Immunohistochemical overexpression of p16 protein associated with cervical cancer in Thailand.

Cervical cancer is caused by persistent infections through high risk (HR) types of human HPVs, particularly HPV 16 and 18. HR-HPV types encode two potent oncogenes, referred to as E6 and E7. Both are required to induce and maintain neoplastic growth of cervical cancer cells. Cyclin dependent kinase inhibitor genes as for example p16INK4A were shown to be negative regulated by active pRb. Inactivation of pRb by E7 thus releases the p16 gene from its negative transcriptional control and results in significant overexpression of p16 encoded protein in HPV transformed cells. It has been demonstrated that p16 protein can be detected in cervical preneoplasia all high grade SIL or invasive cancers, whereas no expression was detected in normal, metaplastic or inflammatory cervical lesions. Moreover, low grade cervical lesions induced by low risk HPV infection but histological indistinguishable from low grade lesions induced by HR-HPV-infections could be clearly differentiated by p16INK4A immunohistochemistry, showing negative staining for p16 protein. The objective of this study is to examine the expression of p16 protein in cervical carcinoma in Thailand. Immunohistochemical analysis of p16INK4A was performed on 53 formalin fixed and paraffin embedded samples of various stages of cervical neoplastic lesions. There are squamous cell carcinoma in situ 8 cases, squamous cell carcinoma in situ with glandular involvement 16 cases, microinvasive squamous cell carcinoma 13 cases and invasive squamous cell carcinoma 16 cases. The specimens were taken from cervical biopsy, cervical conization and hysterectomy in the year 2000 at National Cancer Institute. Strong immunoreactivity for the p16 protein was observed in only the nuclei and cytoplasm of all cervical neoplastic cells. This study supported the idea that immunohistochemical overexpression of the p16 protein may be a useful screening test for cervical cancer. In addition, p16 immunohistochemistry is useful for helping in the interpretation of cervical histology samples, facilitating more rapid diagnosis.

Monitoring and evaluation of a model demonstration project for the control of cervical cancer in Nakhon Phanom province, Thailand.

Cancer of the uterine cervix is the second most common cancer in females in the world with about half a million new patients per year. Since the introduction by Papanicolaou of cervical smear screening, the incidence of cervical cancer has declined in many developed countries. The decrease in the incidence of and mortality from cervical cancer is mainly due to the organized mass screening using Pap smear programmes. Uterine cervical cancer is the leading cancer among women in Thailand with age-standardized incidence rates of 24.7 per 100,000 in 1999. Most cases present at advanced stages with poor prognoses of survival and cure. In the present study, cervical cancer screening programme with cervical cytology was organized for Nakhon Phanom province, Thailand. The specific objectives were: 1) to evaluate the reduction in incidence and mortality from cervical cancer in the province by means of an organised low-intensity cervical cytology programme. 2) to demonstrate the different aspects of programme implementation as a potential model for nationwide implementation. The screening activities were integrated in the existing health care system. Organized screening for women in the target population (aged 35-54 years) at 5-year intervals was free of charge. Sample taking was done by trained nurses (midwives) and primary health care personnel in the local health care centers. Sample quality was under continuous controlled by the cytology laboratories and pathologists. Confirmation and treatment were integrated into the normal health care routines. The screening results of the programme, including histologically confirmed diagnosis, were registered at the National Cancer Institute using PapReg and CanReg 4 programmes. A population-based cancer registry in Nakhon Phanom province was also set up in 1997. In the period 1999-2002, 32,632 women aged 35-54 years were screened. Women with low-grade lesions returned for routine follow-up smears. High-grade preinvasive disease was further evaluated by repeating Pap smear, conization or biopsy and subsequent treatment through surgical removal or ablation. This organized low-intensity cervical cytology programme showed a considerable increase in early carcinoma in situ and CIN II -III cases and should reduce incidence of and mortality from cervical cancer in Nakhon Phanom province in the future. Screening with the Papanicolaou smear plus adequate follow-up diagnosis and therapy can achieve major reductions in both incidence and mortality rates.

