Progression of naive intraepithelial neoplasia genome to aggressive squamous cell carcinoma genome of uterine cervix.
Although cervical intraepithelial neoplasia (CIN) is considered a neoplasia, its genomic alterations remain unknown. For this, we performed whole-exome sequencing and copy number profiling of three CINs, a microinvasive carcinoma (MIC) and four cervical squamous cell carcinomas (CSCC). Both total mutation and driver mutation numbers of the CINs were significantly fewer than those of the MIC/CSCCs (P = 0.036 and P = 0.018, respectively). Importantly, PIK3CA was altered in all MIC/CSCCs by either mutation or amplification, but not in CINs. The CINs harbored significantly lower numbers of copy number alterations (CNAs) than the MIC/CSCCs as well (P = 0.036). Pathway analysis predicted that the MIC/CSCCs were enriched with cancer-related signalings such as cell adhesion, mTOR signaling pathway and cell migration that were depleted in the CINs. The mutation-based estimation of evolutionary ages identified that CIN genomes were younger than MIC/CSCC genomes. The data indicate that CIN genomes harbor unfixed mutations in addition to human papilloma virus infection but require additional driver hits such as PIK3CA, TP53, STK11 and MAPK1 mutations for CSCC progression. Taken together, our data may explain the long latency from CIN to CSCC progression and provide useful information for molecular diagnosis of CIN and CSCC.
Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.|Department of Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
Seung-Hyun
SH
Jung
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
Youn Jin
YJ
Choi
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
Min Sung
MS
Kim
Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.|Department of Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
In-Pyo
IP
Baek
Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
Sung Hak
SH
Lee
Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
Ah Won
AW
Lee
Department of Obstetrics/Gynecology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
Soo Young
SY
Hur
Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
Tae-Min
TM
Kim
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
Sug Hyung
SH
Lee
Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.|Department of Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
Yeun-Jun
YJ
Chung
D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008875:Middle Aged; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000473:pathology