**4. IL10 polymorphims related to the development and prognosis of cancer**

Single nucleotide polymorphisms (SNPs) has been described on IL10 promoter, where adenine was substituted by guanine at −1082 bp (rs1800896). Thymine was replaced by cytosine at −819 bp (rs1800871) and adenine by cytosine at −592 bp (rs1800872). All of those contribute to the variation in protein expression [76]. The IL10 production have a hereditary component estimated in 75%, suggesting that

#### *Translational Research in Cancer*

clinical outcome imparted by IL10 genetic variants may be mediated by effects on the tumor micro-environment composition or modulation [47]. The possibility that SNPs participate in the development, establishment, and the prognosis of cancer has been investigated by numerous research groups and includes several group malignances.

Eastern European patients with breast cancer, IL10 −1082A > G, −819 T > C, −592A > C polymorphisms, and phased haplotypes have not revealed a prognostic value [77]. Nevertheless, another study report 592C > A polymorphisms could modify disease-free and overall survival in women with lymph node-positive breast cancer [78]. In a Chinese Han population study, the −1082AA genotype was associated with a significantly increase risk of lymph node involvement and larger tumor size at the time of diagnosis [79]. After meta-analysis, it showed that IL10 rs1800896 and rs1800871 polymorphisms had no association with breast cancer risk, while rs1800872 polymorphism had a decreased risk of breast cancer in Caucasians [3]. However, another meta-analysis suggests that IL10 rs1800871 and rs1800872 polymorphisms might contribute to breast cancer susceptibility in the overall population, but not by ethnicity [6].

Chinese men, diagnostic with prostate cancer, do not show significant differences in (−1082A/G, −819 T/C, and −592A/C) SNPs between patients and control subjects [80]. Meta-analysis performed with a Caucasian and Asiatic population suggests that there is no association between IL10 gene rs1800896, rs1800871, and rs1800872 polymorphisms and prostate cancer [81]. A study looking for the participation of variant alleles at both −819 and −592 polymorphisms was modestly associated with the advanced stages of prostate cancer [82, 83]. Other meta-analysis reports that rs1800896 polymorphism is associated with a decreased risk of prostate cancer [84].

In a meta-analysis including 26 studies designed to search the risk of skin cancer and IL10 polymorphism, the results show that there is not a significant association of −1082G > A or −592C > A and risk to skin cancer. Nevertheless, it suggested a potential association between −819C > T polymorphism and decreased risk of skin cancer [38]. A meta-analysis carried out for possible association between polymorphism and melanoma did not find an association between skin cancer risk and the −592A/C or IL-10-1082G/A. However, there was a correlation between IL10 −819T/C polymorphisms and skin cancer [85].

Association between IL10 −1082A/G, −592C/A, and −819T/C gene polymorphisms and risk of lung cancer was also investigated by meta-analysis, but until now, there are inconsistent results: on Asian populations, IL10 −1082A/G and −819T/C polymorphisms might have a significant association with the risk of lung cancer [86]. Another meta-analysis suggests that the polymorphism associated with a risk factor for lung cancer was IL10 −592A > C polymorphism, especially among Asians and Caucasians. In contrast, the IL10 −819 T > C and −1082A > G polymorphisms are not significantly associated with an increased risk of lung cancer [87].

Cervical cancer associated with a polymorphism at this time is not conclusive: −1082 polymorphism was suggested as a marker of genetic susceptibility to cervical cancer among Japanese women but was not significantly increased in Zimbabwean women or Korean women [88]. In a meta-analysis, including 17 publications of Asian, African, and Caucasian populations, it did not find a significant association between the polymorphism and cervical cancer risk [89]. Other meta-analysis looking for association between −1082 G/A polymorphism and cervical cancer risk, including the same population, report as well that there is no association [90].

Association between rs1800896 polymorphism and head and neck cancer risk and its clinical stages in Caucasian and Asiatic evaluated by meta-analysis gave a significant association with head and neck cancer risk but not with the clinical

**31**

Head and neck cancer

*IL10 as Cancer Biomarker*

*DOI: http://dx.doi.org/10.5772/intechopen.90806*

Breast cancer Eastern European IL10 −1082A/G, IL10

Prostate Chinese men study IL10 −1082A/G, IL10

Caucasian, African-Americans, and Asiatic

Caucasian, African-Americans, and Asiatic

Caucasian and Asiatic

Caucasian and Asiatic

Americans, and Asiatic

Caucasian and Asiatic

Zimbabwean women and Korean women

Caucasian, African-Americans, and Asiatic

Caucasian, African-Americans, and Asiatic

Caucasian and Asiatic

Caucasian, and Asiatic

Caucasian, African-Americans, and Asiatic

Lung cancer Asiatic IL10 −1082A/G, IL10-

Caucasian IL10 −1082A/G, IL10-

Cervix cancer Japanese women IL10 −1081 Associated with

Skin cancer Caucasian, African-

**Disease Population Polymorphism Association Reference**

No prognostic value [77]

