This document discusses novel biomarkers for the diagnosis of ovarian carcinoma. It covers gene-based biomarkers like inherited mutations in BRCA1, BRCA2, and DNA mismatch repair genes. Epigenetic changes like DNA methylation and histone modifications in tumor suppressor genes are also discussed. For protein-based biomarkers, the document outlines proteomic pattern diagnostics using mass spectrometry techniques, as well as single biomarker panels like OVA1 that include CA-125, beta-2 microglobulin, transferrin, apolipoprotein A1, and transthyretin. While no single biomarker currently exists for early detection of ovarian cancer, these emerging approaches show promise as non-invasive diagnostic tools.
The types of breast cancer biomarkers in cancer detection provide a unique view of what is occurring in the bloodstream and can help improve breast cancer detection.
The types of breast cancer biomarkers in cancer detection provide a unique view of what is occurring in the bloodstream and can help improve breast cancer detection.
Breast cancer & biomarkers, their types, novelty of breast cancer biomarkers. Detailed study of her2, p53, BRCA1, BRCA2, DPD, 21-Gene signature, 70-Gene signature, cd106, vcam1, nlr, bFGF, mammaglobin, ER, PR, CEA. Pthological samples for biomarkers test, Ranges of various biomarkers, breast cancer diagnosis, prognosis, occurance, selection of breast caner treatment like targeted therapy.
Tumor markers (TMs) refer to a class of substances that are directly produced by tumor cells or other cells of the body in response to tumors during its development and proliferation stages. Tumor markers essentially are proteins, hormones,
enzymes (isozymes), polyamines, and oncogene products, which presents in the blood, body fluids, cells or tissues of patients. They can quantitatively and qualitatively reveal the presence of tumors, which provides strong experimental
basis to estimate what the type of tumor is, what stage of the tumor has been developed to, the therapeutic effect and prognosis. www.antibody-creativebiolabs.com
It describes the prevalence of Breast Cancer among BRCA 1/2 mutations with special consideration to biological background, detection and screening, actions taken upon discovering mutation carriers and whether we have a different therapeutic algorithm than sporadic cases. Special emphasis on the role of PARP inhibitors in the management of metastatic disease.
Prophylaxis and early diagnosis of breast cancerINVICTA GENETICS
The BRCA 1/2 Test allows performing the analysis of the entire sequence coding both genes in order to detect the mutations which influence the increased risk of developing a cancer disease. One of the most important indications for performing the test is the positive family history.
Tumour Markers are substances present in the tumour, produced by the tumour or by the host as a response to the presence of the tumour, providing information about biological characteristics of the tumour. these tumour markers may specific for the tissue but often get elevated in neoplastic as well non-neoplastic lesions, further Various analytical platforms available for serum tumour markers lack standardisation. These factors add to interpretative challenges in serum tumour markers
Tumor markers (also known as biomarkers) are substances found at higher than normal levels in the blood, urine, or body tissue of some people with cancer. Although cancer cells often produce tumor markers, other healthy cells in the body produce them as well.
Tumor markers are substances, such as proteins, biochemicals, hormones or enzymes, produced by tumor cells or by the body in response to tumor cells. As tumor cells multiply, cancer spreads, and tissue is damaged, these substances increase and leak into the bloodstream. Tumor marker levels in blood help physicians evaluate people for certain types of cancer
In a narrow sense of cancer biomarker, it is limited to proteins the most used to challenge in the clinical applications, especially in the CAR-T therapy. Specifically, a cancer biomarker of the CAR-T provides the most prominent signal of cancer cells for distinguishing from normal cells and the most effective CAR T target for immune recognition and destruction. https://www.creative-biolabs.com/car-t/biomarker-identification-selection.htm
Tumor markers
Many cancers are associated with the abnormal production of some molecules which can be measured in plasma. These molecules are known as tumor markers.
A good tumor maker should have those properties:
1. A tumor marker should be present in or produced by tumor itself.
2. A tumor marker should not be present in healthy tissues.
3. Plasma level of a tumor marker should be at a minimum level in healthy subjects and in benign conditions.
4. A tumor marker should be specific for a tissue, it should have different immunological properties when it is synthesized in other tissues.
