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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 7  |  Page : 1656-1663

The prevalence of human papillomavirus in colorectal cancer and adenoma: A meta-analysis


1 Department of Family Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
2 Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China

Date of Submission15-May-2020
Date of Decision13-Oct-2020
Date of Acceptance30-Nov-2020
Date of Web Publication9-Feb-2021

Correspondence Address:
Shuo Zhang
Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_636_20

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 > Abstract 


Objective: The objective of this study is to further clarify the correlation between colorectal cancer (CRC) and human papillomavirus (HPV) through literature search and meta-analysis, which is conducive to the formulation of further prevention programs.
Methods: Searching Web of Science, PubMed, MEDLINE, Scopus, and CENTRAL for studies investigating the relationship between CRC and HPV. All analyses were performed through Revman (version 5.3, the Cochrane Collaboration, Oxford, UK). Data from selected studies were extracted into two by two tables. Moreover, all included studies were weighted and summarized.
Results: Eighteen studies were included. The expression of HPV in CRC tissues was obviously higher than that in nonmalignant tissues (odds ratio [OR] = 5.56, 95% confidence interval [CI] = 3.18–9.72, Z = 6.02, P < 0.00001). The expression of HPV in CRC tissues and adenoma tissues showed no significant abnormalities (OR = 1.74, 95% CI = 0.92–3.29, Z = 1.70, P = 0.09). The expression of HPV in CRC tissues was obviously higher than that in normal tissues (OR = 7.23, 95% CI = 3.89–13.42, Z = 6.27, P < 0.00001).
Conclusion: HPV infection in CRC tissues was obviously higher than that in nonmalignant tumor tissues and normal colon tissues, but there were no statistically significant abnormalities between CRC tissues and adenoma tissues.

Keywords: Adenoma, colorectal cancer, human papillomavirus, meta-analysis


How to cite this article:
Chao G, Hong X, Chen X, Zhang S. The prevalence of human papillomavirus in colorectal cancer and adenoma: A meta-analysis. J Can Res Ther 2020;16:1656-63

How to cite this URL:
Chao G, Hong X, Chen X, Zhang S. The prevalence of human papillomavirus in colorectal cancer and adenoma: A meta-analysis. J Can Res Ther [serial online] 2020 [cited 2021 Mar 8];16:1656-63. Available from: https://www.cancerjournal.net/text.asp?2020/16/7/1656/308771




 > Introduction Top


Colorectal cancer (CRC) is the third-most common malignancy in the world and the fourth leading cause of death in developing countries.[1] In western countries, CRC is the second most common malignancy followed by skin cancer.[2] Although the current level of medical care has significantly improved, the 5-year survival rate of CRC is 67%, compared with 64% for colon cancer.[3] Even among survivors, CRC has a high recurrence rate and is prone to secondary tumors, especially in the digestive tract.[4] The high mortality rate of CRC is ascribed to the late detection of CRC and the high recurrence rate to a great extent. The 5-year survival rate of CRC depends on the current stage of CRC.[5] Although colonoscopy is widely used to detect early tumors, more studies were carried out to prevent CRC. Exploring the mechanism of CRC is a research hotspot recently. The researchers supposed that gene mutations in KRAS, NRAS, and BRAF are closely related to the occurrence of CRC.[6] In addition to genetic factors, factors such as behavior and diet are also associated with the occurrence of CRC.[7]

