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Circulating cell-free cancer-testis MAGE-A RNA, BORIS RNA, let-7b and miR-202 in the blood of patients with breast cancer and benign breast diseases.

Joosse SA, Müller V, Steinbach B, Pantel K, Schwarzenbach H - Br. J. Cancer (2014)

Bottom Line: The serum levels of MAGE-A and BORIS mRNA, as well as let-7b were significantly higher in patients with invasive carcinomas than in patients with benign breast diseases or healthy women (P<0.001), whereas the levels of miR-202 were elevated in both patient cohorts (P<0.001).In uni- and multivariate analyses, high levels of miR-202 significantly correlated with poor overall survival (P=0.0001).Moreover, serum miR-202 is associated with prognosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

ABSTRACT

Background: MAGE-A (melanoma-associated antigen-A) are promising targets for specific immunotherapy and their expression may be induced by the epigenetic factor BORIS.

Methods: To determine their relevance for breast cancer, we quantified the levels of MAGE-A1, -A2, -A3, -A12 and BORIS mRNA, as well as microRNAs let-7b and miR-202 in pre- and postoperative serum of 102 and 34 breast cancer patients, respectively, and in serum of 26 patients with benign breast diseases and 37 healthy women by real-time PCR. The mean follow-up time of the cancer patients was 6.2 years.

Results: The serum levels of MAGE-A and BORIS mRNA, as well as let-7b were significantly higher in patients with invasive carcinomas than in patients with benign breast diseases or healthy women (P<0.001), whereas the levels of miR-202 were elevated in both patient cohorts (P<0.001). In uni- and multivariate analyses, high levels of miR-202 significantly correlated with poor overall survival (P=0.0001). Transfection of breast cancer cells with synthetic microRNAs and their inhibitors showed that let-7b and miR-202 did not affect the protein expression of MAGE-A1.

Conclusions: Based on their cancer-specific increase in breast cancer patients, circulating MAGE-A and BORIS mRNAs may be further explored for early detection of breast cancer and monitoring of MAGE-directed immunotherapies. Moreover, serum miR-202 is associated with prognosis.

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Serum levels of miR-202 and BORIS significantly correlate with overall survival. Univariate Kaplan–Meier survival curves related to concentrations of circulating miR-202 and BORIS in breast cancer patients. Overall survival is significantly associated with serum miR-202 levels in the whole patient cohort (A, n=102), in the subgroups of nodal-positive patients (B, n=48), patients with tumour stages pT2-4 (C, n=57) and patients without DTCs in their bone marrow (D, n=66). Overall survival is also associated with serum BORIS levels in the subgroup of nodal-positive patients (E, n=48). For miR-202 and BORIS median values of 0.3 and 0.2 were used for grouping the serum samples according to low and high levels, respectively.
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fig3: Serum levels of miR-202 and BORIS significantly correlate with overall survival. Univariate Kaplan–Meier survival curves related to concentrations of circulating miR-202 and BORIS in breast cancer patients. Overall survival is significantly associated with serum miR-202 levels in the whole patient cohort (A, n=102), in the subgroups of nodal-positive patients (B, n=48), patients with tumour stages pT2-4 (C, n=57) and patients without DTCs in their bone marrow (D, n=66). Overall survival is also associated with serum BORIS levels in the subgroup of nodal-positive patients (E, n=48). For miR-202 and BORIS median values of 0.3 and 0.2 were used for grouping the serum samples according to low and high levels, respectively.

Mentions: To assess whether the serum levels of circulating RNA and miRs were related to patient outcome (overall survival, OS; disease-free survival, DFS), Kaplan–Meier and log-rank models, as well as univariate and multivariate Cox regression models were carried out. The mean follow-up time of the cancer patients was 6.2 years (range 0.6–11.9 years). The REMARK criteria for prognostic studies (McShane et al, 2006) have been taken into consideration. Median values of RNA and miRs were used for grouping the serum samples according to low and high levels. As shown in Figure 3, higher serum concentrations of miR-202 (log-rank test: P=0.004, Cox: P=0.0001) significantly correlated with poor OS. The mean OS periods were 139 and 110 months (95% CI 129–149 and 96–125) in patients who had miR-202 concentrations of <0.3 and >0.3 ng ml−1 serum, respectively (Figure 3A). Based on these significant results of miR-202, we also performed univariate OS analyses with the postoperative miR-202 concentrations. Although the number of 34 postoperative samples is small, we detected that high serum levels of miR-202 after surgery correlated with decreased OS (log-rank test: P=0.063, Cox: P=0.022, data not shown). With the exception of a tendency of correlation of BORIS RNA concentrations with patient prognosis (P=0.071), no further significant associations were found. In addition, there was no correlation of the serum levels of circulating RNA and miRs with DFS.


