Identification of Biomarkers and Drug Target in Human Cancers

INDEX

1. Introduction
   1. Cancer
      1.    Burden of Cancer in World & India
      2.    Types of Cancer
      3.    Pathogenesis of Cancer
      4.    Stages of Cancer
      5.    Screening Methods
      6.    Early diagnosis of Cancer is essential
   2. Cancer Biomarkers
      1.    Properties of an ideal cancer biomarkers
      2.    Advantages of cancer biomarkers
      3.    Historical overview of cancer biomarkers
      4.    Current applications of cancer biomarkers and their clinical utility
      5.    Currently available cancer biomarkers: clinical utility and limitations
   3. Mechanism of biomarker dysregulation
      1.    Gene expression
      2.    MicroRNA
   4. Technologies
      1.    Microarray
      2.    Next-generation sequencing
   5. Obstacles in delaying biomarker’s clinical translation
   6. Role of systemic review and meta-analysis in biomarker development
   7. Project aim and objectives

 CHAPTER 1:

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1. INTRODUCTION
   1.  Cancer

Cell are the fundamental unit of life. Human cells grow and divide to form new cells as the body needs them. When cells grow old or become damaged, they die, and new cells take their place. But sometimes this orderly process breaks down and the abnormal growth of cells occurs. As cells become more and more abnormal, old or damaged cells survive when they should die, and new cells form when they are not needed. These extra cells can divide without stopping and may form growths called tumors. Tumor may be benign or malignant. Malignant tumor are cancerous growth [1]. Malignant tumor or Cancer has the potential to invade and spread from one body part to another through blood or lymphatic system.

Cancers are generally classified by the type of cells or organ from which they originate. Since malignant growth can occur in virtually all locations of the body, there are over 100 different types of cancers. Cancer is an immensely complex and diverse disease; however, a set of characteristics are shared among almost all malignancies. Those characteristics, named hallmarks of cancer, are a unified set of capabilities that are acquired during tumorgenesis.

Figure 1.1: The Hallmarks of Cancer. A: The set of hallmarks of cancer proposed in year 2000. B: Extended Emerging Hallmarks and Enabling Characteristics.

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Source: Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144: 646–674.

The originally proposed hallmarks of cancer are self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of programmed cell death, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis [2]. The list has been further extended with emerging hallmarks such as deregulating cellular energetics and avoiding immune response. Additionally, enabling characteristics were proposed, which are tumor promoting inflammation, and genome instability and mutation [3].

1.      Burden of Cancer in world & India

According to the World Health Organization (WHO) fact sheet 2012, out of 171 million deaths that occurred worldwide in 2008, 7.6 million (13%) were attributed to cancer [4]. In addition, more than 14.1 million people were diagnosed with cancer in 2012 of which 8.2 million succumbed to the disease. Table1 shows cases, deaths and 5-year prevalence of cancer by regions [5]. Around 8 million (57%) new cancer cases, 5.3 million (65%) cancer deaths and 15.6 million (48%) 5-year prevalent cancer cases occurred in the less developed regions. In context to India, 1.015 million cases were reported which constitutes ~7.2% of total cancer cases and .68 million deaths due to cancer. The incidence rate in women is higher than men in India as shown in Table 1.

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Table 1: Estimated cases, deaths and 5-year prevalence of cancer. Source: Globocan 2012 [5].

The most commonly diagnosed cancers worldwide are lung (1.82 million, 13% of the total), breast (1.67 million, 11.9%) and colorectal cancers (1.36 million, 9.7%). The most common causes of cancer death are lung (1.58 million, 19.4 % of the total), liver (0.74 million, 9.1%) and colorectal cancer (.69 million, 8.5%) [5]. Cancer is a major health burden in both developed and developing countries. Every year about 8,50,000 new cancer cases being diagnosed and about 5,80,000 cancer related death occurs every year in India. India had the highest number of the oral and throat cancer cases in the world [6]. Number of deaths due to cancer are rising continuously with approximate nine million people are estimated to die in 2015, and more than 11 million in 2030 [7]. Lung, liver, stomach, colorectal and breast cancers cause the most cancer deaths each year. In India, the highest cases occurred due to breast, cervical, lip, oral cavity, lung and colorectal cancers. Breast and cervical cancer are one of the most reported cancers in Indian women while in men cancer like lip, oral cavity and lung are present.

