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

Jung SH, Choi YJ, Kim MS, Baek IP, Lee SH, Lee AW, Hur SY, Kim TM, Lee SH, Chung YJ - Oncotarget (2015)

Bottom Line: The CINs harbored significantly lower numbers of copy number alterations (CNAs) than the MIC/CSCCs as well (P = 0.036).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.

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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Copy number profiles, amplification and chromothripsis(A) Frequencies (y-axis) of copy number gains and losses across the whole genomes of the eight cervical neoplasia genomes (upper panel) and their heatmap for probe-level signal intensities (lower panel). Blue denotes the copy number gains and the red denotes the copy number losses. (B) Amplification on chromosome 3q21.2-q29 in MIC-1, where the PIK3CA and SOX2 oncogenes are located. (C) Amplification on chromosome 22q11.21-q11.22 in CSCC-13, where the MAPK1 and BCR oncogenes are located. (D) The complex recombination event (chromothripsis) on chromosome 11q22.1-q25 in CSCC-12. X-axis represents the genomic location and y-axis represents signal intensities on the log2 scale.
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Figure 2: Copy number profiles, amplification and chromothripsis(A) Frequencies (y-axis) of copy number gains and losses across the whole genomes of the eight cervical neoplasia genomes (upper panel) and their heatmap for probe-level signal intensities (lower panel). Blue denotes the copy number gains and the red denotes the copy number losses. (B) Amplification on chromosome 3q21.2-q29 in MIC-1, where the PIK3CA and SOX2 oncogenes are located. (C) Amplification on chromosome 22q11.21-q11.22 in CSCC-13, where the MAPK1 and BCR oncogenes are located. (D) The complex recombination event (chromothripsis) on chromosome 11q22.1-q25 in CSCC-12. X-axis represents the genomic location and y-axis represents signal intensities on the log2 scale.

Mentions: We next performed array-CGH for the eight cervical neoplasia genomes with their matched normal genomes as references. A total of 92 CNAs were identified in the eight samples (Figure 2A, Supporting Information Table S3). The MIC/CSCC genomes harbored significantly higher numbers of CNAs than the CIN genomes (median of 18 vs. 4 CNAs, respectively, P = 0.036). The MIC/CSCC genomes harbored significantly longer CNAs (655 Mb-sized regions per MIC/CSCC genome, ranged 368–962 Mb) than the CIN genomes (93 Mb, ranged 1.7–275 Mb) (P = 0.01, Table 2).


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

Jung SH, Choi YJ, Kim MS, Baek IP, Lee SH, Lee AW, Hur SY, Kim TM, Lee SH, Chung YJ - Oncotarget (2015)

Copy number profiles, amplification and chromothripsis(A) Frequencies (y-axis) of copy number gains and losses across the whole genomes of the eight cervical neoplasia genomes (upper panel) and their heatmap for probe-level signal intensities (lower panel). Blue denotes the copy number gains and the red denotes the copy number losses. (B) Amplification on chromosome 3q21.2-q29 in MIC-1, where the PIK3CA and SOX2 oncogenes are located. (C) Amplification on chromosome 22q11.21-q11.22 in CSCC-13, where the MAPK1 and BCR oncogenes are located. (D) The complex recombination event (chromothripsis) on chromosome 11q22.1-q25 in CSCC-12. X-axis represents the genomic location and y-axis represents signal intensities on the log2 scale.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414197&req=5

Figure 2: Copy number profiles, amplification and chromothripsis(A) Frequencies (y-axis) of copy number gains and losses across the whole genomes of the eight cervical neoplasia genomes (upper panel) and their heatmap for probe-level signal intensities (lower panel). Blue denotes the copy number gains and the red denotes the copy number losses. (B) Amplification on chromosome 3q21.2-q29 in MIC-1, where the PIK3CA and SOX2 oncogenes are located. (C) Amplification on chromosome 22q11.21-q11.22 in CSCC-13, where the MAPK1 and BCR oncogenes are located. (D) The complex recombination event (chromothripsis) on chromosome 11q22.1-q25 in CSCC-12. X-axis represents the genomic location and y-axis represents signal intensities on the log2 scale.
Mentions: We next performed array-CGH for the eight cervical neoplasia genomes with their matched normal genomes as references. A total of 92 CNAs were identified in the eight samples (Figure 2A, Supporting Information Table S3). The MIC/CSCC genomes harbored significantly higher numbers of CNAs than the CIN genomes (median of 18 vs. 4 CNAs, respectively, P = 0.036). The MIC/CSCC genomes harbored significantly longer CNAs (655 Mb-sized regions per MIC/CSCC genome, ranged 368–962 Mb) than the CIN genomes (93 Mb, ranged 1.7–275 Mb) (P = 0.01, Table 2).

Bottom Line: The CINs harbored significantly lower numbers of copy number alterations (CNAs) than the MIC/CSCCs as well (P = 0.036).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.

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.

Show MeSH
Related in: MedlinePlus