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What are the Biomarkers of Ovarian Cancer?

Garrett Heinrich
Tags: Cancer,

  • Ovarian cancer is the deadliest gynecological disease and is often not detected until the later stages of the disease due to a lack of overt symptoms.
  • Testing for non-invasive biomarkers can be an effective way for early detection of ovarian cancer and predict future prognosis.
  • Methods that span the entire genome within tumor cells can identify novel biomarkers that can be used to develop new diagnostics.



Ovarian cancer is the eighth most common cancer in women, with the highest mortality of any gynecological disease. There were 21,410 new cases in the US in 2021, representing 1.1% of all new cancer cases (1). However, ovarian cancer was responsible for 13,770 deaths in 2021, representing 2.3% of all cancer deaths, largely due to the cancer rarely being detected in its early stages. Early ovarian cancer is often present with no symptoms, leading to silent cancer advancement and a high mortality rate when finally discovered later (i.e., the 5-year survival rate is just 49.1%). Common symptoms are easily written off as related to other conditions. These common symptoms include bloating, difficulty eating, lower abdominal pain, back pain, abnormal vaginal bleeding, nausea, vomiting, indigestion, weight fluctuations, increased urinary frequency, tiredness, and shortness of breath (1). Ovarian cancer can be tested with physical exams for lumps or swelling, and ultrasounds for abnormal growth, but a tumor biopsy is ultimately required to confirm its presence. Around 1.2% of all women will be diagnosed with ovarian cancer in their lifetime. With a lower mortality rate associated with earlier disease discovery, developing effective biomarkers is important in identifying individuals most at risk or in the early stages of tumor development.

Unfortunately, predicting who will develop ovarian cancer is complicated by the fact that few cases can be traced by family history. In addition, the disease is heterogeneous with no single cause, and related genetic mutations are commonly somatic, which means that most are not inherited gene mutations but changes that accumulate over a lifetime. While this makes most ovarian cancer risk difficult to determine, 10-25% of ovarian cancer may be caused by inherited genes. However, the exact risk contribution of each is still a matter of debate. In these cases, the risk of ovarian cancer is elevated when the subject also has a hereditary cancer syndrome. The most common mutations related to these syndromes are the BRCA1 or BRCA2 gene mutations. Another syndrome called Lynch syndrome results from mutations in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes. Mutations in the STK11 gene result in Puetz-Jeghers syndrome, which correlates with elevated ovarian cancer risk (2). Even with these challenges, several biomarkers have been developed to help identify early ovarian cancer and predict the prognosis and chance of survival.


Carbohydrate Antigen 125 (CA125)

Carbohydrate Antigen 125, aka cancer antigen 125, is a protein elevated in some people with a very high risk of ovarian cancer. As a screening tool in the blood, its effectiveness is limited by the fact that other conditions can increase CA125 levels, such as endometriosis, liver cirrhosis, menstruation, uterine fibroids, and some other cancers. CA125 can still be used as a screen in individuals with high risk or the BRCA mutations, or to check for cancer recurrence after treatment. Enzo offers a CA125 monoclonal antibody that can be used with immunohistochemistry to detect the presence of CA125 in tissue (Figure 1).

CA-125 antibody stained endometrial tissue

Figure 1. Formalin-fixed paraffin-embedded endometrial tissue stained using Enzo’s CA-125 antibody (ENZ-ABS775). IHC staining was performed on an automated Leica BOND III.



Osteopontin (OPN)

Osteopontin (OPN) is a phosphorylated glycoprotein that has increased expression in many cancers, including ovarian cancer. OPN is secreted by activated T lymphocytes, macrophages, and leukocytes. OPN was identified as elevated by a microarray on ovarian cancer cell lines and in plasma from a study of women with epithelial ovarian cancer (EOC). OPN is believed to promote tumor survival through a number of pathways. These include the activation of the Phosphoinositide 3-kinase (PI3-K)/Akt pathway and induction of Hypoxia inducible factor 1 alpha (HIF-1α), as well as by inhibiting inducible nitric oxide synthase (iNOS) and preventing macrophage cytotoxic attack on cancer cells. OPN expression can also be used to predict tumor metastasis to other organs. The ability to measure OPN in either urine or blood makes it a promising candidate as a non-invasive biomarker for early ovarian cancer diagnosis. Enzo’s Osteopontin (human) ELISA kit is validated in plasma and urine and can be effectively incorporated into your ovarian cancer research.