2.      Types of Cancer

According to NCI, cancers can be grouped according to the type of cell they start in. There are 5 main categories:

• Carcinoma – cancer that begins in the skin or in tissues that line or cover internal organs. There are a number of subtypes, including adenocarcinoma, basal cell carcinoma, squamous cell carcinoma, and transitional cell carcinoma
• Sarcoma – cancer that begins in the connective or supportive tissues such as bone, cartilage, fat, muscle, or blood vessels
• Leukaemia – cancer that starts in blood forming tissue such as the bone marrow and causes large numbers of abnormal blood cells to be produced and go into the blood
• Lymphoma and myeloma – cancers that begin in the cells of the immune system
• Brain and spinal cord cancers – these are known as central nervous system cancers

3.      Pathogenesis of Cancer

Cancer is often described as the disease of the genome because it acquires the hallmarks of cancer through the accumulation of DNA mutations and genome instability [2]. Till date cancer is not curable, many theories have been proposed to understand the cause of cancer. These theories include cancer is caused by various viruses [8], chromosomal abnormalities [9,10], somatic mutations [11], accumulated multiple mutations [12], immunological surveillances [13,14], nonhealing wounds [15], non-mutagenic mechanism [16], tissue organization field theories [17] and wound-oncogene-wound healing theory [18]. Current prevalent cancer theories hold that cancer is an uncontrolled somatic cell proliferation caused by the genetic alterations in critical genes that control cell growth and differentiation [19,20,21,22,23]. Alterations in three types of genes are responsible for tumorigenesis: oncogenes, tumor-suppressor genes and stability genes (Table 2). Oncogene and tumor-suppressor gene mutations all operate similarly at the physiologic level: they drive the neoplastic process by increasing tumor cell number through the stimulation of cell birth or the inhibition of cell death or cell-cycle arrest. The increase can be caused by activating genes that drive the cell cycle, by inhibiting normal apoptotic processes or by facilitating the provision of nutrients through enhanced angiogenesis. A third class of cancer genes, called stability genes or caretakers, promotes tumorigenesis in a completely different way when mutated. This class includes the mismatch repair (MMR), nucleotide-excision repair (NER) and base-excision repair (BER) genes responsible for repairing subtle mistakes made during normal DNA replication or induced by exposure to mutagens. Stability genes keep genetic alterations to a minimum, and thus when they are inactivated, mutations in other genes occurs at a higher rate [23]. Recently it was reported that various microRNA genes are also involved in initiation and progression of cancer. These microRNA genes altered the expression of genes having role in cell growth and differentiation [24, 25, 26].

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Table 2: Few examples of oncogenes, tumor-suppressor genes and stability genes those are associated with cancers.

It is well reported that the genetic alteration related to these cancer-related molecules are associated with initiation and progression of cancer (Figure 2) [19,20,21,22,23,27].

Figure 2: Initiation & Progression of cancer.

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These alterations may be transmitted through germline and result in susceptibility to cancer, or can arise by somatic mutation. A single genetic change is rarely sufficient for the development of a malignant tumor. Most evidence points to a multistep process of sequential alterations in several, often many, oncogenes, tumor-suppressor genes, or microRNA genes in cancer cells [27]. These genetic variations may be referred as “drivers” or “passengers”. Drivers include the genomic alterations that cause or promote cancer whereas the passengers referred to alterations present in the cancer genome but without obvious advantage to the cancerous cells when they occurred [28]. The major known alterations in the cancer genome include amplifications, frameshift mutations, germline mutations, large deletions, missense mutations, nonsense mutations, somatic mutations, splicing mutations, translocations etc. (Figure 3) [29, 30,31]. These cancer-related molecules may be transcription factors, chromatin remodelers, growth factors, growth factor receptors, signal transducers, and apoptosis regulators which help the cell to undergo uncontrolled growth and differentiation. These cancer-related molecules may be activated by various phenomenon mainly chromosomal rearrangements, mutations, gene amplification [27]. These genetic alterations are most likely reflected by the altered expression of sets of genes or pathways, rather than individual genes [32]. In addition, to the somatic and germline mutations, epigenetic alterations that regulate gene expression also involved in most of the cancers [33, 34]. All of these acquired changes occur in the setting of germline variations of copy number and nucleotide sequence, which may influence the rate of occurrence and/or the effects of somatic genetic alterations [35].