[78]

[79]

[3]

[3]

[80]

[84]

[81]

[82]

[83]

[82]

[85]

[86]

[86]

[87]

[87]

[88]

[88]

[89]

[90]

[91]

[92]

survival

cancer risk

cancer risk

cancer risk

No associated with cancer risk

reduced cancer risk

No association with risk cancer

No association with cancer risk

No associated with cancer skin risk

No associated with cancer risk

Associated with cancer risk

cancer risk

cancer risk

cancer risk

cancer risk

Associated with cancer risk

risk

risk

IL10 −1082 No associated with

IL10 −1082A > G No associated with

IL10 −1082 G/A No associated with

rs1800896 Associated with

No association with cancer risk

No associated with cancer risk

cancer risk

−592A, IL10 −819C

Eastern European IL10 −592C > A Associated with

Chinese Han IL10 −1082AA Associated with

Chinese Han rs1800896, rs1800871 No associated with

Caucasian rs1800872 Associated with

−592A/C, IL10 −819 T/C

rs1800896, rs1800871,

IL10-1082 A4G, IL10-819 C4, IL10-592 C4A

IL10 −1082A/G, IL10- 592A, IL10-819C

IL10 −592A/C, IL10 −1082G/A

592A, IL10-819C

592A, IL10-819C

Caucasian IL10 −592A > C Associated with

IL10 −819 T > C, IL10 −1082A > G

IL10 −1082A > G, IL10

−819 T > C

rs1800872

rs1800896 Associated with

IL10--592A > C No association with

*IL10 as Cancer Biomarker DOI: http://dx.doi.org/10.5772/intechopen.90806*

*Translational Research in Cancer*

overall population, but not by ethnicity [6].

−819T/C polymorphisms and skin cancer [85].

malignances.

cancer [84].

clinical outcome imparted by IL10 genetic variants may be mediated by effects on the tumor micro-environment composition or modulation [47]. The possibility that SNPs participate in the development, establishment, and the prognosis of cancer has been investigated by numerous research groups and includes several group

Eastern European patients with breast cancer, IL10 −1082A > G, −819 T > C, −592A > C polymorphisms, and phased haplotypes have not revealed a prognostic value [77]. Nevertheless, another study report 592C > A polymorphisms could modify disease-free and overall survival in women with lymph node-positive breast cancer [78]. In a Chinese Han population study, the −1082AA genotype was associated with a significantly increase risk of lymph node involvement and larger tumor size at the time of diagnosis [79]. After meta-analysis, it showed that IL10 rs1800896 and rs1800871 polymorphisms had no association with breast cancer risk, while rs1800872 polymorphism had a decreased risk of breast cancer in Caucasians [3]. However, another meta-analysis suggests that IL10 rs1800871 and rs1800872 polymorphisms might contribute to breast cancer susceptibility in the

Chinese men, diagnostic with prostate cancer, do not show significant differences in (−1082A/G, −819 T/C, and −592A/C) SNPs between patients and control subjects [80]. Meta-analysis performed with a Caucasian and Asiatic population suggests that there is no association between IL10 gene rs1800896, rs1800871, and rs1800872 polymorphisms and prostate cancer [81]. A study looking for the participation of variant alleles at both −819 and −592 polymorphisms was modestly associated with the advanced stages of prostate cancer [82, 83]. Other meta-analysis reports that rs1800896 polymorphism is associated with a decreased risk of prostate

In a meta-analysis including 26 studies designed to search the risk of skin cancer and IL10 polymorphism, the results show that there is not a significant association of −1082G > A or −592C > A and risk to skin cancer. Nevertheless, it suggested a potential association between −819C > T polymorphism and decreased risk of skin cancer [38]. A meta-analysis carried out for possible association between polymorphism and melanoma did not find an association between skin cancer risk and the −592A/C or IL-10-1082G/A. However, there was a correlation between IL10