In recent years, due to increased concern about human papillomavirus (HPV), researchers have begun to pay attention to the correlation between HPV and CRC. HPV is a DNA tumor virus which is the main cause of sexually transmitted infections.[8] HPV is considered a risk factor of many malignancies, such as cervical cancer, head and neck cancer.[9] Through meta-analysis, the researchers identified a close relationship between HPV infection and esophageal squamous cell carcinoma.[10] Studies carried out on HPV-related prostate cancer found that HPV colonization can also occur in benign tumors prior to the onset of prostate cancer.[11] A new study suggests that HPV may be link to CRC, but appears to be influenced by location, diet, and lifestyle.[12] Some researchers have also found that HPV16 was found in more than 50% of HPV positive colon cancer tissues, thus suggesting that the occurrence of local CRC is related to the high rate of HPV infection.[13] However, a large case–control study shown that HPV was detected in both CRC tissues and control normal tissues, denying the relevance between CRC and HPV infection.[14] Therefore, the correlation between CRC and HPV infection is still controversial. The target of this research is to further clarify the correlation between CRC and HPV through literature search and meta-analysis, which is conducive to the formulation of further prevention programs.


 > Methods Top


Search strategy

For this meta-analysis, we searched Web of Science PubMed, MEDLINE, Scopus and CENTRAL with the goal of identifying the relevance of HPV and CRC. Data were collected from 1966 to 2020 (as of January). The terms we used in the search included two aspects. One included “colorectal cancer,” “colorectal tumor,” “rectal cancer,” “rectal tumor,” “colon cancer,” “colon tumor” and “colorectal carcinomas.” The other included “Human papillomavirus” and “HPV.” The search had a language restriction to English. We searched full-text articles through various websites, and collected dates as original as possible. All documents we reviewed were in duplicate, independently reviewed by the investigator.

Selection criteria

Data were extracted by three reviewers from studies that met the inclusion criteria. All controlled studies investigating the relationship between HPV and CRC were included. Our inclusion criteria were: (1) random control; (2) tissues from patients who had a CRC diagnosis were regarded as the cases; (3) normal tissues and adenoma tissues were regarded as the controls; (4) HPV DNA was detected in the tissue. Our exclusion criteria were: (1) The researchers came from people with specific diseases, such as HIV; (2) the number of detected cases is not summarized in the literature; (3) animal experiments; and (4) overview or systematic analysis. Each article was a study reviewed by reviewers individually and ultimately selected. Research process, research method, research results, loss of follow-up, and adverse reactions must be included in these articles.

Quality appraisal

From four aspects (patient selection, index detection, reference criteria, and flow and time), quality appraisal was done using QUADAS-2 tools[15],[16] for this study.

Data analysis

All analyses were performed through Revman (version 5.3, The Cochrane Collaboration, Oxford, UK). Data from selected studies were extracted into two by two tables. All included studies were weighted and summarized. We used a meta-analysis program (RevMan 5.3, The Cochrane Collaboration, Oxford, UK) to calculate the relative risk odds ratio (OR) and 95% confidence interval (CI) between cases and controls, and we performed a meta-analysis of the effect value (weighted mean difference). The l abbe plot was used to calculate the event rate of the experimental group compared to the control group to explore the heterogeneity of effect estimation. We used fixed-effects models to pool data for it had homogeneity; in addition, we used a random-effects model as well.


 > Results Top


Selection process

We identified 398 studies, of which 266 were aimed on other subjects, 35 were non-English articles, 17 were reviewers, 27 were experiments, 3 were case reports, 12 with special diseases, 1 was letter, 6 were repeated articles, 13 clinical studies did not meet the requirements of meta-analysis. Ultimately, 18 articles met the inclusion criteria and were included in the meta-analysis. [Figure 1] shows the flow chart of research selection.
Figure 1: The flow diagram of study selection

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Clinical information

All of 18 articles were included as qualified researches, which were published from 1993 to 2017. All of these articles were published in English. [Table 1] shows the characteristics of the included studies.
Table 1: The characteristics of the included studies

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Publication bias assessment and quality assessment

From four aspects (patient selection, index detection, reference criteria, and flow and time), the quality appraisal of 18 studies was done using QUADAS-2 tools. [Figure 2]a shows the detailed appraisal results.
Figure 2: Methodological quality diagram and publication bias assessment (a) Quality assessment based on the questions of QUADAS-2 quality assessment. Red, yellow, and green colors show the high, unclear, and low risk of bias and applicability concerns. (b) Red, yellow, and green colors show the high, unclear, and low risk of bias

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To investigate the underlying publication bias, we did the analysis by Revman 5.3. We found no publication bias [Figure 2]b. The reason why we analyzed publication bias is that in the process of publication, the authors tend to publish articles with positive results, while those with negative results tend to be omitted.

