Does Human JC Virus Play a Role in the International Variations and Temporal Trends of Early-Onset Colorectal Cancer? A Meta-Analysis

Hytham K. S. Hamid1, MRCSEd, Artur Marc-Hernández2, MD, Jaime Ruiz-Tovar3, MD, PhD

1 Department of Surgery, Soba University Hospital, Khartoum, Sudan;
2 Department of Surgery, University Hospital Rey Juan Carlos, Madrid, Spain;
3 Department of Surgery, University Alfonso X, Madrid, Spain.

Conflict-of-interest statement: The authors declare that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Hytham K. S. Hamid, Department of Surgery, Soba University Hospital, Khartoum, Sudan.
Email: kujali2@gmail.com
Telephone: +249902517760
ORCID No: 0000-0001-8068-0154

Received: July 21, 2020
Revised: Septmber 30, 2020
Accepted: October 2, 2020
Published online: October 21, 2020


The prevalence and incidence trend of early-onset colorectal cancer (EO-CRC) exhibit wide variations across the world, which could be attributed to early-life exposures such as diet and viral infections. We carried out a systematic review and meta-analysis to examine the association between John Cunningham virus (JCV) infection and EO-CRC. Literature was searched for studies comparing the presence of JCV DNA in colorectal cancerous and non-cancerous tissues. Countries where the studies were conducted were categorized into high and low prevalence settings for EO-CRC, and according to the time-weighted average annual per cent change in incidence rates of EO-CRC into rising-trend, stable-trend, and decreasing-trend settings. A total of 19 studies with 3065 participants were included. The meta-analysis showed that JCV increased the odds for colorectal adenoma development (6-fold) more than colorectal cancer (4.1-fold), in comparison to controls. The odds for colorectal tumor development with JCV infection were significantly higher in the high-prevalence settings than in the low-prevalence settings when compared with controls and matched adjacent colorectal tissues. Similarly, the odds for colorectal tumor development trended to be higher in the rising-trend settings than in the stable-trend settings when compared with controls and matched adjacent colorectal tissues; no JCV DNA was detected in the decreasing-trend settings in both cancerous and non-cancerous colorectal tissues. These results suggest that JCV is likely involved in early stage of colorectal carcinogenesis, and may play a role in the international variations and temporal trends of EO-CRC in some parts of the world.

Key words: John Cunningham virus; Early-onset colorectal cancer; Colorectal adenoma; Prevalence; Incidence trend

© 2020 The Authors. Published by ACT Publishing Group Ltd. All rights reserved.

Hamid HKS, Marc-Hernández A, Ruiz-Tovar J. Does Human JC Virus Play a Role in the International Variations and Temporal Trends of Early-Onset Colorectal Cancer? A Meta-Analysis. Journal of Gastroenterology and Hepatology Research 2020; 9(5): 3340-3350 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/3001


Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, accounting for nearly 1.8 million new cases in 2018 and is projected to increase to more than 2.2 million new cases by 2030[1,2]. The distribution of CRC burden varies widely, with more than two-thirds of cases occurring in countries with a high or very high human developmental index[2]. For early-onset colorectal cancer (EO-CRC), defined as CRC diagnosed before the age of 50, the incidence rates were shown to be highest in developed countries like USA and Australia, while the lowest rates were recorded in developing countries such as Uganda and India[3]. Similarly, the prevalence of EO-CRC exhibits wide variations across the world with higher proportions of patients diagnosed under 50 years reported in Africa and Asia (16-52%) compared to Europe and North America (< 10 %)[4]. This geographical disparity unlikely relates to hereditary factors, since familial tumors and hereditary syndromes are implicated in only a fraction (20%) of EO-CRC[4], and would rather signal differences in early-life exposures such as diet and viral infections that influence colorectal carcinogenesis[5,6].

John Cunningham virus (JCV) is a neurotropic human polyoma virus with cell transforming properties, which is highly prevalent in human upper and lower gastrointestinal tract[7]. Since the first report by Laghi et al[8]. demonstrating presence of JCV DNA in malignant colorectal epithelium, several studies have pointed out an association between JCV infection and colorectal tumors[9-17]. Considering that JCV infection occurs during childhood, we hypothesized that JCV may play a role in the international variation and temporal trends of EO-CRC. Therefore, we conducted this systematic review and meta-analysis to investigate the possible association between JCV infection and colorectal tumors with special reference to EO-CRC.


