Background (pdf file)
"Epithelial Ovarian Cancer (EOC) is the most lethal female reproductive tract malignancy with nearly 200,000 new cases and >125,000 deaths attributable to the disease each year worldwide (1).........The search for reliable, specific, and sensitive serum-based biomarkers for EOC
has a long history and its major highlight remains the identification of CA125 nearly 30 years ago (4)."
"Papillary serous tumor samples were collected across all stages (five stage I/II, 11 stage III/IV, two disseminated peritoneal lesions, and two recurrent tumors). For comparison, two borderline tumors were also sequenced."
Research
IGFBP-4 tumor and serum levels are increased across all stages of epithelial ovarian cancer.
Published: 20 January 2012
Abstract (provisional)
Background
We sought to identify candidate serum biomarkers for the detection and surveillance of EOC. Based on RNA-Seq transcriptome analysis of patient-derived tumors, highly expressed secreted proteins were identified using a bioinformatic approach.
Methods
RNA-Seq was used to quantify papillary serous ovarian cancer transcriptomes.......... Serum samples from women with benign and malignant pelvic masses and serial samples from women during chemotherapy regimens were measured for IGFBP-4 by ELISA.....
Results
Insulin-like growth factor binding protein (IGFBP-4) was consistently present in the top 7.5% of all expressed genes in all tumor samples. We then screened serum samples to determine if increased tumor expression correlated with serum expression. In an initial discovery set of 21 samples, IGFBP-4 levels were found to be elevated in patients, including those with early stage disease and normal CA125 levels. In a larger and independent validation set (82 controls, 78 cases), IGFBP-4 levels were significantly increased (p<5x10-5). IGFBP-4 levels were ~3x greater in women with malignant pelvic masses compared to women with benign masses. ROC sensitivity was 73% at 93% specificity (AUC 0.816). In women receiving chemotherapy, average IGFBP-4 levels were below the ROC-determined threshold and lower in NED patients compared to AWD patients.
Conclusions
This study, the first to our knowledge to use RNA-Seq for biomarker discovery, identified IGFBP-4 as overexpressed in ovarian cancer patients.
Beyond this, these studies identified two additional intriguing findings. First, IGFBP-4 can be elevated in early stage disease without elevated CA125. Second, IGFBP-4 levels are significantly elevated with malignant versus benign disease. These findings provide the rationale for future validation studies.
pdf:
Future studies are planned primarily to increase sample size and diversity of patients. Unexpectedly, we noted that Hispanic cases have significantly higher serum IGFPB-4 levels compared to other non-Hispanic cases or all controls . We are unaware of previous reports or studies suggesting a biologic basis for this finding. Thus, this intriguing finding will be specifically explored in future studies.
pdf:
Future studies are planned primarily to increase sample size and diversity of patients. Unexpectedly, we noted that Hispanic cases have significantly higher serum IGFPB-4 levels compared to other non-Hispanic cases or all controls . We are unaware of previous reports or studies suggesting a biologic basis for this finding. Thus, this intriguing finding will be specifically explored in future studies.
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