Heterogeneity test

Colorectal cancer tissue versus nonmalignant tissue

The heterogeneity test was performed by the Chi-square test. χ2 = 40.23, P = 0.0002 [Figure 3]a. The results shown that heterogeneity was discovered in our meta-analysis. Thus, a random-effect model could be analyzed in the meta-analysis.
Figure 3: The forest plot of meta-analysis. (a) The forest plot of meta-analysis of human papillomavirus between colorectal cancer tissue and nonmalignant tissue (b) The forest plot of meta-analysis of human papillomavirus between colorectal cancer tissue and adenoma tissue (c) The forest plot of meta-analysis of human papillomavirus between colorectal cancer tissue and normal tissue

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Colorectal cancer tissue versus adenoma tissue

The heterogeneity test was performed by the Chi-square test. χ2 = 2.59, P = 0.27 [Figure 3]b. The results shown that this study did not exist heterogeneity in our meta-analysis. Thus, a fixed-effect model could be analyzed in the meta-analysis.

Colorectal cancer tissue versus normal tissue

The heterogeneity test was performed by the Chi-square test. χ2 = 33.56, P = 0.0008 [Figure 3]c. The results shown that heterogeneity was discovered in our meta-analysis. Thus, a random-effect model could be analyzed in the meta-analysis.

Merging and meta-analysis

Colorectal cancer tissue versus nonmalignant tissue

Based on the meta-analysis and the forest map, we found that the rhombus was on the right side of the vertical line and did not intersect with it. Based on [Figure 3]a, we determined the following values: OR = 5.56, 95%CI = 3.18–9.72, Z = 6.02, P < 0.00001. Therefore, the OR value was statistically significant. It indicated that the expression of HPV in CRC tissues was significantly higher compared with nonmalignant tissues. However, the number of included articles was limited, more studies should be conducted.

Colorectal cancer tissue versus adenoma tissue

Based on the meta-analysis and the forest map, we found that the rhombus was crossed with the vertical line. Based on [Figure 3]b, we determined the following values: OR = 1.74, 95% CI = 0.92–3.29, Z = 1.70, P = 0.09. It indicated that the expression of HPV in CRC tissues and adenoma tissues showed no significant abnormalities. However, the number of included literature was limited, and more studies are needed.

Colorectal cancer tissue versus normal tissue

Based on the meta-analysis and the forest map, we found that the rhombus was on the right side of the vertical line and did not intersect with it. Based on [Figure 3]c, we determined the following values: OR = 7.23, 95% CI = 3.89–13.42, Z = 6.27, P < 0.00001. Therefore, the OR value was statistically significant. It indicated that the expression of HPV in CRC tissues was obviously higher than that in normal tissues. However, the number of included articles was limited, more studies should be conducted.


 > Discussion Top


It is estimated that nearly 41% of CRC cases occur in the proximal colon, 22% in the distal colon, and 28% in the rectum.[33] Currently, the incidence of CRC is generally in decline thanks to the improving medical care ability, but patients aged <50 years who were diagnosed with CRC has increased by 2%. By 2030, the rate of colonic and rectal cancer patients aged 20–34 years is projected to increase to 90.0% and 124.2%, respectively.[34] Studies have shown that genes are related to the development of CRC. Compared with the general population, the incidence of CRC in people whose first-degree relatives have CRC is significantly doubled.[35] Meta-analysis found that heavy drinking was positively correlated with CRC mortality.[36] Obesity is related to the development of CRC, especially in women.[37] Meanwhile, Vitamin D is thought to be associated with CRC, the higher Vitamin D content is, the lower incidence of CRC is.[38] A recent study suggests that male smokers have higher probability to develop colon cancer on the left side, whereas female smokers have higher probability to develop colon cancer on the right side, and that female smokers have a higher risk of colon cancer than male smokers.[39] Thus, genes, gender, and lifestyle may be relevant to the occurrence of CRC, but it is difficult to change.[40]