5. Plasma level of the tumor marker should be in proportion to the both size of the tumor and the activity of the tumor.
6. Half-life of a tumor should not be very long
7. A tumor marker should be present in plasma at a detectable level, even though tumor size is very small
Breast cancer & biomarkers, their types, novelty of breast cancer biomarkers. Detailed study of her2, p53, BRCA1, BRCA2, DPD, 21-Gene signature, 70-Gene signature, cd106, vcam1, nlr, bFGF, mammaglobin, ER, PR, CEA. Pthological samples for biomarkers test, Ranges of various biomarkers, breast cancer diagnosis, prognosis, occurance, selection of breast caner treatment like targeted therapy.
Tumor markers (TMs) refer to a class of substances that are directly produced by tumor cells or other cells of the body in response to tumors during its development and proliferation stages. Tumor markers essentially are proteins, hormones,
enzymes (isozymes), polyamines, and oncogene products, which presents in the blood, body fluids, cells or tissues of patients. They can quantitatively and qualitatively reveal the presence of tumors, which provides strong experimental
basis to estimate what the type of tumor is, what stage of the tumor has been developed to, the therapeutic effect and prognosis. www.antibody-creativebiolabs.com
It describes the prevalence of Breast Cancer among BRCA 1/2 mutations with special consideration to biological background, detection and screening, actions taken upon discovering mutation carriers and whether we have a different therapeutic algorithm than sporadic cases. Special emphasis on the role of PARP inhibitors in the management of metastatic disease.
Prophylaxis and early diagnosis of breast cancerINVICTA GENETICS
The BRCA 1/2 Test allows performing the analysis of the entire sequence coding both genes in order to detect the mutations which influence the increased risk of developing a cancer disease. One of the most important indications for performing the test is the positive family history.
Tumour Markers are substances present in the tumour, produced by the tumour or by the host as a response to the presence of the tumour, providing information about biological characteristics of the tumour. these tumour markers may specific for the tissue but often get elevated in neoplastic as well non-neoplastic lesions, further Various analytical platforms available for serum tumour markers lack standardisation. These factors add to interpretative challenges in serum tumour markers
Tumor markers (also known as biomarkers) are substances found at higher than normal levels in the blood, urine, or body tissue of some people with cancer. Although cancer cells often produce tumor markers, other healthy cells in the body produce them as well.
Tumor markers are substances, such as proteins, biochemicals, hormones or enzymes, produced by tumor cells or by the body in response to tumor cells. As tumor cells multiply, cancer spreads, and tissue is damaged, these substances increase and leak into the bloodstream. Tumor marker levels in blood help physicians evaluate people for certain types of cancer
In a narrow sense of cancer biomarker, it is limited to proteins the most used to challenge in the clinical applications, especially in the CAR-T therapy. Specifically, a cancer biomarker of the CAR-T provides the most prominent signal of cancer cells for distinguishing from normal cells and the most effective CAR T target for immune recognition and destruction. https://www.creative-biolabs.com/car-t/biomarker-identification-selection.htm
Tumor markers
Many cancers are associated with the abnormal production of some molecules which can be measured in plasma. These molecules are known as tumor markers.
A good tumor maker should have those properties:
1. A tumor marker should be present in or produced by tumor itself.
2. A tumor marker should not be present in healthy tissues.
3. Plasma level of a tumor marker should be at a minimum level in healthy subjects and in benign conditions.
4. A tumor marker should be specific for a tissue, it should have different immunological properties when it is synthesized in other tissues.
5. Plasma level of the tumor marker should be in proportion to the both size of the tumor and the activity of the tumor.
6. Half-life of a tumor should not be very long
7. A tumor marker should be present in plasma at a detectable level, even though tumor size is very small
Genetics and "Genomics" Dr. Roisin O’Cearbhaill slidesbkling
The words genetics and “genomics” are sometimes used interchangeably, but what exactly do these two terms mean and how are they different?
This program will help unpack the confusion surrounding these very different forms of testing. Join Peggy Cottrell, MS, CGC, board certified genetic counselor at Sharsheret and Dr. Roisin O’Cearbhaill, Research Director of the Gynecologic Medical Oncology Service at Memorial Sloan Kettering Cancer Center (MSKCC), as they explain the types of tests you may have had and what tests you should consider.
