Oncotarget

Research Papers:

Progression of naive intraepithelial neoplasia genome to aggressive squamous cell carcinoma genome of uterine cervix

Seung-Hyun Jung _, Youn Jin Choi, Min Sung Kim, In-Pyo Baek, Sung Hak Lee, Ah Won Lee, Soo Young Hur, Tae-Min Kim, Sug Hyung Lee and Yeun-Jun Chung

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Oncotarget. 2015; 6:4385-4393. https://doi.org/10.18632/oncotarget.2981

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Abstract

Seung-Hyun Jung1,3,*, Youn Jin Choi2,*, Min Sung Kim2, In-Pyo Baek1,3, Sung Hak Lee4, Ah Won Lee4, Soo Young Hur5, Tae-Min Kim6, Sug Hyung Lee2, Yeun-Jun Chung1,3

1Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

2Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

3Department of Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

4Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

5Department of Obstetrics/Gynecology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

6Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea

*These authors have contributed equally to this work

Correspondence to:

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

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

Keywords: Uterine cervix cancer, Cervical intraepithelial neoplasia, Cervical squamous cell carcinoma, Mutation, Copy number alteration

Received: November 03, 2014     Accepted: December 20, 2014     Published: January 23, 2015

ABSTRACT

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.


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