Recent research on CRC has focused on early screening and prevention. Because CRC is associated with genes, multi-target stool DNA testing has also been studied for early risk detection.[41] At the same time, a comprehensive risk model combining family history, personal characteristics, and environmental factors were also studied and developed for risk stratification and risk assessment of CRC.[42] Previous studies have emphasized the importance of endoscopic examination in the early detection of CRC, but institutions with limited economic power need to bear a certain economic burden.[43] Although, tens of studies have been done in the treatment aspect of CRC, and a number of methods have been found to predict risk early. However, CRC has a high mortality rate, more researchers are looking for related mechanisms to prevent CRC. In recent years, for CRC researchers, HPV has become the hotspot.[44]

At present, studies on the mechanism of CRC have reached the molecular level, but its etiology remains unclear. A study has found that in Puerto Rican Hispanics, HPV has the characteristics of high popularity in CRC.[13] Meanwhile, another study suggested that HPV infection is relevant to CRC and may be an important prognostic factor.[29] HPV infection had been found a risk factor of CRC in studies of Chinese populations.[28] Therefore, multiple researchers have found HPV infection is related to the development of CRC, which may be an important risk factor for CRC, but there are also controversial, and some studies hold the opposite results. Taherian et al. concluded that there exist no significant association between HPV infection and CRC occurrence, but the authors considered that it might be related to the lack of study samples.[31] Ranjbar et al. also suggested that there was no causal relationship between HPV infection and CRC, but suggested that high-risk types of HPV may increase the aggressiveness of CRC.[30]

Our meta-analysis showed that HPV infection does increase the risk of CRC: HPV infection in CRC tissues was obviously higher compared with nonmalignant tumor tissues and normal colon tissues, but no statistically significant difference exist between CRC tissues and adenoma tissues. In this study, 8 articles were included in the meta-analysis, thus the sample size was large, and the results were reliable. However, there are also some limitations: (1) Because the study believes that genes and lifestyle are related to the occurrence of CRC, this study did not conduct further stratification study on genes or lifestyle; (2) most of the research results are published with positive results, so some negative results may be missed; (3) in the included articles, HPV neither detected in the experimental group or the control group, so such literature was not selected in our meta-analysis. However, in accordance with our analysis, CRC and colorectal adenoma have a high probability of HPV infection, whereas the mechanism of CRC caused by HPV infection needs further research and follow-up with more cases. On the other hand, based on its correlation, the development of HPV vaccine may be effective in preventing CRC and also has important significance for social health care.


 > Conclusion Top


Our findings support the hypothesis that HPV infection and CRC/adenoma share some disease links, which may indicate that further study of the relevant mechanism of HPV and the development of HPV-related vaccine may have great significance for the prevention of CRC.

Financial support and sponsorship

This research was supported by National National Natural Science Foundation of China (82074214, 81973598, 81573760); funding from Zhejiang Provincial Natural Science Foundation of China under Grant No.LY18H030001; the Medicine and Health Science and Technology Plan Projects in Zhejiang province (2017KY413), Traditional Chinese Medicine Science and Technology Plan of Zhejiang Province (2017ZA089, 2016ZB071, 2015ZZ012, 2014ZA030); ;Medical Health Platform Plan Projects of Zhejiang Province (2015RCA020); Zhejiang Provincial Natural Science Foundation of China (LY16H030010).

Conflicts of interest

There are no conflicts of interest.



 
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