Biomarkers for Early Detection of Ovarian Cancer

• US 20080038754A1
• Filed: 07/14/2005
• Published: 02/14/2008
• Est. Priority Date: 07/14/2004
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Reddy, Srinivasa, Farias-Eisner, Robin
• Granted Patent: US 7,670,792 B2
• Time in Patent Office: Days
• US Class Current: 435/7.23
• CPC Class Codes: G01N 33/57449 of ovaries
• CPC Class Codes: G01N 33/721 Haemoglobin
• CPC Class Codes: Y10S 435/81 Packaged device or kit

Abstract

Three panels of biomarker proteins that can be used in the diagnosis of early-stage ovarian cancer (OC) are described. The biomarker panels not only permit the distinction of patients with ovarian neoplasia (benign or malignant) from normal subjects, but they also allow the identification of patients with early-stage (stage I/II) ovarian cancer from those patients with benign ovarian tumors or normal individuals. The invention additionally provides methods for detecting and treating various cancers, including cancer of the ovary using OC-related molecules.

Claims

1. A method of screening for ovarian neoplasia in a subject comprising:

(a) measuring hemoglobin in a tissue sample of the subject, and

(b) comparing the measured hemoglobin of the tissue sample to a measurement of hemoglobin in normal tissue, wherein a two-fold or greater increase in the measured of hemoglobin of the tissue sample compared to the measurement of hemoglobin in normal tissue is indicative of ovarian neoplasia.

2. The method of claim 1, wherein the measuring further comprises measuring at least two biomarkers in the tissue sample, wherein the at least two biomarkers are selected from a first group of biomarkers whose up-regulation is associated with ovarian cancer and/or a second group of biomarkers whose down-regulation is associated with ovarian cancer,

wherein the first group of biomarkers consists of:

(i) a protein having an m/z of 1.953 kDa, 2.065 kDa, 2.216 kDa, 2.928 kDa, 2.937 kDa, 3.143 kDa, 3.423 kDa, 3.427 kDa, 4.144 kDa, 4.375 kDa, 4.456 kDa, 4.629 kDa, 5.064 kDa, 7.550 kDa, 7.657 kDa, 7.756 kDa, 8.117 kDa, 10.874 kDa, 16.850 kDa, 18.559 kDa, 18.912 kDa, 18.98 kDa, 19.186 kDa, 22.959 kDa, 29.19 kDa, 29.512 kDa, 30.103 kDa, 33.217 kDa, 36.296 kDa, 42.401 kDa, 53.11 kDa (α

1-AT), 53.531 kDa, 83.689 kDa, or 84.133 kDa;

and wherein the second group of biomarkers consists of;

(ii) a protein having an m/z of 6.884 kDa, 6.931 kDa, 12.785 kDa (transthyretin), 13.797 kDa (transthyretin), 20.989 kDa, 27.595 kDa, 27.977 kDa (apolipoprotein Al), 40.067 kDa, 54.605 kDa, 78.9 kDa (transferrin), 79.909 kDa, 90.834 kDa, 91.878 kDa, 92.935 kDa, 105.778 kDa, or 106.624 kDa (IgG); and

comparing the measurements of the at least two biomarkers in the tissue sample to a known profile of the at least two biomarkers in normal tissue,

wherein a measurement indicating a two-fold or greater increase in a member of the first group of biomarkers, or a two-fold or greater decrease in a member of the second group of biomarkers, relative to normal tissue, is indicative of ovarian neoplasia.

3. The method of claim 2, wherein the at least two biomarkers comprise transthyretin (12.785 kDa and/or 13.797 kDa), apolipoprotein Al (27.977 kDa) and/or transferrin (78.9 kDa) of the second group of biomarkers.

4. The method of claim 1, wherein the tissue sample comprises serum.

5. The method of claim 1, wherein the measuring comprises spectrometry.

6. The method of claim 5, wherein the spectrometry comprises surface enhanced laser desorption/ionization (SELDI) mass spectrometry.

7. The method of claim 1, wherein the measuring comprises immunoassay.

8. The method of claim 1, wherein the first group of biomarkers consists of proteins having an m/z of 4.144 kDa, 4.456 kDa, 7.756 kDa, 15.074 kDa, 15.85 kDa, 18.912 kDa, 22.959 kDa, 30.103 kDa and 53.531 kDa, and the second group of biomarkers consists of a protein having an m/z of 12.785 kDa.

9. The method of claim 8, wherein the measuring comprises measuring each member of the first and second groups of biomarkers.

10. The method of claim 1, wherein the first group of biomarkers consists of proteins having an m/z of 3.143 kDa, 4.456 kDa, 5.064 kDa, 7.756 kDa, 8.117 kDa, 16.85 kDa, and 18.559 kDa, and the second group of biomarkers consists of proteins having an m/z of 13.797 kDa, 20.989 kDa, 27.977 kDa, 78.715 kDa, 92.935 kDa and 106.624 kDa.

11. The method of claim 10, wherein the measuring comprises measuring each member of the first and second groups of biomarkers.

12. The method of claim 1, wherein the first group of biomarkers consists of proteins having an m/z of 4.456 kDa, 15.85 kDa, 18.912 kDa, 22.959 kDa and 30.103 kDa.

