Changes in Median Ages at Death from Selected Cancer Types in Relation to HLA-DRB 1 / DQB 1

Cancer is multigenic, with several susceptibility genes acting together with environmental factors to produce an abnormal phenotype, and anti-cancer mechanisms have evolved to contend with the consequences of cancer (Monteiro et al., 2013; Shames et al., 2014). The healthy state (i.e., absence of cancer) is one of the inherent anticancer mechanisms, such as the immune system’s intrinsic ability to fight against cancer, and the final result of cancer depends on rehabilitative efficacy with nature or with the medical help from cancer. It is necessary to evaluate a basal kind of instinct to repair cancer. From experience, we know that the instinct to repair cancer or anti-diseases have increased because of the increase in life expectancy in China since 1980. In this research, we calculated the median age at death from cancer during the last 20 years to demonstrate that the instinct to repair cancer may be a common pathway of an anti-cancer mechanism for different cancers. Human leukocyte antigen complex (HLA) genes are located on the short arm of chromosome 6 and the most polymorphic loci within the human genome. The primary function of HLA is to allow the immune system to identify infectious pathogens and eliminate them. HLA alleles play a significant role in immune responses and immunologic tolerance (Fischer et al., 2001). Hence, HLA genes are the most significant genetic predisposition factor or genetic markers on chromosome 6 for diseases


Introduction
Cancer is multigenic, with several susceptibility genes acting together with environmental factors to produce an abnormal phenotype, and anti-cancer mechanisms have evolved to contend with the consequences of cancer (Monteiro et al., 2013;Shames et al., 2014).The healthy state (i.e., absence of cancer) is one of the inherent anticancer mechanisms, such as the immune system's intrinsic ability to fight against cancer, and the final result of cancer depends on rehabilitative efficacy with nature or with the medical help from cancer.It is necessary to evaluate a basal kind of instinct to repair cancer.From experience, we know that the instinct to repair cancer or anti-diseases have increased because of the increase in life expectancy in China since 1980.In this research, we calculated the median age at death from cancer during the last 20 years to demonstrate that the instinct to repair cancer may be a common pathway of an anti-cancer mechanism for different cancers.
Human leukocyte antigen complex (HLA) genes are located on the short arm of chromosome 6 and the most polymorphic loci within the human genome.The primary function of HLA is to allow the immune system to identify infectious pathogens and eliminate them.HLA alleles play a significant role in immune responses and immunologic tolerance (Fischer et al., 2001).Hence, HLA genes are the most significant genetic predisposition factor or genetic markers on chromosome 6 for diseases

Changes in Median Ages at Death from Selected Cancer Types in Relation to HLA-DRB1/DQB1
Wan-Xin An1,2 , Ya-Xin Fan 1 , Xiao-Hua Liang 1 , Hui Liu 2 * and cancers affecting the immune system (Shugart et al., 2011;Hildesheim et al., 2012).Since HLA class II loci have a distinctive role in diseases, associations are usually observed with HLA-DR and DQ genes (Sugihara, 2012;Zhao et al., 2012;Pratesi et al., 2013).We are also interested in understanding whether the HLA class II DR /DQ allelic polymorphism is a common risk factor in the development of cancer with the instinct to repair cancer or not.There is very little information about this hypothesis.

Original death data of the population and cancer
The population deaths and cancer by age during the interval 2000 through 2006, is shown in Table 1 (Xiudan et al., 2004; Department of population and employment statistics national bureau of statistics of China, 2006;Shiming et al., 2007;Jing, 2008).The population deaths and cancer by age during the interval, 1980 through 1989, is shown in Table 2 (Chengxiao et al., 1987;Changming, 1988; Department of population and employment statistics national bureau of statistics of China, 1988;Yijian, 1988).For mortality statistics, the underlying causes of death are classified according to ICD-10 coding.

Subjects
Two hundred nine individuals of the northern Han Chinese living in Dalian during 2004-2007 who expressed an interest to take part in the study were included in this study.Seventy-eight patients (46 males and 32 females; mean age, 61±16 years) with different cancers, including 17 gastric, 18 liver, and 20 lung cancers, and 23 other cancers, such as colon carcinoma, rectal cancer, and gynecologic cancer, were recruited as the solid cancer group (as evidenced by surgical intervention).The leukemia group consisted of 31 patients (17 males and 14 females; mean age, 32±5.5 years) with acute lymphoblastic leukemia, acute non-lymphocytic leukemia, or chronic myelocytic leukemia (as evidenced by pathologic findings).The control population was comprised of 100 healthy blood donors (50 males and 50 females; mean age, 38±9.5 years) from the same geographic area.

HLA-DRB1/DQB1 allele typing
Genomic DNA was extracted from white blood cells using standard techniques for HLA typing.The samples were typed using an HLA-DR/DQ "low resolution" PCR-SSP typing kit (Pel-Freez Clinical Systems

Statistical analysis
The median ages at death were calculated with a frequency table.The ratio of age at death (the ratio of median ages at deaths from a disease to that from all causes in same period) was obtained.
Genotype and allele frequencies in the different groups were obtained.Frequencies in the solid cancer and leukemia groups were compared to the control group by the (chi) 2 test or Fisher's exact test (when the expected frequencies were too small).Differences were considered significant when p values were <0.05.
All analyses were performed using the SPSS 11.0 statistical software package.