Figure 3: Cancer Gene Census (Source: http://cancer.sanger.ac.uk/cancergenome/projects/census/ )

4.      Stages of Cancer

Cancer staging refers to the extent of the tumor or cancer growth. Stage of cancer is determined by means of X-rays, biopsy and other lab tests and procedures. Staging system gives the information like location, grade and size of tumor in body, cell type (adenocarcinoma / squamous cell carcinoma), spread of cancer (in other body parts / lymph nodes)[36].

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TNM Staging System

The TNM system is the most widely used cancer staging system. TNM is used to determine the extent of tumor (T), spread of tumor to lymph nodes (N) and presence of metastasis (M). TNM staging is developed, maintained and regulated by AJCC (American Joint Committee on Cancer) and by UICC (Union for International Cancer Control). The TNM classification system was developed as a tool for doctors to stage different types of cancer based on certain, standardized criteria and among the most used staging system by medicos worldwide.

The “T” category designates the original tumor:

The category “N” describes whether or not the cancer has reached nearby lymph nodes:

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The M category tells whether there are distant metastases (spread of cancer to other parts of the body):

Once the T, N, and M are determined, they are combined, and an overall stage of 0, I, II, III, IV is assigned (Table 3).

Table 3: Cancer Stages

Source: https://www.cancer.gov/about-cancer/diagnosis-staging/staging

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Another staging system that is used for all types of cancer groups the cancer into one of five main categories.

• In situ—abnormal cells are present but have not spread to nearby tissue.
• Localized—Cancer is limited to the place where it started, with no sign that it has spread.
• Regional—Cancer has spread to nearby lymph nodes, tissues, or organs.
• Distant—Cancer has spread to distant parts of the body.
• Unknown—there is not enough information to figure out the stage.
  5.      Screening Methods

The primary goal of screening is to prevent lethal, progressive disease by detecting cancer at an earlier, more treatable stage or by detecting precursor lesions that can be removed before they develop into invasive cancers. Screening is a presumptive identification for disease; it is not a diagnostic tool. Screening alerts individuals for further testing. There are different kinds of screening tests which includes:

• Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
• Laboratory tests: Medical procedures that test samples of tissue, blood, urine, or other substances in the body.
• Imaging procedures: Procedures that make pictures of areas inside the body.
• Genetic tests: Tests that look for certain gene mutations (changes) that are linked to some types of cancer.

Table 4: Commonly available screening methods [37].

6.      Early diagnosis of Cancer is essential

The concept of early detection of various forms of cancer before they spread and become incurable, has enticed physicians and research scientists for decades [38]. Most of the cancers have regional or distant spread of their disease at the time of diagnosis [39]. Moreover, less survival rates for people diagnosed with advanced cancer stage as compared to the diagnosed when it is at early stage as shown in Table 5. Without doubt, shifting all cases to early detection will have a profound impact on overall mortality and economic burden. There are very few screening test is presently suitable for the early detection of cancers. This is because sufficiently high sensitivity (the probability of the test being positive in individuals with the disease) and specificity (the probability of the test being negative in individuals without the disease) are usually both not attributes of the same test; an increase in sensitivity tends to result in a reduction in specificity, and vice versa. Newer diagnostic methods with improved sensitivity and specificity are clearly needed to identify early stage cancers. The criteria for effective early detection state that the disease must be common with a high mortality rate. Second, the screening test must accurately detect early-stage disease. Third, the treatment after detection through screening must demonstrate improvements in prognosis and finally, the potential benefits must outweigh the potential harms and costs of screening [38]. One of the most promising ways to achieve this is through the use of cancer biomarkers.

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Table 5: 5-year relative survival rate of mostly occurred cancers at different stages of detection.

