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. 2014 Dec 11;9(12):e114616.
doi: 10.1371/journal.pone.0114616. eCollection 2014.

Identification of genomic alterations in pancreatic cancer using array-based comparative genomic hybridization

Jian-Wei Liang  1 , Zhi-Zhou Shi  2 , Tian-Yun Shen  2 , Xu Che  1 , Zheng Wang  1 , Su-Sheng Shi  3 , Xin Xu  4 , Yan Cai  4 , Ping Zhao  1 , Cheng-Feng Wang  1 , Zhi-Xiang Zhou  1 , Ming-Rong Wang  4
Affiliations

Identification of genomic alterations in pancreatic cancer using array-based comparative genomic hybridization

Jian-Wei Liang et al. PLoS One. .

Abstract

Background: Genomic aberration is a common feature of human cancers and also is one of the basic mechanisms that lead to overexpression of oncogenes and underexpression of tumor suppressor genes. Our study aims to identify frequent genomic changes in pancreatic cancer.

Materials and methods: We used array comparative genomic hybridization (array CGH) to identify recurrent genomic alterations and validated the protein expression of selected genes by immunohistochemistry.

Results: Sixteen gains and thirty-two losses occurred in more than 30% and 60% of the tumors, respectively. High-level amplifications at 7q21.3-q22.1 and 19q13.2 and homozygous deletions at 1p33-p32.3, 1p22.1, 1q22, 3q27.2, 6p22.3, 6p21.31, 12q13.2, 17p13.2, 17q21.31 and 22q13.1 were identified. Especially, amplification of AKT2 was detected in two carcinomas and homozygous deletion of CDKN2C in other two cases. In 15 independent validation samples, we found that AKT2 (19q13.2) and MCM7 (7q22.1) were amplified in 6 and 9 cases, and CAMTA2 (17p13.2) and PFN1 (17p13.2) were homozygously deleted in 3 and 1 cases. AKT2 and MCM7 were overexpressed, and CAMTA2 and PFN1 were underexpressed in pancreatic cancer tissues than in morphologically normal operative margin tissues. Both GISTIC and Genomic Workbench software identified 22q13.1 containing APOBEC3A and APOBEC3B as the only homozygous deletion region. And the expression levels of APOBEC3A and APOBEC3B were significantly lower in tumor tissues than in morphologically normal operative margin tissues. Further validation showed that overexpression of PSCA was significantly associated with lymph node metastasis, and overexpression of HMGA2 was significantly associated with invasive depth of pancreatic cancer.

Conclusion: These recurrent genomic changes may be useful for revealing the mechanism of pancreatic carcinogenesis and providing candidate biomarkers.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Genomic aberrations in pancreatic cancer.
A. Genome-wide frequency plot of pancreatic cancer by array CGH analysis. Line on the right of 0%-axis, gain; line on the left of 0%-axis, loss. B. Numbers of aberrations in pancreatic cancer. X, number of aberrations; Y, number of cases. C. Gains and losses (HDs) identified by GISTIC.
Figure 2
Figure 2. Amplification of AKT2 and homozygous deletion of CDKN2C in pancreatic cancer.
A. amplification of AKT2. B. homozygous deletion of CDKN2C. Arrows indicate the position of AKT2 and CDKN2C.
Figure 3
Figure 3. Homozygous deletion of APOBEC3A and APOBEC3B in pancreatic cancer.
Cycles represent the probes of APOBEC3A and APOBEC3B.
Figure 4
Figure 4. Validation of amplifications and homozygous deletions of candidate genes in independent pacreatic cancer tissues.
A. amplication of AKT2 and MCM7. B. homozygous deletion of CAMTA2 and PFN1. C. homozygous deletion of APOBEC3A and APOBEC3B. Ratio = (Copy number of candidate gene in tumor tissues)/(Copy number of candidate gene in commercial human genomic DNA).
Figure 5
Figure 5. mRNA expression of candidate genes in pancreatic cancer as compared with that in morphologically normal operative margin tissues detected by using Real-time PCR.
A. Overexpression of AKT2 and MCM7. B. Underexpression of CAMTA2 and PFN1. C. Underexpression of APOBEC3A and APOBEC3B.
Figure 6
Figure 6. Representative immunohistochemistry results of HMGA2 and PSCA in pancreatic cancer as compared with those in morphologically normal operative margin tissues.
A. Strong and negative expression of HMGA2. B. Strong and negative expression of PSCA.
See this image and copyright information in PMC

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