Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma.
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.
Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, South Korea.|Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Tae-Min
TM
Kim
Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Chang Hyeok
CH
An
Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, South Korea.|Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Je-Keun
JK
Rhee
Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.|Department of Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, South Korea.|Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Seung-Hyun
SH
Jung
Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Sung Hak
SH
Lee
Department of Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, South Korea.|Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
In-Pyo
IP
Baek
Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.|Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Min Sung
MS
Kim
Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.|Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Sug Hyung
SH
Lee
Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.|Department of Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, South Korea.|Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Yeun-Jun
YJ
Chung
D000236:Adenoma / Q000235:genetics / Q000473:pathology*; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D004260:DNA Repair; D018450:Disease Progression; D019143:Evolution, Molecular; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation
carcinogenesis; colorectal cancer; evolution; exome sequencing; mutations