Source: American Cancer Society

2.      Cancer Biomarkers

According to NCI, a biomarker is “a biological molecule found in blood, other body fluids, or tissues as a sign of a normal or abnormal process or of a condition or disease like cancer”. Biomarkers typically distinguish suffering patient from a healthy person. The variations can be due to a number of factors like germline or somatic mutations, transcriptional changes and post-translational modifications. Generally, biomarkers are used in three primary ways [40]:

• To help diagnose conditions, as in case of identifying early stage cancers (Diagnostic)
• To forecast how aggressive a condition is, as in the case of determining a patient’s ability to fare in the absence of treatment (Prognostic)
• To predict how well a patient will respond to treatment (Predictive)

There is great variety of biomarkers, which can comprise

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• Genetic biomarkers (eg. Gene Mutations)
• Transcriptional biomarkers (eg. Altered gene or microrna expression)
• Proteomic biomarkers (eg. Altered protein status)
• Metabolic biomarkers (eg. Altered metabolites

These biomarkers can be identified during the process of carcinogenesis as shown in Figure 4.

Figure 4: Cancer biomarkers which can be identified during the cancer progression.

A biomarker can also be a collection of alterations, such as gene expression, proteomic, and metabolomic signatures. Biomarkers can be detected in the circulation (whole blood, serum, or plasma) or excretions or secretions (stool, urine, sputum, or nipple discharge), and thus easily assessed non-invasively and serially, or can be tissue-derived, and require either biopsy or special imaging for evaluation. Genetic biomarkers can be inherited, and detected as sequence variations in germ line DNA isolated from whole blood, sputum, or buccal cells, or can be somatic, and identified as mutations in DNA derived from tumor tissue [41].

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Tumor markers are the chemical substances produced by cancerous cells or by other cells of the body in response to cancer and related conditions. Most of the tumor markers are produced by both normal and cancer cells. In cancer, the levels become much higher and could be found in blood, urine, stool, bodily fluids, tumor tissues and other body tissues of the patient. Mostly, the tumor markers are proteinous in nature. Recently, gene expression patterns and changes in genetic material have also begun to be used as cancer markers.  Many different tumor markers have been characterized and are in clinical use. Some are associated with only one type of cancer, whereas others are associated with two or more cancer types. There is no universal tumor marker is available to detect all types of cancer yet. [42].

1.      Properties of an ideal cancer biomarkers [43,44]–

• Tumor marker should be measured easily.
• Reliable
• Cost-effective
• High-analytical sensitivity and specificity
• Specific
• Should be present in detectable (or higher than normal) quantities at early or preclinical stages and the quantitative levels of the tumor marker should reflect the tumor burden
• Demonstrate high diagnostic sensitivity (few false negatives) and specificity (few false positives)
  2.      Advantages of cancer biomarkers –

• Help in detecting, diagnosing and managing many cancer types. Elevated level of tumor marker suggests presence of cancer therefore this measurement is combined with other examinations like biopsy in order to confirm the presence of cancer.
• Help doctors to plan the appropriate therapy for the treatment.
• Tumor markers reflect the stages of cancers and prognosis.
• Periodic measurement of tumor markers during cancer therapy. An alleviation in level of the tumor marker indicate that the cancer is responding to the treatment and vice versa [45].
• Tumor markers might also be measured after treatment has ended to check for recurrence of the cancer [46].
• Aid in determining malignant tissue with the benign.
• Biomarkers have been identified that can be used to determine an individual’s risk of developing cancer. For example, a woman with a strong family history of ovarian cancer can undergo genetic testing to determine if she is a carrier of a germline mutation, such as BRCA1, which will increase her risk of developing breast and/or ovarian cancer [47].
• In a patient with an abnormality, biomarkers can also be used to distinguish between different possibilities that are in the differential diagnosis [41].
  3.      Historical overview of cancer biomarkers

The first cancer marker ever reported was the presence of the light chain of immunoglobulin in the urine, of 75% of myeloma patients [48]. Since its discovery in 1847, the test is still employed by clinicians today, but with use of modern quantification techniques. From 1930–1960, scientists identified numerous hormones, enzymes, and other proteins whose concentration was altered in biological fluids from cancer patients. The modern era of monitoring malignant disease, however, began in the 1960s with the discovery of alpha-fetoprotein (AFP)  and carcinoembryonic antigen (CEA), which was facilitated by the introduction of immunological techniques such as the radioimmunoassay [49,50]. In the 1980s, the era of hybridoma technology enabled development of the ovarian epithelial cancer marker, carbohydrate antigen 125 (CA 125) [51]. In 1980, prostate specific antigen (PSA), considered one of the best cancer markers, was discovered [52].

