HE4
Basics
Aliases:
This biomarker is also known as:- EDDM4,
- WAP domain containing protein HE4-V4,
- dJ461P17.6,
- Epididymal secretory protein E4,
- WAP four-disulfide core domain 2,
- epididymal protein 4,
- WFDC2,
- Major epididymis-specific protein E4,
- Putative protease inhibitor WAP5,
- WAP four-disulfide core domain 2 [Precursor],
- epididymis-specific, whey-acidic protein type, four-disulfide core,
- WAP5,
Description…
11 kDa protein that is a precursor to the epididymal secretory protein HE4; an inhibitor of an as yet unidentified protease. Highly expressed in a number of tumors cells lines, such ovarian, colon, breast, lung and renal cells lines.
Attributes
| QA State: | Accepted |
|---|---|
| Type: | Protein |
| Short Name: |
Organs
The following organs have data associated with this biomarker…
Lung
Attributes
| Phase: | Two |
|---|---|
| QA State: | Under Review |
Overview
Performance Comment
Supporting Study Data
The following studies/protocols provide evidence supporting HE4 indications for the Lung…
No supporting studies or protocols found.
Organ-Specific Protocols
No organ-specific protocols defined.
Organ-Specific Publications
No organ-specific publications defined.
Organ-Specific Resources
No organ-specific resources defined.
Ovary
Attributes
| Phase: | Three |
|---|---|
| QA State: | Accepted |
Overview
Selected for study because of upregulation (mRNA) and overexpression (protein) studies in ovarian cancer.
Performance Comment
Of the 28 ovarian cancer biomarkers tested in prediagnostic specimens, from the PLCO, CA125 remains the the single best biomarker for ovarian cancer and has its strongest signal within six months of diagnosis. HE4 alone was not a strong predictor. In 2009 HE4 was FDA approved to monitor for ovarian cancer recurrence, but not for early detection.
Supporting Study Data
The following studies/protocols provide evidence supporting HE4 indications for the Ovary…
PLCO Ovarian Phase III Validation Study
The obvious appeal of a strategy for the early detection of ovarian cancer is based upon the tendency for the disease to present at advanced stages associated with poor survival. If the diagnosis could be largely shifted to stages I or II associated with survival close to 90%, then the overall mortality for this disease could be dramatically altered without any advances in therapy. While approaches to ovarian cancer screening might include pelvic examination or sonography, a vast amount of information exists on potential blood markers for the disease. The precision of sensitivity and specificity estimates will be greater for larger versus smaller study populations; but the effect produced by differences in the populations studied cannot as easily be predicted. Most of the studies relied on phase II validation (i.e. case vs. control differences); but case groups may differ by disease stage and histology that may affect overall estimates of sensitivity. Many studies have limited case specimens to those collected pre-operatively, but not all were explicit in this regard. Few studies have used pre-diagnostic sera months or years before diagnosis, so-called Phase III studies. Similarly, the nature of the control group will also affect specificity estimates. Inclusion of surgical controls that have benign gynecological conditions such as fibroids, endometriosis, or benign ovarian tumors may elevate marker levels and lower specificity. One strategy, besides combining markers, to improve the sensitivity and/or specificity would be to use marker history in the context of serial testing. Elevated but declining marker levels would indicate a transient condition associated with marker production. Elevated but stable levels might indicate chronic but benign conditions associated with marker production, while elevated and increasing levels are more likely indicative of cancer. Our hypothesis is that a panel of biomarkers will have better performance characteristics as a screening test for pre-clinical ovarian cancer than any single marker, and yield a longer lead time than CA125 alone.
View more about this studyBiomarker Characteristics Summary
| Notes | Sensitivity | Specificity | Prevalence | NPV | PPV | Specific Assay Type |
|---|---|---|---|---|---|---|
| Cases chosen with diagnosis of ovarian cancer (on average) 9 months prior. Controls were matched to cases by age and timing of specimen collection including general population controls (50%), false positive CA125 (25%), and family history of breast cancer (25%). All cases (n=60). | 42.0 | 95.0 | 0.0 | |||
| Cases diagnosed <= 6 months after draw (n=25). | 68.0 | 95.0 | 0.0 | |||
| Cases diagnosed > 6 months after draw (n=35). | 23.0 | 95.0 | 0.0 |
Decision Rule
PMID:21372037
Additional Study-Specific Protocols
Study-Specific Publications
- A framework for evaluating biomarkers for early detection: validation of biomarker panels for ovarian cancer.
- Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens.
Study-Specific Resources
No study-specific resources defined.
SPORE/EDRN/PRE-PLCO Ovarian Phase II Validation Study
Phase II specimens from 160 ovarian cancer cases and 640 benign disease or general population controls were assembled from four Early Detection Research Network (EDRN) or Ovarian Cancer Specialized Program of Research Excellence (SPORE) sites and used to rank 51 biomarkers. Top markers in phase II specimens included CA125, HE4, transthyretin, CA15.3, and CA72.4 with sensitivity at 95% specificity ranging from 0.73 to 0.40.
View more about this studyBiomarker Characteristics Summary
| Notes | Sensitivity | Specificity | Prevalence | NPV | PPV | Specific Assay Type |
|---|---|---|---|---|---|---|
| For all cases, using all controls. Results from preliminary analysis, 50% of 114 sample set. Daniel Cramer laboratory. | 38.0 | 95.0 | 0.0 | |||
| For early stage (more than 12 months prior to diagnosis), using all controls. Results from preliminary analysis, 50% of 114 sample set. Daniel Cramer laboratory. | 51.0 | 95.0 | 0.0 | |||
| For late stage (within 12 months of diagnosis), using all controls. Results from preliminary analysis, 50% of 114 sample set. Daniel Cramer laboratory. | 17.0 | 95.0 | 0.0 | |||
| Cases chosen with diagnosis of ovarian cancer (on average) 9 months prior. Controls were matched to cases by age and timing of specimen collection including general population controls (50%), false positive CA125 (25%), and family history of breast cancer (25%). All cases (n=60). | 42.0 | 95.0 | 0.0 | |||
| Cases diagnosed <= 6 months after draw (n=25). | 68.0 | 95.0 | 0.0 | |||
| Cases diagnosed > 6 months after draw (n=35). | 23.0 | 95.0 | 0.0 |
Decision Rule
PMID:21372037
Additional Study-Specific Protocols
Study-Specific Publications
- A framework for evaluating biomarkers for early detection: validation of biomarker panels for ovarian cancer.
- Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens.
Study-Specific Resources
No study-specific resources defined.
Organ-Specific Protocols
No organ-specific protocols defined.
Organ-Specific Publications
Organ-Specific Resources
Studies
No associated studies or protocols found.
Publications
- The State of Molecular Biomarkers for the Early Detection of Lung Cancer.
- Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas.
- A framework for evaluating biomarkers for early detection: validation of biomarker panels for ovarian cancer.
- Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens.
- Lung cancer signatures in plasma based on proteome profiling of mouse tumor models.
Resources
- KEGG entry 10406 for WAP four-disulfide core domain 2
- Human Protein Atlas entry for human WFDC2 (HE4)
- UniProtKB/Swiss-Prot entry Q14508 for WFDC2_HUMAN, WAP four-disulfide core domain protein 2 [Precursor] also called HE4, WAP5
- HGNC entry 15939 for WAP four-disulfide core domain 2, also called WFDC2, HE4, WAP5