Circulating cell-free cancer-testis MAGE-A RNA, BORIS RNA, let-7b and miR-202 in the blood of patients with breast cancer and benign breast diseases.

Joosse SA, Müller V, Steinbach B, Pantel K, Schwarzenbach H - Br. J. Cancer (2014)

Serum levels of miR-202 and BORIS significantly correlate with overall survival. Univariate Kaplan–Meier survival curves related to concentrations of circulating miR-202 and BORIS in breast cancer patients. Overall survival is significantly associated with serum miR-202 levels in the whole patient cohort (A, n=102), in the subgroups of nodal-positive patients (B, n=48), patients with tumour stages pT2-4 (C, n=57) and patients without DTCs in their bone marrow (D, n=66). Overall survival is also associated with serum BORIS levels in the subgroup of nodal-positive patients (E, n=48). For miR-202 and BORIS median values of 0.3 and 0.2 were used for grouping the serum samples according to low and high levels, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150270&req=5

fig3: Serum levels of miR-202 and BORIS significantly correlate with overall survival. Univariate Kaplan–Meier survival curves related to concentrations of circulating miR-202 and BORIS in breast cancer patients. Overall survival is significantly associated with serum miR-202 levels in the whole patient cohort (A, n=102), in the subgroups of nodal-positive patients (B, n=48), patients with tumour stages pT2-4 (C, n=57) and patients without DTCs in their bone marrow (D, n=66). Overall survival is also associated with serum BORIS levels in the subgroup of nodal-positive patients (E, n=48). For miR-202 and BORIS median values of 0.3 and 0.2 were used for grouping the serum samples according to low and high levels, respectively.
Mentions: To assess whether the serum levels of circulating RNA and miRs were related to patient outcome (overall survival, OS; disease-free survival, DFS), Kaplan–Meier and log-rank models, as well as univariate and multivariate Cox regression models were carried out. The mean follow-up time of the cancer patients was 6.2 years (range 0.6–11.9 years). The REMARK criteria for prognostic studies (McShane et al, 2006) have been taken into consideration. Median values of RNA and miRs were used for grouping the serum samples according to low and high levels. As shown in Figure 3, higher serum concentrations of miR-202 (log-rank test: P=0.004, Cox: P=0.0001) significantly correlated with poor OS. The mean OS periods were 139 and 110 months (95% CI 129–149 and 96–125) in patients who had miR-202 concentrations of <0.3 and >0.3 ng ml−1 serum, respectively (Figure 3A). Based on these significant results of miR-202, we also performed univariate OS analyses with the postoperative miR-202 concentrations. Although the number of 34 postoperative samples is small, we detected that high serum levels of miR-202 after surgery correlated with decreased OS (log-rank test: P=0.063, Cox: P=0.022, data not shown). With the exception of a tendency of correlation of BORIS RNA concentrations with patient prognosis (P=0.071), no further significant associations were found. In addition, there was no correlation of the serum levels of circulating RNA and miRs with DFS.

Bottom Line: The serum levels of MAGE-A and BORIS mRNA, as well as let-7b were significantly higher in patients with invasive carcinomas than in patients with benign breast diseases or healthy women (P<0.001), whereas the levels of miR-202 were elevated in both patient cohorts (P<0.001).In uni- and multivariate analyses, high levels of miR-202 significantly correlated with poor overall survival (P=0.0001).Moreover, serum miR-202 is associated with prognosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

ABSTRACT

Background: MAGE-A (melanoma-associated antigen-A) are promising targets for specific immunotherapy and their expression may be induced by the epigenetic factor BORIS.

Methods: To determine their relevance for breast cancer, we quantified the levels of MAGE-A1, -A2, -A3, -A12 and BORIS mRNA, as well as microRNAs let-7b and miR-202 in pre- and postoperative serum of 102 and 34 breast cancer patients, respectively, and in serum of 26 patients with benign breast diseases and 37 healthy women by real-time PCR. The mean follow-up time of the cancer patients was 6.2 years.

Results: The serum levels of MAGE-A and BORIS mRNA, as well as let-7b were significantly higher in patients with invasive carcinomas than in patients with benign breast diseases or healthy women (P<0.001), whereas the levels of miR-202 were elevated in both patient cohorts (P<0.001). In uni- and multivariate analyses, high levels of miR-202 significantly correlated with poor overall survival (P=0.0001). Transfection of breast cancer cells with synthetic microRNAs and their inhibitors showed that let-7b and miR-202 did not affect the protein expression of MAGE-A1.

Conclusions: Based on their cancer-specific increase in breast cancer patients, circulating MAGE-A and BORIS mRNAs may be further explored for early detection of breast cancer and monitoring of MAGE-directed immunotherapies. Moreover, serum miR-202 is associated with prognosis.

Show MeSH
Related in: MedlinePlus