PREDICTIVE AND DIAGNOSTIC BIOMARKERS FOR OVARIAN CANCERDr. Girija Wagh
OVARIAN CANCER HAS ELUDED SCREENING AND EARLY DETECTION . SEVERAL BIOMARKERS ARE PROPOSED AND HERE IS A AN UPDATED REVIEW OF WHAT EXISTS IN THE CURRENT CLIMATE FOR THE SAME Ovarian carcinomas relate to highest death rate in gynecologic malignancies as absence of symptoms shield the disease in the early stage. Current evidences have been devoted to discovering early effective screening mechanism prior to the onset of clinical symptoms.Serum biomarkers may aid in the diagnosis of Early ovarian cancer
Distinguish malignant from benign disease
Prevent unnecessary surgery
Improve rates of early detection. Prof Girija Wagh is the Head of the Department of OBG at Bharati University Medical College and Hospital and a well acknowledged teacher and a researcher.This overview will certainly help the learners to approach this condition with more promise
Adipokines as a potential biomarkers for vascular complications in type 2 dia...Moustafa Rezk
Adipose tissue has come into focus as an endocrine organAdipose tissue secretes a variety of bioactive peptides (adipokines).Adipokines may locally regulate fat mass by modulating adipocyte size/number or angiogenesis and inversely increased fat mass leads to dysregulation of adipocyte functions.
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New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
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4. Diagnostic approach
Laboratory
Serum CA125
Increased in about 80–85% of women with advanced
ovarian cancer
Only 50% of patients with stage I ovarian cancer will
have an elevated CA-125 level.
Mostly considered as a useful biomarker for follow-up
(e.g., monitoring of progression and regression)
But has neither sufficient sensitivity nor specificity for
early detection
3/7/2020 5:00 AM
4
5. Other tumor markers for ovarian cancer
3/7/2020 5:00 AM
5
CA19-9
CA72-4
CA15-3
Haptoglobin- alpha
Mesothelin
Lysophosphatidic acid
Osteopontin
7. Risk of Malignancy Index (RMI)
3/7/2020 5:00 AM
7
The best cutoff value for RMI
is
200
RMI score
=
Ultrasound score x menopausal score x CA125 level in U/ml
8. Strategies for early detection require high sensitivity for
early stage disease (>75%) , and must have extremely
high specificity (99.6%) to attain a good PPV.
There is no single screening test nor any existing screening
paradigm that currently has such high specificity. Thus,
discovery of specific molecular biomarkers /panels is
emerging as an important requirement for early detection
of ovarian cancer.
3/7/2020 5:00 AM
8
9. Potential biomarkers for ovarian cancer
diagnosis
A-Gene-based ovarian
cancer biomarkers
1. Inherited gene
mutations
2. Epigenetic changes
3. Gene expression
B-Protein-based ovarian
cancer biomarkers
1. Proteomic pattern diagnostics
2. Serum proteomic profiling
3. Single or panel novel
biomarkers
C-Emerging ovarian cancer
biomarkers
1. MicroRNA-based ovarian
cancer biomarkers
2. Metabolite-based ovarian
cancer biomarkers
3/7/2020 5:00 AM
9
10. A-Gene-based ovarian cancer biomarkers
1-Inherited gene mutations(10%):
Cancer Type
General Population
Risk
Risk for Malignancy
BRCA1 BRCA2
Breast 12% 46%-87%% 38%-84%
Second primary
breast
2% within 5 years
21.1% within 10 yrs
83% by age 70
10.8% within 10 yrs
62% by age 70
Ovarian 1%-2% 39%-63% 16.5%-27%
Male breast 0.1% 1.2% Up to 8.9%%
Prostate 6% through age 69 8.6% by age 65
15% by age 65
20% lifetime
Pancreatic 0.50% 1%-3% 2%-7%
Melanoma
(cutaneous &
ocular)
1.6% Elevated Risk
3/7/2020 5:00 AM
10
Van den Broek AJ, et al. Worse breast cancer prognosis of BRCA1/BRCA2 mutation carriers: what's the evidence? A systematic review with meta-
analysis. PLoS One. 2015;10:e0120189.
a-Germline mutations of the BRCA1 and BRCA2 tumor suppressor genes (90%)
12. A-Gene-based ovarian cancer biomarkers
3/7/2020 5:00 AM
12
1-Inherited gene mutations(10%):
b- Germline mutations of the DNA mismatch repair(10%)
o ~7% of hereditary ovarian cancer cases
o 5% of all colorectal cancer cases
o Most common cancers: colon,endometrial
o Increased incidence of other adenocarcinomas,
including stomach, small bowel
HNPCC or Lynch Syndrome
Mismatch repair genes (MMR) including
MLH1, MSH2, and MSH6
13. Mismatch Repair
Hereditary NonPolyposis Colorectal Cancer
Increased incidence of cancers of the colon,
endometrium, ovary, stomach, and upper urinary
tract
Autosomal dominant
HNPCC due to germline mutations in mismatch
repair genes
hMSH2, hMLH1, MSH6, (PMS1, PMS2)
14. A-Gene-based ovarian cancer biomarkers
3/7/2020 5:00 AM
14
2 - Epigenetic changes:
