Oral Cancer (OC)

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Oral cancer (OC) is a malignant tumor of the oral cavity, and is the sixth most common cancer worldwide. The incidence of OC appears to be increasing, and the rate of increase is higher in Japan than in the US and other Western countries. Physical examination of the mouth is still the most common way to detect OC as it typically occurs in areas that can be readily seen by either the patient him or herself, or by a health care professional such as a dentist (e.g., many cases are identified during routine dental check-ups). However, early OC lesions are often missed as they are confused with simple mouth ulcers (i.e., aphthous stomatitis) which are harmless and very common in the general population. This can cause diagnosis to be delayed for long periods of time by which point an OC may be at an advanced stage and much more difficult to treat.

A biopsy is presently the only assured method to confirm diagnosis of an OC. Handheld devices that emit light of variable wavelengths are available to dentists that result in reflectance from, and/or autofluorescence of, the oral mucosa to more readily visualize OC lesions. However, high-quality clinical data to support the use of these devices to increase diagnostic accuracy or assist in the decision-making process are lacking. Therefore, there is significant interest in identifying molecular biomarkers that might be identified in saliva samples for screening and diagnosis purposes, and for monitoring disease progression during or after treatment.

Saliva is a clinically important fluid as it filters from the blood, thus reflecting systemic physiological conditions. It contains genetic materials such as DNAs and RNAs (e.g., mRNA and micro-RNA), proteins and other small- molecule metabolic compounds that could potentially be used as biomarkers. Compared to biomarkers in blood, salivary biomarkers have obvious advantages including the noninvasive nature of sampling which would facilitate frequent screening. However, early studies showed that conventional tumor biomarkers such as cancer squamous cell carcinoma (SCC) antigen and Cyfra 21-1 measured in either blood or saliva are not clinically accurate enough, especially in the early stages of the disease. For example, in one study, only 10.9% cases of early disease (i.e., Stages I and II) and 46% of advanced-stage disease (i.e., Stages III and IV) were detected as positive based on SCC level (SCC-antigen >2.0 ng/ml).

Salivary metabolomics is an emerging technique to screen for, or diagnose, OC as well as leukoplakia and Sjogren’s syndrome. This approach is feasible because small-molecule metabolites may be transferred into the saliva by various cells, including cancer cells in the oral cavity and the salivary glands. In one recent study, paired tumor and control tissues were obtained from oral cancer patients, and whole saliva samples were collected from patients and healthy controls. A comprehensive metabolomic analysis was undertaken to profile hydrophilic metabolites using capillary electrophoresis time-of-flight mass spectrometry. In total, 85 and 45 metabolites exhibited significant differences between tumor and matched control samples, and between salivary samples from oral cancer and controls, respectively (P<0.05). Seventeen metabolites showed consistent differences in both saliva and tissue-based comparisons and, of these, a combination of just two biomarkers was shown to discriminate oral cancers from controls. This approach, integrating both saliva and tumor tissue metabolomics, helped to eliminate pseudo-molecules coincidentally different between oral cancers and controls. These combination metabolite studies could form the basis of a clinically feasible method for noninvasive oral cancer screening in the future.

Interestingly, studies have suggested that salivary biomarkers could also be used for the early detection of other tumor types such as pancreatic, breast, lung and ovarian cancer. Biomarkers studied in this context include EGFR, BRAF and GREB1 for lung cancer, salivary miRNA for pancreatic cancer, and CA15-3 for breast cancer patients. Detection of CO, and NH, in the mouth has also been used as a potential biomarker for gastric cancer, as these gases are secreted by the microorganism Helicobacter pylori microorganism whose colonization of the gut has been associated with gastric cancer. Other research is focusing on exosomes found in the saliva for detecting and diagnosing cancers.

Bladder Cancer

In the UK alone, approximately 10,000 individuals per annum are diagnosed with bladder cancer, and ~5,000 will die from the disease. As tumors on the epithelial lining of the bladder shed cells, nucleic acids, proteins and other substances into the urine, there has been significant interest in developing a urine test to detect these biomarkers. As urine samples can be readily collected noninvasively, this approach could be used for mass screening of the population to detect early-stage bladder cancer. This would have a significant advantage in allowing early diagnosis and treatment as, at present, bladder cancers are usually well advanced before they are detected often by the person themselves noticing blood in the urine (hematuria), or a bladder associated pain. However, at this time, no major professional organizations recommend routine screening for bladder cancer as no currently available screening test has been shown to lower the risk of dying from bladder cancer in people who are at average risk. Some doctors do recommend bladder screening for individuals at very high risk of the disease, such as individuals who have had bladder cancer before or have a family history of the disease, those with certain bladder birth defects, and some who are exposed to certain chemicals through their work.