4.      Current applications of tumor markers and their clinical utility

One of the applications of a tumor marker is for population screening. A screening test should have very high sensitivity and exceptional specificity, to avoid too many false positives in low cancer prevalence populations. Furthermore, the test must demonstrate a benefit in terms of clinical outcome. Unfortunately, current biomarkers suffer from low diagnostic sensitivity and specificity to serve as screening markers. With the exception of PSA, current tumor markers are more frequently elevated at late stages of disease. Hence, the current clinical utility of any marker to serve as a screening tool is limited. Another application of a tumor marker is for diagnosis. Similar to its utility as a screening marker, the current biomarkers suffer from low diagnostic sensitivity and specificity to serve as diagnostic markers. A further application of a tumor marker is as a prognostic marker. Most cancer markers have some prognostic value however; specific therapeutic interventions cannot be issued since their accuracy of prediction is rather poor. In addition, some markers can serve as a predictive indicator of therapeutic response. In this respect, very few markers have predictive power (exceptions include steroid hormone receptors and HER-2 amplification for breast cancer) but the provided information helps for therapy selection. Yet another application of a tumor marker is for tumor staging. Besides AFP and human chorionic gonadotropin-β (HCG) for use of staging testicular cancer, the accuracy of the other markers to determine tumor staging is poor. Two more current applications of tumor markers exist which include detecting early tumor recurrence and monitoring effectiveness of cancer therapy. The usefulness of the current markers to serve the former role is controversial as lead time is short and does not significantly affect outcome. In addition, therapies for treating recurrent disease are not usually effective and clinical relapses could occur without biomarker elevation or biomarker elevation is non-specific. With respect to the latter application (monitoring effectiveness of cancer therapy), current biomarkers provide information on therapeutic response (effective or non-effective) that is readily interpretable and more economical than imaging modalities. Hence current markers play a very essential clinical role in this application.

5.      Currently available cancer biomarkers: clinical utility and limitations

Cancer biomarkers may be diagnostic or prognostic biomarkers are quantifiable traits that help clinical oncologists at the first interaction with the suspected patients. These particularly aid in (i) identifying who is at risk, (ii) diagnose at an early stage, (iii) select the best treatment modality, and (iv) monitor response to treatment [54]. These biomarkers exist in many different forms; traditional biomarkers include those that can be assessed with radiological techniques viz., mammograms etc., and circulating levels of tumor specific (related) antigens for example, prostate-specific antigen (PSA). With the availability of complete human genome sequence, and advancement in key technologies such as high throughput DNA sequencing, microarrays, and mass spectrometry, the plethora of potentially informative cancer biomarkers has expanded dramatically to include the sequence and expression levels of DNA, RNA, and protein as well as metabolites [55]. Advances in imaging technologies open up the possibility that pertinent molecular biomarkers (e.g., those marking response to therapy) can be monitored in cancer patients non-invasively. The currently available cancer biomarkers are as follows:

A number of tumor markers are currently being used for a wide range of cancer types. Although most of these can be tested in laboratories that meet standards set by the Clinical Laboratory Improvement Amendments, some cannot be and may therefore be considered experimental. Tumor markers that are currently in common use are shown in Table 6. These markers were widely used but they are having some limitations in terms of their sensitivity and specificity. Example: The key problems in using the CA125 test as a screening tool are its lack of sensitivity and its inability to detect early stage cancers. Increased levels of CA 19-9 can also be found in patients with nonmalignant inflammatory diseases, such as cholecystitis and obstructive icterus, cholelithiasis, cholecystolithiasis, acute chlolangitis, toxic hepatitis and other liver diseases and therefore should be used with caution [57,58]. An elevated blood level of hCG is also be found in the urine of pregnant women and therefore may not be useful as a marker under this condition.

Table 6: Currently available cancer biomarkers [56].