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The BRCA1/2-directed miRNA signature predicts a good prognosis in ovarian cancer patients with wild-type BRCA1/2.

Gu Y, Zhang M, Peng F, Fang L, Zhang Y, Liang H, Zhou W, Ao L, Guo Z - Oncotarget (2015)

Bottom Line: However, patients with wild-type BRCA1/2 may also have a favorable prognosis as a result of other mechanisms that remain poorly elucidated, such as the deregulation of miRNAs.By analyzing multidimensional datasets of ovarian cancer patients from the TCGA data portal, we identified three miRNAs (hsa-miR-146a, hsa-miR-148a and hsa-miR-545) that target BRCA1/2 and were associated with overall survival and progression-free survival in patients with wild-type BRCA1/2.By analyzing the expression profiles and Gene Ontology functional enrichment, we found that carriers of BRCA1/2 alterations and patients with miRNA deregulation shared a common mechanism, regulation of the DNA repair-related pathways, that affects the prognosis of ovarian cancer patients.

View Article: PubMed Central - PubMed

Affiliation: College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.

ABSTRACT
Ovarian cancer patients carrying alterations (i.e., germline mutations, somatic mutations, hypermethylations and/or deletions) of BRCA1 or BRCA2 (BRCA1/2) have a better prognosis than BRCA1/2 alteration non-carriers. However, patients with wild-type BRCA1/2 may also have a favorable prognosis as a result of other mechanisms that remain poorly elucidated, such as the deregulation of miRNAs. We therefore sought to identify BRCA1/2-directed miRNA signatures that have prognostic value in ovarian cancer patients with wild-type BRCA1/2 and study how the deregulation of miRNAs impacts the prognosis of patients treated with platinum-based chemotherapy. By analyzing multidimensional datasets of ovarian cancer patients from the TCGA data portal, we identified three miRNAs (hsa-miR-146a, hsa-miR-148a and hsa-miR-545) that target BRCA1/2 and were associated with overall survival and progression-free survival in patients with wild-type BRCA1/2. By analyzing the expression profiles and Gene Ontology functional enrichment, we found that carriers of BRCA1/2 alterations and patients with miRNA deregulation shared a common mechanism, regulation of the DNA repair-related pathways, that affects the prognosis of ovarian cancer patients. Our work highlights that a proportion of patients with wild-type BRCA1/2 ovarian cancers benefit from platinum-based chemotherapy and that the patients who benefit could be predicted from BRCA1/2-directed miRNA signature.

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Schematic overview of our analysis procedureA. By integrating the mutation profile, copy number variation profile and methylation alteration profile, the alteration profile (Mgs) was built: the columns reflect ovarian cancer samples, and the rows reflect genes. If a gene (g) is detected with alterations in a sample (s), Mgs is set to 1; otherwise, Mgs is set to 0. B. The miRNAs that are associated with ovarian cancer prognosis were identified using Cox regression analysis. All of the ovarian cancer samples were divided into three groups: the BRCA 1/2 altered group (BRCA 1/2 alteration carriers), the miRNA-related high-risk group and the miRNA-related low-risk group. Survival difference and differential expression among the groups were then assessed.
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Figure 1: Schematic overview of our analysis procedureA. By integrating the mutation profile, copy number variation profile and methylation alteration profile, the alteration profile (Mgs) was built: the columns reflect ovarian cancer samples, and the rows reflect genes. If a gene (g) is detected with alterations in a sample (s), Mgs is set to 1; otherwise, Mgs is set to 0. B. The miRNAs that are associated with ovarian cancer prognosis were identified using Cox regression analysis. All of the ovarian cancer samples were divided into three groups: the BRCA 1/2 altered group (BRCA 1/2 alteration carriers), the miRNA-related high-risk group and the miRNA-related low-risk group. Survival difference and differential expression among the groups were then assessed.

Mentions: 317 high-grade serous ovarian adenocarcinomas and 8 normal fallopian tube samples, including all information on mRNA expression, miRNA expression, mutation, promoter methylation, DNA copy number and clinical features, were downloaded from the TCGA data portal[2]. The level 3 mutation profile (somatic mutation and germline mutation information) was used. The level 1 copy number data were processed using the dChip software, the GLAD algorithm and the GISTIC algorithm, as described by Gu et al[29]. Level 3 IlluminaInfinium DNA methylation data were processed as described by Yang et al[30]. By integrating the discrete mutation profile, copy number alteration profile and methylation profile, we obtained the gene alteration profile (Mgs), in which the columns reflect ovarian cancer samples and the rows reflect genes. If a gene (g) was detected with alterations in a sample (s), we set Mgs to 1; otherwise, Mgs was set to 0 (Figure 1A). Here, alterations in the Mgs included somatic mutations, germline mutations, copy number amplifications/deletions and hypo/hyper-methylations. All patients received platinum-based chemotherapy after surgery. The detailed clinical features of the patients are listed in Table 1.