Search strategy

A systematic review was performed following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement[18]. The PubMed, Cochrane Collaboration, and Embase databases were explored to identify relevant studies published before November 1, 2019. Our search strategy included terms for: “JCV” OR “JC virus” OR “polyomavirus” AND “colorectal” OR “rectal” OR “rectum” OR “colonic” OR “colon” AND “cancer” OR “carcinoma” OR “adenoma” OR “adenocarcinoma” OR “malignancy” OR “tumor” OR “neoplasm”, without any restrictions for language. The reference lists in each identified article were also searched.

Study selection

A single reviewer (H.H) screened the titles and abstracts. Full articles were assessed by 2 independent reviewers (H.H and A.H) and discrepancies were discussed and resolved by joint discussion. Inclusion criteria included (1) studies comparing the presence of JCV in colorectal cancer and/or adenoma with non-neoplastic colorectal tissues, and (2) studies employing polymerase chain reaction (PCR) to examine for presence of JCV nucleic acid material in tissues.

Exclusion criteria were as follows: non-comparative studies, studies not reporting on colorectal tumors separately, using non-colorectal tissue control, employing method other than PCR to detect JCV infection, and small-sampled studies (< 10 patients). Review articles, case reports, letters, and conference abstracts with no access to the entire report were also excluded.

Data extraction

Data extraction and methodologic quality assessment were carried out by two independent reviewers (H.H and A.M), and any disagreements were resolved through discussion and consensus. The methodological quality of each study was assessed using the Newcastle-Ottawa scale (NOS) for observational studies[19], and any disagreements were resolved through discussion and consensus. Studies with a cumulative score ≥ 7 were considered to be of high quality[20,21].

Data were collected on study design, year of publication, country, method of JCV testing, type of tumor (cancer vs. adenoma), specimen, and control (adjacent vs. non-adjacent tissues), number of positive and negative cases in terms of the presence of JCV, and quality assessment. Adjacent tissues were defined as non-neoplastic colorectal tissues obtained from the same individual, whereas non-adjacent tissues were defined as non-neoplastic colorectal tissues obtained from non-cancer patients. The corresponding authors were contacted by email when required to request incomplete or unpublished data.

Prevalence and incidence trends of EO-CRC

Data on the relative proportion of EO-CRC (ie. proportion of CRC cases diagnosed under age 50 years) in the countries where studies were conducted were retrieved from the most recent and comprehensive report published within the last 10 years[22-33]. Moreover, the trends in the incidence rates of EO-CRC in these countries were obtained from population-based annual incidence data reported by the national cancer registries in each country[3,34-38]. These trends spanned a minimum of 10-year period between 1990 and 2016. The epidemiologic knowledge was used to define high- and low-prevalence settings based on whether the relative proportion of EO-CRC was > 10% or < 10% in the respective countries. Similarly, countries were categorized into rising-trend, stable-trend, and decreasing-trend settings, according to the trends in the incidence rates of EO-CRC. The trend was described as “increasing”, “stable”, or “decreasing” based on the time-weighted average annual per cent change in incidence rates of EO-CRC[3]. One study, conducted in Greece, was excluded from the final subgroup analysis as no data on the relative proportion and the incidence trend of EO-CRC was available[39].

Statistical analysis

All analyses were performed using Review Manager (RevMan version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) and STATA software (version 16, StataCorp., College Station, TX). Dichotomous variables were expressed as odd ratios (ORs) and 95% confidence interval (CI). The Peto method along with an inverse-variance fixed-effect model was used to calculate the ORs, because this method performs well in the settings of low event rates and zero events, and does not require zero-cell corrections[40]. Heterogeneity was assessed using the I2 statistic. Pooled prevalence and Peto ORs were calculated for both colorectal cancer and adenoma. Subgroup analysis was performed to assess the difference in the Peto ORs according to the type of control used, and to evaluate a possible association between the prevalence and incidence trend of EO-CRC and the effect size on evaluated outcomes. A leave-one-out sensitivity analysis was conducted to assess if our results were driven by any study. Publication bias was assessed through funnel plots and Egger’s regression test[41].


Study Identification and Characteristics

The systematic search yielded a total of 426 unique articles. After title and abstract screening, 40 full-text articles were evaluated for eligibility. Finally, 18 articles reporting on 19 studies were included in the quantitative synthesis[9-17,39,42-49]. Details of the study selection process are shown in Figure 1.

