parallel’ evolution of synchronous adenoma-to-carcinoma, rather than a ‘stepwise’ evolution. The abundance of indel (in MSU and MSS pairs) and microsatellite instability (in MSU pairs) was noted in the later adenoma- or carcinoma-specific mutations, indicating that the mutational processes and functional constraints operative in early and late colorectal carcinogenesis are different. All MSU cases exhibited clonal, truncating mutations in ACVR2A, TGFBR2, and DNA mismatch repair genes, but none were present in APC or KRAS. In three MSS pairs, both APC and KRAS mutations were identified as both early and clonal events, often accompanying clonal copy number changes. An MSS case uniquely exhibited clonal ERBB2 amplification, followed by APC and TP53 mutations as carcinoma-specific events. Along with the previously unrecognized clonal origins of synchronous colorectal adenoma-carcinoma pairs, our study revealed that the preferred sequence of mutational events during colorectal carcinogenesis can be context-dependent.


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