The BRCA1/2-directed miRNA signature predicts a good prognosis in ovarian cancer patients with wild-type BRCA1/2.

Gu Y, Zhang M, Peng F, Fang L, Zhang Y, Liang H, Zhou W, Ao L, Guo Z - Oncotarget (2015)

Schematic overview of our analysis procedureA. By integrating the mutation profile, copy number variation profile and methylation alteration profile, the alteration profile (Mgs) was built: the columns reflect ovarian cancer samples, and the rows reflect genes. If a gene (g) is detected with alterations in a sample (s), Mgs is set to 1; otherwise, Mgs is set to 0. B. The miRNAs that are associated with ovarian cancer prognosis were identified using Cox regression analysis. All of the ovarian cancer samples were divided into three groups: the BRCA 1/2 altered group (BRCA 1/2 alteration carriers), the miRNA-related high-risk group and the miRNA-related low-risk group. Survival difference and differential expression among the groups were then assessed.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385859&req=5

Figure 1: Schematic overview of our analysis procedureA. By integrating the mutation profile, copy number variation profile and methylation alteration profile, the alteration profile (Mgs) was built: the columns reflect ovarian cancer samples, and the rows reflect genes. If a gene (g) is detected with alterations in a sample (s), Mgs is set to 1; otherwise, Mgs is set to 0. B. The miRNAs that are associated with ovarian cancer prognosis were identified using Cox regression analysis. All of the ovarian cancer samples were divided into three groups: the BRCA 1/2 altered group (BRCA 1/2 alteration carriers), the miRNA-related high-risk group and the miRNA-related low-risk group. Survival difference and differential expression among the groups were then assessed.
Mentions: 317 high-grade serous ovarian adenocarcinomas and 8 normal fallopian tube samples, including all information on mRNA expression, miRNA expression, mutation, promoter methylation, DNA copy number and clinical features, were downloaded from the TCGA data portal[2]. The level 3 mutation profile (somatic mutation and germline mutation information) was used. The level 1 copy number data were processed using the dChip software, the GLAD algorithm and the GISTIC algorithm, as described by Gu et al[29]. Level 3 IlluminaInfinium DNA methylation data were processed as described by Yang et al[30]. By integrating the discrete mutation profile, copy number alteration profile and methylation profile, we obtained the gene alteration profile (Mgs), in which the columns reflect ovarian cancer samples and the rows reflect genes. If a gene (g) was detected with alterations in a sample (s), we set Mgs to 1; otherwise, Mgs was set to 0 (Figure 1A). Here, alterations in the Mgs included somatic mutations, germline mutations, copy number amplifications/deletions and hypo/hyper-methylations. All patients received platinum-based chemotherapy after surgery. The detailed clinical features of the patients are listed in Table 1.

Bottom Line: However, patients with wild-type BRCA1/2 may also have a favorable prognosis as a result of other mechanisms that remain poorly elucidated, such as the deregulation of miRNAs.By analyzing multidimensional datasets of ovarian cancer patients from the TCGA data portal, we identified three miRNAs (hsa-miR-146a, hsa-miR-148a and hsa-miR-545) that target BRCA1/2 and were associated with overall survival and progression-free survival in patients with wild-type BRCA1/2.By analyzing the expression profiles and Gene Ontology functional enrichment, we found that carriers of BRCA1/2 alterations and patients with miRNA deregulation shared a common mechanism, regulation of the DNA repair-related pathways, that affects the prognosis of ovarian cancer patients.

View Article: PubMed Central - PubMed

Affiliation: College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.

ABSTRACT
Ovarian cancer patients carrying alterations (i.e., germline mutations, somatic mutations, hypermethylations and/or deletions) of BRCA1 or BRCA2 (BRCA1/2) have a better prognosis than BRCA1/2 alteration non-carriers. However, patients with wild-type BRCA1/2 may also have a favorable prognosis as a result of other mechanisms that remain poorly elucidated, such as the deregulation of miRNAs. We therefore sought to identify BRCA1/2-directed miRNA signatures that have prognostic value in ovarian cancer patients with wild-type BRCA1/2 and study how the deregulation of miRNAs impacts the prognosis of patients treated with platinum-based chemotherapy. By analyzing multidimensional datasets of ovarian cancer patients from the TCGA data portal, we identified three miRNAs (hsa-miR-146a, hsa-miR-148a and hsa-miR-545) that target BRCA1/2 and were associated with overall survival and progression-free survival in patients with wild-type BRCA1/2. By analyzing the expression profiles and Gene Ontology functional enrichment, we found that carriers of BRCA1/2 alterations and patients with miRNA deregulation shared a common mechanism, regulation of the DNA repair-related pathways, that affects the prognosis of ovarian cancer patients. Our work highlights that a proportion of patients with wild-type BRCA1/2 ovarian cancers benefit from platinum-based chemotherapy and that the patients who benefit could be predicted from BRCA1/2-directed miRNA signature.

Show MeSH
Related in: MedlinePlus