I. DNA methylation
II. Histone modifications.
Hypermethylation of at least one of a panel of 6 tumor suppressor gene promoters:
BRCA1
RAS association domain family protein 1A (RASSF1A)
Adenomatous polyposis coli (APC)
p14ARF
p16INK4a
Death associated protein-kinase (DAPKinase)
Most studies to date have focused on candidate gene approaches to identify:
Hypermethylated
Silenced candidate tumor suppressor genes
Specific regions of hypomethylation in ovarian cancer
Epigenetic markers can be assayed in circulating DNA of the blood, which provides
the promise of a non-invasive test
15. A-Gene-based ovarian cancer biomarkers
Identifying different
subtypes of ovarian cancer
Identifying cancer likely to
be responsive to therapy
•Claudin 3 (CLDN3)
•WAP four-disulfide core
domain 2 (WFDC2or HE4)
•Folate receptor 1 (FOLR1)
•collagen type XVIII a1
•Cyclin D1 (CCND1)
3/7/2020 5:00 AM
15
3-Gene expression
Microarray technology Data analysis software SAGE
Distinguishing normal
ovarian tissue from
ovarian tumors
16. •Although gene-based biomarkers are known to
have potential for ovarian cancer, there is still no
novel cancer specific biomarker in clinic.
•This is due to the fact that gene levels are not
always linked directly to levels of proteins, the
molecules that biologically do functions.
3/7/2020 5:00 AM
16
17. B-Protein-based ovarian cancer biomarkers
Proteomics has emerged as a powerful
technology to decipher biological processes.
It means large-scale characterization of
proteins including more complicated
features like isoforms, modifications,
interactions and functional structures.
3/7/2020 5:00 AM
17
1. Proteomic pattern diagnostics
18. 3/7/2020 5:00 AM
18
Published studies show that
proteomic pattern analysis in ovarian
cancer has the potential to be a novel,
highly sensitive diagnostic tool for
detection at an early stage.
19. Among several different MS-based proteomics
approaches, currently:
1. Matrix-assisted laser desorption and ionization
time-of-flight (MALDI-TOF)
2. Surface-enhanced laser desorption and
ionization time-of-flight (SELDI-TOF) are two
of the most frequently used methods for new
biomarker discovery
3/7/2020 5:00 AM
19
20. With the impressive results in terms of specificity and
sensitivity in ovarian cancer detection, some criticism
regarding
1. Instrument reproducibility
2. Quality control
3. Standard operating procedures for sample collection,
handling and shipping have been raised.
Recently researchers have emphasized more and more on
the importance of reliability and reproducibility of a MS
technology in protein profiling 3/7/2020 5:00 AM
20
21. 2-Single or panel novel biomarkers
The OVA1 panel
3/7/2020 5:00 AM
21
CA-125
Beta-2 microglobulin
Transferrin
ApolipoproteinA1
Transthyretin
OVA1 above 5.0 in premenopausal people and 4.4 in postmenopausal
people indicates a high risk for cancer.
Ovarian cancer is the most lethal of all common gynecologic malignancies, with more than 204,000 new cases and 125,000 deaths each year, accounting for 4% of all cancer cases and 4.2% of all cancer deaths in women around the world
Contributing to the poor prognosis of ovarian cancer is the lack of symptoms in the early stages of the disease.
More than 70% of the women are diagnosed with late stage disease [International Federation of Gynecology and Obstetrics (FIGO) stage III or IV], after distant metastasis has occurred. The 5-year survival rate for women diagnosed with late stage disease is less than 20% even with extensive surgery and chemotherapy, compared to up to 90% for women diagnosed with early stage disease .
CA-125, which is significantly associated with ovarian cancer, is the only serum molecule now normally used in the clinical practice. While CA-125 serum levels are increased in about 80–85% of women with advanced ovarian cancer, only 50% of patients with stage I ovarian cancer will have an elevated CA-125 level. Therefore, CA-125 is mostly considered as a useful biomarker for follow-up (e.g., monitoring of progression and regression) of patients with established ovarian cancer, but has neither sufficient sensitivity nor specificity for early detection . Positive predictive value is the probability that subjects with a positive screening test truly have the disease. Negative predictive value is the probability that subjects with a negative screening test truly don't have the disease.