Genetic polymorphisms of CYP2E1 and GSTM1 in a Thai population.

Cytochrome P450 2E1 and GSTM1 play major roles in metabolic activation and detoxification of many carcinogens and polymorphisms in the encoding genes have been reported to be individually associated with increased susceptibility to certain cancer. In the present study, we investigated the RsaI, PstI and DraI polymorphisms of the CYP2E1 gene and the null GSTM1 genotype in a Thai population. DNA samples from 485 individuals were analysed by polymerase chain reaction with restriction fragment length (PCR/RFLP). The frequency of RsaI and PstI predominant homozygous alleles (c1/c1) was 73.2%, heterozygous allele (c1/c2) was 25.6% and rare homozygous allele (c2/c2) was 1.2%. For the DraI polymorphism, the frequency of the predominant allele (DD) was 59.6%, heterozygous (CD) was 40% and rare allele (CC) was 0.4%. The frequency of GSTM1 null genotype was 62.7%. The distribution and frequencies of these alleles showed different pattern from those found in Caucasian and some other Asian populations. With the large population in this study, we believed that our results are reliable estimates of the frequencies of the polymorphic CYP2E1 and GSTM1 alleles in Thai population and should provide a base for further epidemiological studies on their links with cancer development.

Glutathione S-transferase M1 gene polymorphism in Thai nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a serious health problem in Thailand. It is caused by the combined effects of Epstein-Barr virus (EBV), carcinogens and genetic susceptibility. The glutathione S-transferase M1 gene (GSTM1) encodes a phase II enzyme responsible for detoxifying carcinogenic electrophiles. Polymorphic null forms of the gene GSTM1 lack enzyme activity and have been associated with susceptibility to several cancers including NPC. To examine the association between GSTM1 polymorphism and NPC susceptibility in Thais, GSTM1 genotypes (normal and null genotypes) in 78 NPC patients and 145 age-matched healthy controls were determined using PCR assays. Overall, no statistically significant differences were observed in the frequency of GSTM1 genotypes between cases and controls, nor among NPC patients compared on the basis of sex and clinical stage of disease. Carriers with the GSTM1 null genotype had a 2.9-fold increased risk for NPC of WHO type III when compared to those with GSTM1 normal genotype (P < 0.05 with OR =2.9, 95% CI = 1.2-6.8). When cases and controls were categorized into 3 age groups (>40, (>45 and (>50 years), the frequencies of GSTM1 null genotype in cases the (>45 and (>50 age groups were significantly different from controls (P< 0.05). In addition, carriers of the GSTM1 null genotype in age groups (>45 and (>50 years had a 2-fold and 3-fold increased risk for NPC when compared to those with GSTM1 normal genotype (OR = 2.2, 95% CI = 1.1-4.7 and OR = 3.0, 95% CI = 1.2-7.5). We suggest that GSTM1 polymorphism may be associated with NPC susceptibility in Thais, especially for GSTM1 null genotype carriers of age higher than 45 years. The GSTM1 null genotype may be a useful genetic marker for predicting Thai NPC and for screening of early stages of Thai NPC.

Epidemiology of liver cancer: an overview.

The incidence of liver cancer varies widely throughout the world, with high rates in sub - Saharan Africa, eastern and southeastern Asia, and Melanesia and a low incidence in Northern and Western Europe and the Americas. Primary cancers of the liver in adults are of two main histological types: hepatocellular carcinoma, which is derived from hepatocytes, and cholangiocarcinoma, which is derived from the epithelial lining of the intrahepatic bile ducts. Hepatocellular cancer is a frequently occurring tumor in individuals in many developing countries, where several important risk factors have been demonstrated, including chronic infection with hepatitis B and C viruses and other environmental factors, such as exposure to aflatoxin, consumption of alcohol, and cigarette smoking. By contrast, cholangiocarcinoma is less common, accounting for only 7.7% of malignant tumors of the liver in the United States. However, in parts of Southeast Asia, cholangiocarcinoma occurs more frequently; it is responsible for more than 60% of liver tumors in northeastern Thailand. The geographic distribution worldwide coincides with endemic areas of the liver flukes, Opisthorchis viverrini and Clonorchis sinensis. The interaction between genes and the environment and the interplay of environmental factors, which include diet and other lifestyle parameters, illustrate the complexity underlying susceptibility.