A simple way to check for bladder cancer is to look for blood in the urine (hematuria) which can be done through urinalysis, a simple test which is often carried out as part of a general health check-up. Blood in the urine is usually caused by benign (i.e., noncancerous) conditions such as infections, but it also can be the first sign of bladder cancer. Urinalysis can help to identify some bladder cancers early, but it has not proved to be useful as a routine screening test. A related test, urine cytology, utilizes a microscope to look for bladder cancer cells in a urine sample. Cytology can be useful to confirm the presence of a tumor, but studies have shown that it is not reliable enough to be used as a screening tool. Cystoscopy (i.e.,

introducing a camera into the bladder through the urethra) is also used to confirm the presence of a tumor in the bladder but clearly cannot be used as a mass screening tool.

Therefore, research in this area focuses on trying to identify biomarkers in the urine that can reliably detect early bladder cancer, and a number of commercial kits have been developed. For example, UroVysion™ is a test that looks for chromosomal changes in cells shed into the urine, and Immunocyt™ detects the presence of antigens such as carcino- embryonic antigen (CEA) and mucin associated with bladder cancer cells. Other tests being developed include BTA tests designed to detect bladder tumor-associated antigen (BTA, also known as CFHrp) that is associated with bladder cancer cells, and NMP22 BladderChek™ that detects a protein called NMP22 which is often found at higher levels in those with bladder cancer. Another example is a urine-based DNA test developed by the Danish Cancer Society Research Centre. It uses a filtration device to separate tumor from nontumor cells, which are smaller in size, and then a PCR-based methodology to look for mutations in the TERT and FGFR3 genes in the captured tumor cells which are thought to be prognostic for a higher risk of developing bladder cancer. Although the researchers found that FGFR3 mutations could be detected in patients up to 15 years before they were diagnosed, the test had only a 77% specificity, insufficient for general population screening. However, it can still be used for monitoring high-risk groups, such as those with hematuria.

Despite the impressive progress in this area, although some of the biomarker tests described above have reached the stage of being capable of identifying some bladder cancers early, they can also miss some. In other cases, the results may indicate an abnormality in otherwise healthy individuals, causing unnecessary concern and distress. Therefore, at this time, all of these tests are used mainly for high-risk individuals rather than general population screening. Further research is needed before these or other newer tests are proven useful as screening tools.

Cervical Cancer

In the UK, approximately 3,000 cases of cervical cancer are diagnosed each year. It can affect sexually active women of all ages, although is most common in women aged 25-29, and is very rare in women under 25. It is associated with infection by the human papilloma virus (HPV) which is sexually transmitted. This has led to the development of HPV vaccines, the first dose of which is offered to all girls (and from 2019, all boys) aged 12-13 (i.e., before they become sexually active), with a second dose after 6-12 months, as part of the NHS Childhood Vaccination Programme. This is leading to significant reductions in the incidence of cervical cancer (and related cancers in men). Prior to the availability of anti-HPV vaccines, the reason cervical cancer was rare in women under 25 years old appears to be because they could mount a robust immune response to the HPV virus without vaccination.

A cervical screening test (previously known as a “smear test”) is offered to woman in the UK through the NHS, with the aim of reducing the number who develop cervical cancer and those who die from it. It is estimated that at least 2,000 cases of cervical cancer are prevented each year in the UK through cervical screening. Approximately 6 out of 100 women who are screened will have an abnormal result, but it is very rare for cancer to be diagnosed directly from the results (i.e., less than 1 in 2,000 test results show invasive cancer). The test is offered every three years and five years to the 25-49 and 50-64 age groups, respectively. It is also offered to women over 65 who have recently had abnormal tests. Since its introduction in the UK in the 1980s, the number of cases of cervical cancer has decreased by about 7% each year. Similar screening programs are also in use in many other countries with well-developed health care systems. There are some recognized disadvantages to the test which include potential discomfort and embarrassment during the test, a very small chance of obtaining incorrect results potentially leading to abnormalities being missed or unnecessary treatment being administered, a chance that treatment may be given unnecessarily as the abnormalities may correct themselves naturally, and a chance that some of the treatments used to remove abnormal cells may increase the risk of giving birth prematurely (before the 37th week of pregnancy) if pregnancy occurs in the future.

Changes to cervical cells are nearly always caused by the human papilloma virus (HPV) of which there are more than 100 different types, some of which are high-risk (e.g., HPV-16 and HPV-18) and associated with cervical cancer, and some which are lower risk and associated with other conditions such as genital warts. The screen works by removing a small number of cells from the cervix using a soft brush. In the UK, the sample is initially subjected to HPV testing (i.e., HPV primary screening) to check for the presence of high-risk HPV. If present, then the laboratory looks for cellular changes in the sample. If changes are found, then the individual is invited for colposcopy, a procedure which allows a clinician to look directly at the cervix to check for any signs of cancer developing. If the cervix appears normal, then the person will be invited back for a further cervical screen after one year. However, if no high-risk HPV is found, then the sample will not be checked for cellular changes, and the person will be invited back for another cervical screen in three or five years’ time depending on their age.

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