Serum CA125 integrated with transvaginal sonography can only detect about 25% of the OC in the early stage . Laparoscopy can identify nearly 100% of the OC within the early stage, but the high cost and invasive properties tremendously impede its feasibility in clinical practice . Given the prevalence of ovarian cancer, strategies for early detection must have high sensitivity for early stage disease (>75%), as well as an extremely high specificity (99.6%) to attain a good positive predictive value.
There are two scoring systems for assessing malignancy risk, the Risk of Malignancy Index 1 (RMI 1) and the Risk of Malignancy Index 2 (RMI 2), each of which calculates scores using ultrasound features, menopausal status and preoperative CA125 level according to the equation: RMI score = ultrasound score x menopausal score x CA125 level in U/ml. (107) The RMI 2 score gives greater weight to the ultrasound findings and menopausal status than the RMI 1. The best cutoff value for RMIs 1 and 2 is 200.
Such high specificity will not likely be met by use of a single screening test alone, and cannot yet be met with any existing screening paradigm. Thus, discovery of novel ovarian cancer specific molecular biomarkers/panels is emerging as an important platform toward early detection. The present review summarizes various types of ovarian cancer markers investigated at present, including gene-, protein-based and emerging ovarian cancer biomarkers (such as microRNA-, metabolite-based).
Contributing to the poor prognosis of ovarian cancer is the lack of symptoms in the early stages of the disease. More than 70% of the women are diagnosed with late stage disease [International Federation of Gynecology and Obstetrics (FIGO) stage III or IV], after distant metastasis has occurred. The 5-year survival rate for women diagnosed with late stage disease is less than 20% even with extensive surgery and chemotherapy, compared to up to 90% for women diagnosed with early stage disease . Therefore, detection of ovarian cancer at an early stage is critical for curative treatment interventions. Unfortunately, current diagnosis methods for the detection of early stage ovarian cancer are inadequate. Only 25% of all ovarian cancer is found at early stage [2] and [3]. CA-125, which is significantly associated with ovarian cancer, is the only serum molecule now normally used in the clinical practice. While CA-125 serum levels are increased in about 80–85% of women with advanced ovarian cancer, only 50% of patients with stage I ovarian cancer will have an elevated CA-125 level. Therefore, CA-125 is mostly considered as a useful biomarker for follow-up (e.g., monitoring of progression and regression) of patients with established ovarian cancer, but has neither sufficient sensitivity nor specificity for early detection .
Risk of Malignancy in Individuals with a Germline BRCA1 or BRCA2-Pathogenic Variant.
At least 10% of all epithelial ovarian cancers (EOCs) are hereditary, with germline mutations of the breast cancer 1/2 (BRCA1 and BRCA2) tumor suppressor genes accounting for approximately 90% of cases. Research showed that both BRCA proteins participate in transcriptional regulation of gene expression as well as the recognition or repair of certain forms of DNA damage, particularly double-strand breaks. Mutations of BRCA1 and BRCA2 are mainly of the frameshift or nonsense variety.
Cancers are thought to arise from genetic alterations, environmental factors and a combination of both. Malignant transformation of normal ovarian epithelial cells is caused by genetic alterations that disrupt regulation of proliferation, programmed cell death and senescence. The vast majority of ovarian tumors arise due to accumulation of genetic damage, but the specific genetic pathways for the development of epithelial ovarian tumors, borderline and malignant, are largely unknown. Considering that a close connection exists between genetic changes and ovarian tumorigenesis, it is obvious that research on gene level (including studies of inherited gene mutations, epigenetic changes and gene expression) would also provide potential ovarian cancer biomarkers. DNA- or RNA-based cancer biomarkers utilize microarrays, polymerase chain reaction (PCR), reverse transcriptase polymerase chain reaction (RT-PCR), DNA sequencing, fluorescent in situ hybridization (FISH) etc. to detect the genetic alterations occurring in the cancerous state.
Risk of Malignancy in Individuals with a Germline BRCA1 or BRCA2-Pathogenic Variant.
At least 10% of all epithelial ovarian cancers (EOCs) are hereditary, with germline mutations of the breast cancer 1/2 (BRCA1 and BRCA2) tumor suppressor genes accounting for approximately 90% of cases. Research showed that both BRCA proteins participate in transcriptional regulation of gene expression as well as the recognition or repair of certain forms of DNA damage, particularly double-strand breaks. Mutations of BRCA1 and BRCA2 are mainly of the frameshift or nonsense variety.