Kallikreins

Kallikrein-related peptidases (KLKs) are a family of 15 related serine proteases, all located on human chromosome 19. Many kallikreins have been identified to be expressed at higher levels in various solid tumor types, with 12 of the 15 upregulated in ovarian cancer. Kallikrein 7 (KLK7), in particular, has been implicated in ovarian cancer (along with other cancers including breast, pancreatic, colorectal, and lung cancer), and is associated with poor prognosis and resistance to paclitaxel (a.k.a. Taxol, a common chemotherapy medication). KLK7 cleaves proteins after phenylalanine, tyrosine, and leucine. In ovarian cancer, KLK7 enhances the expression of α5/β1 integrins, allowing cell adhesion to fibronectin and promoting intra-abdominal dissemination, or the outgrowth of cancer cells from the original tumor site. Enzo offers a Kallikrein-7 (human) ELISA kit that can measure KLK7 in human serum as well as ELISAs for KLK6 and KLK8.


Vascular Endothelial Growth Factor (VEGF)

Vascular Endothelial Growth Factor (VEGF) is a cytokine that has been found to contribute to ovarian cancer through its regulation of angiogenesis and vascular permeability. VEGF is a family of glycoproteins with multiple isoforms due to alternative splicing of its RNA. Like Osteopontin, VEGF can also act on the PI3K/Akt pathway to promote cell survival. VEGF is essential for normal reproductive function as the ovary undergoes regular bouts of angiogenesis during the ovulatory cycle. Ovarian tumor cells, monocytes, macrophages, and fibroblasts all produce VEGF and contribute to tumor vascularization in early cancer development. VEGF is also involved in tumor metastasis, and levels can be used as a prognostic indicator of survival time. The VEGF (human) ELISA kit from Enzo can be used as a sensitive method to detect this cytokine in serum, plasma, or cell culture supernatants. The monoclonal antibody bevacizumab (brand name Avastin) is a VEGF-A inhibitor approved by the US Food and Drug Administration (FDA). Bevacizumab is used in combination with chemotherapy (and sometimes other cancer drugs) in subjects with stage III or IV ovarian cancer (2).


How do you find new biomarkers?

While each of the above tests are used to detect the presence of ovarian cancer and/or the development of the disease, none can detect every ovarian tumor and new tests that are more definitive and able to catch the cancer at an earlier stage are still under development. One strategy has been to use a combination of biomarker tests to increase diagnostic accuracy with higher sensitivity and specificity.
Other researchers looking for new biomarkers aim to analyze the whole genome for aberrations. Comparative genomic hybridization (CGH) can detect DNA copy number gains and losses associated with tumor genetics. Identifying the chromosomal location of DNA mutations and alterations can help reveal genes that can be targeted for new biomarker diagnostics. Kamieniak et al. (2013) used Enzo’s CYTAG CGH labeling kit to perform high-resolution array CGH in formalin-fixed paraffin-embedded (FFPE) epithelial ovarian tumors. Within the 72 tumor samples tested, 57 were from patients at high risk of breast or ovarian cancer, and 15 were from sporadic tumors. Some of the tumor patients had a family history of ovarian and/or breast cancer, and all were tested for BRCA1 and BRCA2 gene mutations. Their array identified several chromosomal gains and losses in many different regions corresponding to both known genes of interest in ovarian cancer and new gene mutations, and mutations specific to the patient risk and tumor type. They also found an association between chromosomal DNA losses with BRCA1 and/or BRCA2 mutations (3). These newly identified genes could then be followed up to determine if they could produce valid biomarkers, whether in the general population or in patients, specifically with BRCA1 and/or BRCA2 mutations.


How can Enzo help guide your research?

Are you searching for new ovarian cancer biomarkers, or are you looking for tools to test for ovarian cancer in your research subjects? Do you have more questions on ovarian cancer and how to find the best tools to support your research or testing development? Reach out to our Technical Support Team. We will be happy to assist!

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References:

  1. Ovarian Cancer — Cancer Stat Facts
  2. https://rarediseases.info.nih.gov/diseases/7295/ovarian-cancer
  3. M.M. Kamieniak et al. DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas. BJC (2013) 108, 1732-1742. Abstract

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