Association between IL10 −1082A/G, −592C/A, and −819T/C gene polymorphisms and risk of lung cancer was also investigated by meta-analysis, but until now, there are inconsistent results: on Asian populations, IL10 −1082A/G and −819T/C polymorphisms might have a significant association with the risk of lung cancer [86]. Another meta-analysis suggests that the polymorphism associated with a risk factor for lung cancer was IL10 −592A > C polymorphism, especially among Asians and Caucasians. In contrast, the IL10 −819 T > C and −1082A > G polymorphisms are not significantly associated with an increased risk of lung cancer [87]. Cervical cancer associated with a polymorphism at this time is not conclusive: −1082 polymorphism was suggested as a marker of genetic susceptibility to cervical cancer among Japanese women but was not significantly increased in Zimbabwean women or Korean women [88]. In a meta-analysis, including 17 publications of Asian, African, and Caucasian populations, it did not find a significant association between the polymorphism and cervical cancer risk [89]. Other meta-analysis looking for association between −1082 G/A polymorphism and cervical cancer risk, including the same population, report as well that there is no association [90]. Association between rs1800896 polymorphism and head and neck cancer risk and its clinical stages in Caucasian and Asiatic evaluated by meta-analysis gave a significant association with head and neck cancer risk but not with the clinical

**30**



#### **Table 2.**

*Relationship of IL10 polymorphism and cancer risk.*

stages [91]. Other analysis reports significant associations between the IL10 −1082A > G and IL10 −819 T > C polymorphism and increased risks of head and neck cancer similar population [92].

Other studies on the relation between risk or prognosis polymorphisms in cancer have been performed. In there, a possible association with gastric cancer showed a significant association with IL10-819 on the Mexican population. Nevertheless, no significant association was found for IL10 −592C/A (rs1800872) and IL10 −1082A/G (rs1800896) [93]. Looking for a possible predispose to oral squamous cell carcinoma (−592), A/C polymorphism was significantly associated with reduced risk [94]. In colorectal cancer IL10 −819 T > C, polymorphism was associated with significantly increased risk [95].

In a clinical study with child Hokdkin disease, −1082GG genotype was associated with lower IL10 mRNA expression. Nevertheless, genotypes of the −592 SNP showed no association with IL10 mRNA expression. However, −1082AACAG genotypes, ATA haplotype, and the presence of the −592AA genotype were associated with unfavorable prognosis [47, 96].

Genotypic variants of IL10 (−1082G/A) polymorphism in adult Sudanese patients with acute myeloid leukemia were investigated as a possible risk factor. In there, no association between IL10 (−1082G/A) and acute myeloid leukemia was detected [7]. Nevertheless, in the Egyptian population, −819 polymorphism was associated with enhanced risk [97]. In the Chinese population, the −819A allele frequencies in the AML group were higher than in the controls [98]. In pediatric patients, Classical Hodgkin lymphoma −1082AA/AG, −592CC genotypes, and ATA haplotype were associated with unfavorable prognosis; interestingly, −1082 was associated with low IL10 mRNA expression [46].

Unfortunately, to date, the results are controversial; the relationship of polymorphism with the presence of cancer and/or the possible risk of developing cancer is shown in **Table 2**.

**33**

*IL10 as Cancer Biomarker*

**5. Conclusions**

conclusive.

**Conflict of interest**

**Author details**

Carmen Maldonado-Bernal

*DOI: http://dx.doi.org/10.5772/intechopen.90806*

homeostasis of the immune system.

High concentrations of IL-10 in the serum of cancer patients seem to correspond not only to the expression of this protein by immune cells. The evidence shows that the cancer cell is capable of synthesizing it, which would cause an imbalance in the

Besides, the presence of polymorphisms suggested the possibility that some of them could be involved in the regulation of the activity of IL10; this gave rise to numerous studies seeking opportunities to explore for cancer risks or implications in the development, establishment, and survival of the cancer cell. The relationship between polymorphisms and the risk and prevalence of different types of cancer had evaluated by meta-analysis. Unfortunately, until now, the results are not

Nevertheless, the fact is that IL-10 can exert the antitumor effect by mechanisms

Because of this, it is essential to study not only the mechanisms that allow this high expression of interleukin IL-10, but its effect on tumor cells and also. It is

such as the activation of natural killer cells (NK), lymphocytes T, macrophages, and nitric oxide; its high concentration shows the deregulation of the immune system, where a high level of IL10 allows the tumor to escape. Nevertheless, the fact that IL-10 can exert the antitumor effect by mechanisms such as the activation of natural killer cells, lymphocytes T, macrophages, and nitric oxide results controversial. Its high concentration induces the deregulation of the immune system, where a high level of IL-10 allows the tumor escape. In some cases, it could be propose as a

biomarker for patient lifespan or chemotherapy respond.

important to consider its relationship with other cytokines.

Maria Teresa Gonzalez-Garza\*, Delia Elva Cruz-Vega and

\*Address all correspondence to: mtgonzalezgarza@itesm.mx

México Federico Gómez, Mexico City, Mexico

provided the original work is properly cited.

Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

The authors declare that they have no competing interests.
