Whole-exome sequencing identified mutational profiles of high-grade colon adenomas.
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.
Departments of Hospital Pathology, The Catholic University of Korea, Seoul, Korea.
Sung Hak
SH
Lee
Departments of Integrated Research Center for Genome Polymorphism, The Catholic University of Korea, Seoul, Korea.|Departments of Cancer Evolution Research Center, The Catholic University of Korea, Seoul, Korea.
Seung Hyun
SH
Jung
Departments of Medical Informatics, The Catholic University of Korea, Seoul, Korea.
Tae-Min
TM
Kim
Departments of Medical Informatics, The Catholic University of Korea, Seoul, Korea.
Je-Keun
JK
Rhee
Departments of Microbiology, The Catholic University of Korea, Seoul, Korea.|Departments of Integrated Research Center for Genome Polymorphism, The Catholic University of Korea, Seoul, Korea.
Hyeon-Chun
HC
Park
Departments of Pathology, The Catholic University of Korea, Seoul, Korea.|Departments of Cancer Evolution Research Center, The Catholic University of Korea, Seoul, Korea.
Min Sung
MS
Kim
Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
Sung Soo
SS
Kim
Departments of General Surgery The Catholic University of Korea, Seoul, Korea.
Chang Hyeok
CH
An
Departments of Pathology, The Catholic University of Korea, Seoul, Korea.|Departments of Cancer Evolution Research Center, The Catholic University of Korea, Seoul, Korea.
Sug Hyung
SH
Lee
Departments of Microbiology, The Catholic University of Korea, Seoul, Korea.|Departments of Integrated Research Center for Genome Polymorphism, The Catholic University of Korea, Seoul, Korea.|Departments of Pathology, The Catholic University of Korea, Seoul, Korea.
Yeun-Jun
YJ
Chung
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D010641:Phenotype; D011237:Predictive Value of Tests; D056910:Republic of Korea; D059467:Transcriptome; D000073359:Exome Sequencing
D014408:Biomarkers, Tumor
adenoma; colon; high grade adenoma; mutation; whole-exome sequencing