Epigenetic mechanisms including DNA methylation and histone modifications are important means of gene regulation and play essential roles in tumor initiation and progression. Measurement of the methylation status of the promoter regions of specific genes can aid early detection of cancer, determine prognosis and predict therapy responses. The identification of specific genes that are altered by epigenetic events is currently under active investigation in ovarian cancer. For example, Tumor-specific hypermethylation of at least one of a panel of six tumor suppressor gene promoters, including BRCA1, RAS association domain family protein 1A (RASSF1A), adenomatous polyposis coli (APC), p14ARF, p16INK4a, and death associated protein-kinase (DAPKinase), was found in tumor DNA obtained from 50 patients with ovarian or primary peritoneal tumors. An identical pattern of gene hypermethylation was detected in the matched serum DNA from 41 of 50 patients (82% sensitivity), including 13 of 17 cases of stage I disease. In contrast, no hypermethylation was observed in nonneoplastic tissue or serum from 40 control women (100% specificity) [7] . Most studies to date have focused on candidate gene approaches to identify hypermethylated and silenced candidate tumor suppressor genes, but there is also a growing literature on specific regions of hypomethylation in ovarian cancer. Moreover, epigenetic markers can be assayed in circulating DNA of the blood, which provides the promise of a non-invasive test [7] .
Quantitative or semi-quantitative measurement of the expression of particular genes in serum or tumor tissue has the potential for helping tumor diagnosis. In the last decade, the field of gene expression has progressed rapidly due in large part to the development of microarray technology, which enables us to measure the expression of tens of thousands of genes in a given tissue sample through a single experiment. This high-throughput technology, when coupled with powerful data analysis software, allows to rapidly compare gene expression between normal and malignant cells and to identify genes that are differentially regulated during cancer development. Microarray data can also be used to categorize tumors on the basis of their transcriptional profile, which may provide important biological, diagnostic and prognostic information. The current state of knowledge about the potential clinical value of gene expression profiling in ovarian cancer is discussed, focusing on three main areas: distinguishing normal ovarian tissue from ovarian tumors, identifying different subtypes of ovarian cancer and identifying cancer likely to be responsive to therapy. In EOC, gene-expression profiling has been used to provide prognostic information, to predict response to first-line platinum-based chemotherapy, and to discriminate between different histological subtypes [8] . In addition to microarray technology, serial analysis of gene expression (SAGE) represents another major class of technology currently available for the quantitative analysis of gene expression in ovarian cancer. SAGE facilitates the measurement of mRNA transcripts and generates a non-biased gene expression profile of normal and pathological disease tissue. Particularly, the SAGE technique has the capacity of detecting the expression of novel transcripts allowing for the identification of previously uncharacterized genes, thus providing a unique advantage over the traditional microarray-based approach for expression profiling. In ovarian cancer, several known and novel genes whose expressions are elevated have been identified by SAGE technology. These genes included claudin 3 (CLDN3) [9] , WAP four-disulfide core domain 2 (WFDC2, also known as HE4) [9] , folate receptor 1 (FOLR1) [9] , collagen type XVIII a1 (COL18A1) [9] , cyclin D1 (CCND1) [9] , FLJ12988 [9] .
Use of blood test panels may help in diagnosis.The OVA1 panel includes CA-125, beta-2 microglobulin, transferrin, apolipoprotein A1, and transthyretin. OVA1 above 5.0 in premenopausal people and 4.4 in postmenopausal people indicates a high risk for cancer
. The major proteomics technique that fundamentally supported the discovery of cancer biomarkers is MS which can determine precise mass and charge of protein, thus identity of the actual precursor proteins or protein profiles. Among several different MS-based proteomics approaches, currently, matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) and surface-enhanced laser desorption and ionization time-of-flight (SELDI-TOF) are two of the most frequently used methods for new biomarker discovery [10] .
Proteomic applications to ovarian cancer diagnosis have followed two paths [11] : one, called “proteomic pattern diagnostics” or “serum proteomic profiling”, is based on complex mass spectrometric differences between proteomic patterns of samples with and without cancer identified by bioinformatics. Many previously published studies showed that proteomic pattern analysis in ovarian cancer has the potential to be a novel, highly sensitive diagnostic tool for detection at an early stage [12] . However, with the impressive results in terms of specificity and sensitivity in ovarian cancer detection, some criticism regarding instrument reproducibility, quality control and standard operating procedures for sample collection, handling and shipping have been raised. Recently researchers have emphasized more and more on the importance of reliability and reproducibility of a MS technology in protein profiling.