13. The method of claim 12, wherein the measuring comprises measuring each member of the first group of biomarkers.

14. The method of claim 13, further comprising:

(a) measuring a validation biomarker panel I (VBPI) consisting of a first VBPI group of biomarkers that consists of a protein having an m/z of 3.143 kDa, and a second VBPI group of biomarkers that consists of proteins having an m/z of 13.797 kDa, 20.989 kDa, 78.715 kDa and 106.624 kDa;

(b) wherein a measurement indicating a two-fold or greater increase in a member of the first VBPI group of biomarkers, or a two-fold or greater decrease in a member of the second VBPI group of biomarkers, relative to normal tissue, is indicative of malignant ovarian neoplasia.

15. The method of claim 14, further comprising:

(a) measuring a validation biomarker panel II (VBPII) consisting of a first VBPII group of biomarkers that consists of proteins having an m/z of 5.064 kDa and 16.85 kDa, and a second VBPII group of biomarkers that consists of proteins having an m/z of 27.977 kDa and 92.935 kDa;

(b) wherein a measurement indicating a two-fold or greater increase in a member of the first VBPII group of biomarkers, or a two-fold or greater decrease in a member of the second VBPII group of biomarkers, relative to normal tissue, is indicative of malignant ovarian neoplasia.

20. The method of claim 1, further comprising measuring CA125.

16. A method of detecting ovarian neoplasia in a test subject comprising:

(a) measuring biomarkers consisting of transthyretin, hemoglobin, ApoAI and transferrin in a tissue sample from the test subject; and

(b) comparing the amount of the biomarkers in the tissue sample with the amount of biomarkers observed in a tissue sample from a normal subject, wherein increased hemoglobin and decreased transthyretin, ApoAI and transferrin are indicative of ovarian neoplasia in the test subject.

17. The method of claim 16, wherein the ovarian neoplasia comprises a mucinous tumor.

18. A method of screening for ovarian neoplasia in a subject comprising:

(a) measuring at least three biomarkers in a tissue sample of the subject, wherein the at least three biomarkers are selected from a first group of biomarkers whose up-regulation is associated with ovarian cancer and a second group of biomarkers whose down-regulation is associated with ovarian cancer,

wherein the first group of biomarkers consists of;

(i) a protein having an m/z of 1.953 kDa, 2.065 kDa, 2.216 kDa, 2.928 kDa, 2.937 kDa, 3.143 kDa, 3.423 kDa, 3.427 kDa, 4.144 kDa, 4.456 kDa, 4.629 kDa, 5.064 kDa, 7.550 kDa, 7.657 kDa, 7.756 kDa, 8.117 kDa, 10.874 kDa, 15.074 kDa (hemoglobin A), 15.850 kDa (hemoglobin B), 16.850 kDa, 18.559 kDa, 18.912 kDa, 18.98 kDa, 19.186 kDa, 22.959 kDa, 29.19 kDa, 29.512 kDa, 33.217 kDa, 36.296 kDa, 42.401 kDa, 53.11 kDa (α

1-AT), 53.531 kDa, 83.689 kDa, or 84.133 kDa;

and wherein the second group of biomarkers consists of;

(ii) a protein having an m/z of 6.884 kDa, 6.931 kDa, 20.989 kDa, 27.595 kDa, 40.067 kDa, 54.605 kDa, 79.909 kDa, 90.834 kDa, 91.878 kDa, 92.935 kDa, 105.778 kDa, or 106.624 kDa (IgG); and

(b) comparing the measurements of the at least three biomarkers in the tissue sample to a known profile of the at least three biomarkers in normal tissue,

wherein a measurement indicating a two-fold or greater increase in a member of the first group of biomarkers, or a two-fold or greater decrease in a member of the second group of biomarkers, relative to normal tissue, is indicative of ovarian neoplasia.

19. The method of claim 18, wherein the measuring further comprises measuring at least one additional biomarker selected from:

proteins having an m/z of 4.375 kDa and 30.103 kDa of the first group of biomarkers; and

proteins having an m/z of 12.785 kDa (transthyretin), 13.797 kDa (transthyretin), 27.977 kDa (ApoA1) and 78.715 kDa (transferrin) of the second group of biomarkers.

21. A kit comprising:

(a) at least one agent that binds a biomarker selected from α

-hemoglobin, β

-hemoglobin, alpha1-antitrypsin (α

1-AT) and any combination thereof; and

(b) instructions for use of the at least one agent for determining status of ovarian neoplasia in a test sample.

22. The kit of claim 21, further comprising a container for housing the at least one agent.

23. The kit of claim 21, further comprising at least one agent that binds a biomarker selected from transthyretin, ApoAI, transferrin, CA125 and any combination thereof.

24. The kit of claim 21, further comprising a substrate to which the at least one agent is bound.

25. The kit of claim 21, wherein the agent is an antibody that specifically binds the biomarker.

26. The kit of claim 21, wherein the agent is a mass spectrometry probe.

27. The kit of claim 21, wherein the status of ovarian neoplasia comprises absence of neoplasia, benign, low malignant potential (LMP), malignant neoplasia.