Results
The median ages at death from all causes and each of the 4 leading cancers are shown in Table 1, 2. The ratios of age at death for each of the 4 leading cancers are shown in Table 3.There were no major differences, with the exception of leukemia, between the ratio of ages at death in 2005 and 1985.The raw data of alleles in HLA-DRB1/DQB1 of the total study population and subgroups are listed in Tables 4, 5. Quantitative comparisons between the solid cancer group, leukemia group, and control population were performed.The frequency of DRB1*03 was 9.6% in the

Discussion
The quality of life in China has shown a marked improvement since 1980.The life expectancy at birth was 68.9 years in 1985 and 73.0 years in 2005.In this study, we chose the Chinese literature published in scientific journals since 1980 and obtained the values for the number of deaths attributed to cancer in different age groups.The median ages at death were calculated.The median ages at death from all causes was 64.68 years in 1985 and 70.13 years in 2005 (Table 1, 2).These results were in parallel with the increase in life expectancy at birth since 1980 and implied that the data obtained in this study were sufficiently representative.
The median ages at death from all cancers were 63.21 years in 1985 and 68.65 years in 2005.The range of the median ages at death from all cancers was similar to the corresponding value for deaths attributed to all causes.These findings indicate that a change in basal health status may have played a more significant role than development of medicine in the observed enhancement of the median age at deaths from cancer.
The numbers of deaths from cancer were mainly attributed to gastric cancer, liver cancer, and lung cancer, and represented >50% of all cancer deaths in China (Department of population and employment statistics national bureau of statistics of China, 1988China, , 2006)).Therefore, the present study focused on those three cancers as representative of solid cancers.The results showed that the differences in the median ages at death from the three cancers between 2005 and 1985 were similar with the exception of leukemia and the ratio of age at death from 3 solid cancers in 2005 and 1985 were almost equal (Table 3).These findings suggest the presence of a common inherent anticancer pathway.These considerations led us to establish a solid cancer group and a leukemia group to explore the regularity of cancer occurrence and development.
For most sporadic cancers, genetic susceptibility results from the additive effect of multiple genetic variants, each of which contributes a modest risk individually (Monteiro et al., 2013;Shames et al., 2014).Genetic polymorphisms in functionally critical genes have been suggested as risk factors for the development of a variety of cancers.Candidate genes may be involved in DNA damage repair, carcinogen metabolism, cell-cycle control, apoptosis, and immune response (Meyer et al., 2008).Particularly important is the anti-cancer adaptive immune response.It is widely accepted that the anti-cancer adaptive immune response is the T lymphocyte.T lymphocyte activation requires the completion of a carefully orchestrated series of specific steps that can be pre-empted or disrupted by any number of critical events (Inman et al., 2007;DeNardo et al., 2008).It is now recognized that antigen presentation by HLA class II molecules plays an important role in this process.Specifically, persistent pro-tumor immune responses, now generally accepted as potentiating primary tumor development, are also recognized as mediators of cancer metastasis (Kim et al., 2008;Mangalam et al., 2008;Sun et al., 2008).Clearly, the immune response is an important inherent defense mechanism against cancer.Therefore, the study of polymorphisms of HLA may help explain the differences in individual cancer susceptibility and may assist in identifying novel markers of risk that can be utilized to create more effective and tailored cancer prevention strategies.HLA class I and II alleles polymorphisms have been shown to associate with many cancers (Yang et al., 2011;Bonamigo et al., 2012;Xiao et al., 2013).
Quantitative comparisons between the solid cancer group, the leukemia group, and the control group were performed.We found that the frequency of DRB1*03 was 9.6% in the solid cancer group and 3.0% in the control population (p<0.05).It is suggested that there may be common susceptibility genes in solid cancer.The frequency data of DRB1*04 was lower in the leukemia group than in the control population (p<0.05).A significant increase was found in both DRB1*13 and DQB1*06 of the leukemia group compared to the control population (p<0.05).These findings indicated that there may be  Another possibility is that the role of HLA-DRB1/ DQB1 alleles implicated in this study is due to linkage to the neighboring genes of HLA-DRB1/DQB1 alleles, which may be involved in a common pathway of anticancer mechanism for different cancers.Whether our findings are a matter of haplotype or whether they suggest a direct role for HLA-DRB1/DQB1 alleles needs to be investigated further.The hypothesis proposed in this study may allow focusing research on the involvement of quality of life, nutritional status, life style, and other factors in a common anticancer mechanism; the results of these studies may assist in identifying novel targets that can be used to create more effective and personalized cancerprevention strategies.We expect increasing integration of genetics, epidemiology, and clinical trials through valuable data among laboratories leading to genetically informative designs that will not only identify cancer genes, but also clarify how they interact with each other and how the environment influences their effects.

Table 5 . Allele Distributions for Locus HLA-DRB1 in Different Groups f% (p values)
Number of chromosomes analyzed; Bold-faced values indicate significant difference at the 5% level common susceptibility or resistance genes which are different from solid cancer in different kinds of leukemia.