Grand challenges in global health and the practical prevention program? Asian focus on cancer prevention in females of the developing world.

In response to the request for 'Breakthrough Questions' for 'Grand Challenges in Global Health' recently published in Nature, the Asian Pacific Organization for Cancer Prevention should focus its attention on what projects are of the highest priority for integration with its Practical Prevention Program (PPP). The most common female cancers in most of the countries of Asia are carcinoma of the breast, followed by the uterine cervix. While the incidences of breast adenocarcinomas are still generally lower than in the Western world they are rapidly increasing, and squamous cell carcinomas of the cervix are a major problem. Clearly there are many areas which would reward research. One factor which appears of major relevance in the mammary gland case is the diet, and particularly the phytoestrogens included in 'tofu', along with physical exercise. The age at which these could be operating needs to be elucidated, with reference to timing of menarche and menopause, and also breast mammographic density, another predictor of likelihood of neoplasia. In the cervix, the predominant influence is well established to be persistent infection with a high risk 'oncogenic' type of human papilloma virus (HPV). Vaccines therefore hold much promise, but a better understanding of the mechanisms underlying spontaneous clearance of both infection and cervical intraepithelial neoplasia (CIN) of different grades is also essential for optimal intervention. The roles of smoking and antioxidant intake in particular deserve emphasis. In Asia, with the considerable variation evident in both breast and cervical cancer incidence rates, as well as in cultural and other environmental factors, we are in a very favourable position to meet two specific challenges: 1). elucidation of how diet in adolescence determines susceptibility to neoplasia of the mammary glands; and 2). determination of what governs persistence of HPV infection. Realisation of these pivotal research aims, with especial emphasis on the context of the PPP, is our shared goal.

Significance of plasma IgA and IgG antibodies to Epstein-Barr virus early and viral capsid antigens in Thai nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) is an important causal factor of human nasopharyngeal carcinoma (NPC). High levels of serum IgA and IgG antibodies to EBV early and viral capsid antigens (IgA/EA, IgA/VCA, IgG/EA and IgG/VCA) have been reported in NPC patients. Since specific serum IgA/EA, IgA/VCA and IgG/EA are claimed to be useful serological markers for NPC. In order to evaluate whether plasma IgA/EA, IgA/VCA, IgG/EA and IgG/VCA antibody levels are useful markers for diagnosis and prognosis of Thai NPC, we examined the prevalence of these antibodies in 79 NPC patients, and 127 age-matched controls (47 healthy subjects (HS), 32 cases of other disease (OD) and 48 cases of other cancer (OC)) by using an indirect immunofluorescence assay. The prevalence of plasma IgA/EA, IgA/VCA, and IgG/EA in NPC patients (55.7, 68.4 and 68.4%) was significantly higher than in the HS (0.0, 0.0 and 20.5%,), OD (0.0, 0.0 and 3.1%) and OC (0.0, 0.0 and 20.8%) groups (p<0.05). The prevalence of plasma IgG/VCA in NPC patients (93.7%) was significantly different from those for the OD and OC groups (71.9 and 43.8%) but not for the HS group (89.4%). In NPC patients, the geometric mean titers (GMT) of plasma IgA/EA, IgA/VCA and IgG/EA were increased with an advanced clinical stage of disease but not IgG/VCA. In contrast, GMT of IgG/VCA was increased with aggressive type of disease (histological type) but not IgA/EA, IgA/VCA, and IgG/VCA. The results of our study suggest that plasma IgA/EA, IgA/VCA and IgG/EA antibodies may be useful markers for diagnosis and assessing prognosis of Thai NPC.