Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma
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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
Yeun-Jun Chung, e-mail: email@example.com
Sug Hyung Lee, e-mail: firstname.lastname@example.org
Keywords: colorectal cancer, carcinogenesis, exome sequencing, mutations, evolution
Received: June 10, 2015 Accepted: July 27, 2015 Published: August 07, 2015
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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