Validity of the proliferation markers Ki67, TOP2A, and RacGAP1 in molecular subgroups of breast cancer.
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Validity of the proliferation markers Ki67, TOP2A, and RacGAP1 in molecular subgroups of breast cancer. / Milde-Langosch, Karin; Karn, Thomas; Müller, Volkmar; Witzel, Isabell; Rody, Achim; Schmidt, Markus; Wirtz, Ralph M.
In: BREAST CANCER RES TR, Vol. 137, No. 1, 1, 2013, p. 57-67.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Validity of the proliferation markers Ki67, TOP2A, and RacGAP1 in molecular subgroups of breast cancer.
AU - Milde-Langosch, Karin
AU - Karn, Thomas
AU - Müller, Volkmar
AU - Witzel, Isabell
AU - Rody, Achim
AU - Schmidt, Markus
AU - Wirtz, Ralph M
PY - 2013
Y1 - 2013
N2 - High proliferation rates are characteristic of cancer, and proliferation markers make up the majority of genes included in RNA-based prognostic gene signatures applied for breast cancer patients. Based on prior data on differences in molecular subgroups of breast cancer, we hypothesized that the significance of single proliferation markers might differ in luminal, Her2-positive and triple-negative subtypes. Therefore, we compared mRNA expression data of Ki67, TOP2A, and RacGAP1 using a pool of 562 Affymetrix U133A microarrays from breast cancer samples. "Luminal," "triple-negative," and "Her2-positive" subcohorts were defined by ESR1 and ERBB2 mRNA expression using pre-defined cut-offs. The analysis of the three potential proliferation markers revealed subtype-specific differences: in luminal carcinomas, expression of all three markers was a significant indictor of early recurrence in univariate and multivariate analysis, but RacGAP1 was superior to Ki67 and TOP2A in significance. In triple-negative tumors, only Ki67 was a significant and independent marker, whereas none of the markers showed a significant prognostic impact in Her2-positive cases. Within the group of luminal carcinomas, the proliferation markers had different impact depending on the treatment of patients: in untreated patients, Ki67, TOP2A, and RacGAP1 were significant and independent prognostic markers. In chemotherapy-treated patients, overexpression of all three markers was predictive for early recurrence, but only RacGAP1 retained significance in multivariate analysis. In contrast, RacGAP1 was the only predictive proliferation marker in the endocrine treatment group. These data point to subtype-specific differences in the relevance of proliferation-associated genes, and RacGAP1 might be a strong prognostic and predictive marker in the luminal subgroup.
AB - High proliferation rates are characteristic of cancer, and proliferation markers make up the majority of genes included in RNA-based prognostic gene signatures applied for breast cancer patients. Based on prior data on differences in molecular subgroups of breast cancer, we hypothesized that the significance of single proliferation markers might differ in luminal, Her2-positive and triple-negative subtypes. Therefore, we compared mRNA expression data of Ki67, TOP2A, and RacGAP1 using a pool of 562 Affymetrix U133A microarrays from breast cancer samples. "Luminal," "triple-negative," and "Her2-positive" subcohorts were defined by ESR1 and ERBB2 mRNA expression using pre-defined cut-offs. The analysis of the three potential proliferation markers revealed subtype-specific differences: in luminal carcinomas, expression of all three markers was a significant indictor of early recurrence in univariate and multivariate analysis, but RacGAP1 was superior to Ki67 and TOP2A in significance. In triple-negative tumors, only Ki67 was a significant and independent marker, whereas none of the markers showed a significant prognostic impact in Her2-positive cases. Within the group of luminal carcinomas, the proliferation markers had different impact depending on the treatment of patients: in untreated patients, Ki67, TOP2A, and RacGAP1 were significant and independent prognostic markers. In chemotherapy-treated patients, overexpression of all three markers was predictive for early recurrence, but only RacGAP1 retained significance in multivariate analysis. In contrast, RacGAP1 was the only predictive proliferation marker in the endocrine treatment group. These data point to subtype-specific differences in the relevance of proliferation-associated genes, and RacGAP1 might be a strong prognostic and predictive marker in the luminal subgroup.
KW - Adult
KW - Humans
KW - Aged
KW - Female
KW - Middle Aged
KW - Aged, 80 and over
KW - Multivariate Analysis
KW - Treatment Outcome
KW - Prognosis
KW - Disease-Free Survival
KW - Proportional Hazards Models
KW - Retrospective Studies
KW - Gene Expression
KW - Cell Proliferation
KW - Kaplan-Meier Estimate
KW - Receptor, erbB-2/metabolism
KW - Tumor Markers, Biological/genetics/metabolism
KW - DNA-Binding Proteins/genetics/metabolism
KW - Receptors, Progesterone/metabolism
KW - RNA, Messenger/genetics/metabolism
KW - Receptors, Estrogen/metabolism
KW - Antigens, Neoplasm/genetics/metabolism
KW - Breast Neoplasms/metabolism/mortality/pathology/therapy
KW - Carcinoma, Ductal, Breast/metabolism/mortality/pathology/therapy
KW - Carcinoma, Lobular/metabolism/mortality/pathology/therapy
KW - DNA Topoisomerases, Type II/genetics/metabolism
KW - GTPase-Activating Proteins/genetics/metabolism
KW - Ki-67 Antigen/genetics/metabolism
KW - Adult
KW - Humans
KW - Aged
KW - Female
KW - Middle Aged
KW - Aged, 80 and over
KW - Multivariate Analysis
KW - Treatment Outcome
KW - Prognosis
KW - Disease-Free Survival
KW - Proportional Hazards Models
KW - Retrospective Studies
KW - Gene Expression
KW - Cell Proliferation
KW - Kaplan-Meier Estimate
KW - Receptor, erbB-2/metabolism
KW - Tumor Markers, Biological/genetics/metabolism
KW - DNA-Binding Proteins/genetics/metabolism
KW - Receptors, Progesterone/metabolism
KW - RNA, Messenger/genetics/metabolism
KW - Receptors, Estrogen/metabolism
KW - Antigens, Neoplasm/genetics/metabolism
KW - Breast Neoplasms/metabolism/mortality/pathology/therapy
KW - Carcinoma, Ductal, Breast/metabolism/mortality/pathology/therapy
KW - Carcinoma, Lobular/metabolism/mortality/pathology/therapy
KW - DNA Topoisomerases, Type II/genetics/metabolism
KW - GTPase-Activating Proteins/genetics/metabolism
KW - Ki-67 Antigen/genetics/metabolism
M3 - SCORING: Journal article
VL - 137
SP - 57
EP - 67
JO - BREAST CANCER RES TR
JF - BREAST CANCER RES TR
SN - 0167-6806
IS - 1
M1 - 1
ER -