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A functional copy-number variation in MAPKAPK2 predicts risk and prognosis of lung cancer.

ABSTRACT: Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) may promote cancer development and progression by inducing tumorigenesis and drug resistance. To assess whether the copy-number variation g.CNV-30450 located in the MAPKAPK2 promoter has any effect on lung cancer risk or prognosis, we investigated the association between g.CNV-30450 and cancer risk in three independent case-control studies of 2,332 individuals with lung cancer and 2,457 controls and the effects of g.CNV-30450 on cancer prognosis in 1,137 individuals with lung cancer with survival data in southern and eastern Chinese populations. We found that those subjects who had four copies of g.CNV-30450 had an increased cancer risk (odds ratio = 1.94, 95% confidence interval [CI] = 1.61-2.35) and a worse prognosis for individuals with lung cancer (with a median survival time of only 9 months) (hazard ratio = 1.47, 95% CI = 1.22-1.78) compared with those with two or three copies (with a median survival time of 14 months). Meanwhile, four copies of g.CNV-30450 significantly increased MAPKAPK2 expression, both in vitro and in vivo, compared with two or three copies. Our study establishes a robust association between the functional g.CNV-30450 in MAPKAPK2 and risk as well as prognosis of lung cancer, and it presents this functional copy-number variation as a potential biomarker for susceptibility to and prognosis for lung cancer.

SUBMITTER: Liu B

PROVIDER: S-EPMC3415537 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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A functional copy-number variation in MAPKAPK2 predicts risk and prognosis of lung cancer.

Liu Bin B Yang Lei L Huang Binfang B Cheng Mei M Wang Hui H Li Yinyan Y Huang Dongsheng D Zheng Jian J Li Qingchu Q Zhang Xin X Ji Weidong W Zhou Yifeng Y Lu Jiachun J

American journal of human genetics 20120801 2

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) may promote cancer development and progression by inducing tumorigenesis and drug resistance. To assess whether the copy-number variation g.CNV-30450 located in the MAPKAPK2 promoter has any effect on lung cancer risk or prognosis, we investigated the association between g.CNV-30450 and cancer risk in three independent case-control studies of 2,332 individuals with lung cancer and 2,457 controls and the effects of g.CNV-30450 ...[more]

PMID: 22883146

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Project description:Background: Lung adenocarcinoma (LUAD) possesses a poor prognosis with a low 5-year survival rate even for stages I-III resected patients, it is thus critical to understand the determinants that affect the survival and discover new potentially prognostic biomarkers. Somatic copy number alterations (CNAs) are major source of genomic variations driving tumor evolution, CNAs screening may identify prognostic biomarkers. Methods: Oncoscan MIP array was used to analyze the patterns of CNAs on formalin fixed paraffin embedded(FFPE) tumor specimens from 163 consecutive stage I-III resected LUAD patients, 145 out of which received platinum-based adjuvant chemotherapy. Results: Of the 163 patients, 91(55.8%) were recurred within 3 years after surgery. The most common aberrations in our cohort were 1q, 5p, 5q, 7p, 8q, 14p, 16p, 17q, 20q for copy number gains and 8p, 9p, 13p, 16q, 18q for losses. The GISTIC2 analysis produced 45 amplification peaks and 40 deletion peaks, involving some reported genes TERT, EGFR, MYC, CCND1, CDK4, MDM2, ERBB2, NKX2-1, CCNE1, and CDKN2A, most of which were consistent with TCGA database. The amplifications of 12p12.1 (CMAS, GOLT1B, YS2, LDHB, RECQL, ETNK1, IAPP, PYROXD1, KRAS) and KDM5A were correlated with worse prognosis in our cohort, this result was further validated in 506 LUAD patients from TCGA. In addition, 163 patients could be well-classified into five groups, and the clinical outcomes were significantly different based on threshold copy number at reoccurring alteration peaks. Among the 145 patients who received adjuvant chemotherapy, focal amplification of ERBB2 and deletion of 4q34.3 were found to be specific in relapsed patients, this result was validated in an independent group of Imielinski et al., demonstrating these two CNAs may contribute to resected LUAD recurrence after adjuvant chemotherapy. Conclusion: This study suggests that CNAs profiling may be a potential prognostic classifier in resected LAUD patients. Amplifications of 12p12.1 and KDM5A might be prognostic biomarkers for LUAD, and amplification of ERBB2 and deletion of 4q34.3 predicted early relapse after adjuvant chemotherapy. These novel findings may provide implication for better implementation of precision therapy for lung cancer patients.

Project description:Identification of a unique genomic biomarker in de novo inflammatory breast cancer (IBC) may provide an insight into the biology of this aggressive disease. The goal of our study was to elucidate biomarkers associated with IBC. We examined breast biopsies collected from Dana-Farber Cancer Institute patients with IBC prior to initiating preoperative systemic treatment (30 samples were examined, of which 14 were eligible). Patients without available biopsies (n = 1), with insufficient tumor epithelial cells (n = 10), or insufficient DNA yield (n = 5) were excluded from the analysis. Molecular subtype and tumor grade were abstracted from a medical records' review. Ten IBC tumors were estrogen-receptor-positive (ER+) and human epidermal growth factor receptor 2 (HER2)-negative (n = 10 out of 14). Sufficient RNA and DNA were simultaneously extracted from 14 biopsy specimens using the Qiagen AllPrep Kit. RNA was amplified using the Sensation kit and profiled using the Affymetrix Human Transcriptome Array 2.0. DNA was profiled for genome-wide copy number variation (CNV) using the Affymetrix OncoScan Array and analyzed using the Nexus Chromosome Analysis Suite. Among the 14 eligible samples, we first confirmed biological concordance and quality control metrics using replicates and gene expression data. Second, we examined CNVs and gene expression change by IBC subtype. We identified significant CNVs in IBC patients after adjusting for multiple comparisons. Next, to assess whether the CNVs were unique to IBC, we compared the IBC CNV data to fresh-frozen non-IBC CNV data from The Cancer Genome Atlas (n = 388). On chromosome 7p11.2, we identified significant CN gain located at position 58,019,983-58,025,423 in 8 ER+ IBC samples compared to 338 non-IBC ER+ samples (region length: 5440 bp gain and 69,039 bp, False Discovery Rate (FDR) p-value = 3.12 × 10-10) and at position 57,950,944-58,025,423 in 3 TN-IBC samples compared to 50 non-IBC TN samples (74,479 base pair, gain, FDR p-value = 4.27 × 10-5; near the EGFR gene). We also observed significant CN loss on chromosome 21, located at position 9,648,315-9,764,385 (p-value = 4.27 × 10-5). Secondarily, differential gene expression in IBC patients with 7p11.2 CN gain compared to SUM149 were explored after FDR correction for multiple testing (p-value = 0.0016), but the results should be interpreted with caution due to the small sample size. Finally, the data presented are hypothesis-generating. Validation of CNVs that contribute to the unique presentation and biological features associated with IBC in larger datasets may lead to the optimization of treatment strategies.

Dataset Information

A functional copy-number variation in MAPKAPK2 predicts risk and prognosis of lung cancer.

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A functional copy-number variation in MAPKAPK2 predicts risk and prognosis of lung cancer.

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