The characteristics and methodologic quality evaluation of 19 eligible studies are summarized in Table 1 and Supplementary Table 1. These studies were published between 2003 and 2018, and involved 3065 participants (1544 patients and 1521 controls). Of the 19 studies, 17 were case-control[9-16,39,43-49], and 2 were cross-sectional[17,42]. Eight studies were conducted in Europe, 6 in Asia, 3 in Africa, and 2 in North America. Testing for JCV infection was performed using PCR in 12 studies[10,11,13,15,16,42-44,47-49], and nested PCR in 7 studies[9,12,14,17,39,45,46]; all but one study[39] employed primers targeting JCV large T antigen (T-Ag) sequence. Nine studies examined for JCV infection in colorectal cancer and adjacent tissues[10,13,17,42,43,45,46,48,49]. Five studies compared JCV infection in colorectal cancer/adenoma with nonadjacent tissues[12,15,16,44,47]. Another 5 studies included colorectal cancer/adenoma and controlled for both adjacent and non-adjacent tissues[9,11,14,39,42]. The NOS scores of the included studies ranged from 5 to 9; 10 studies were considered high quality.

Figure 1 PRISMA flow chart.

Table 1 Characteristics and quality assessment of the included studies.
AuthorYearStudy designCountryTemporal trend of EO-CRCPrevalence of EO-CRCNOS quality score
Hernandez- Losa et al.2003Case-controlSpainStableLow6
Newcomb et al.2004Case-controlUSARisingLow9
Theodoropoulos et al.2005Case-controlGreeceNANA7
Hori et al.2005Case-controlJapanStableLow6
Casini et al.2005Case-controlTunisiaStableHigh6
Goel et al.2006Case-controlUSARisingLow8
Lin et al.2008Cross-sectionalTaiwanRisingHigh8
Selgrad et al.2008Case-controlNetherlandsRisingLow5
Militello et al. (1)2009Case-controlItalyDecreasingLow7
Militello et al. (2)2009Cross-sectionalItalyDecreasingLow6
Campello et al.2010Case-controlItalyDecreasingLow5
Mou et al.2012Case-controlChinaStableLow8
Vilkin et al.2012Case-controlIsraelStableLow9
Coelho et al.2013Case-controlPortugalRisingLow7
Matalka et al.2013Case-controlJordanStableHigh6
Fiorina et al.2014Case-controlItalyDecreasingLow6
Ksiaa et al.2015Case-controlTunisiaStableHigh8
Toumi et al.2017Case-controlTunisiaStableHigh7
Sarvari et al.2018Case-controlIranRisingHigh5
EO-CRC early-onset colorectal cancer, NOS Newcastle-Ottawa scale, NA not available.

Supplementary Table 1 Methods and outcomes of JCV testing in the included studies.
AuthorType of tissueJCV DNA detection methodTumour (n)Adjacent tissues (n)Non-adjacent tissues (n) †
JCV positiveTotalJCV positiveTotalJCV positiveTotal
Hernandez- Losa et al.FFNested PCR11000100------
Newcomb et al.FFPENested PCR02331233------
Theodoropoulos et al.FFPENested PCR64 (15)105 (25)1358620
Hori et al.FFPENested PCR7 (1)44 (21)------020
Casini et al.FFPEPCR15181316------
Goel et al.FFPEPCR771001825------
Lin et al.FFPENested PCR1922022------
Selgrad et al.FFPEPCR20 (20)40 (40)------521
Militello et al. (1)FFPEPCR072072------
Militello et al. (2)FFPCR048 (20)048015
Campello et al.FFPCR093------071
Mou et al.FFNested PCR56137341371180
Vilkin et al.FFPEPCR630330------
Coelho et al.FFNested PCR67 (55)74 (60)4810040100
Matalka et al.FFPEPCR4092------1483
Fiorina et al.NAPCR044044------
Ksiaa et al.FFPEPCR611051389------
Toumi et al.FFPEPCR2247047020
Sarvari et al.FFPEPCR1 (0)140 (70)------070
JCV John Cunningham virus, FFPE formalin-fixed paraffin-embedded, FF fresh-frozen, PCR polymerase chain reaction, NA not available.Figures in parentheses are the numbers of patients with colorectal adenoma. † Non-adjacent colorectal tissue samples were obtained from non-cancer patients.

Association between JCV and colorectal tumors

Overall, the pooled prevalence of JCV infection in colorectal cancer and adenoma was 0.34 (95% CI 0.29-0.40) and 0.37 (95% CI 0.08-0.66), respectively. Compared to controls, JCV infection was significantly associated with increased risk of colorectal cancer (Peto OR 4.07 [95% CI 3.29-5.04], p < 0.001; I2 = 58%) and colorectal adenoma (Peto OR 5.95 [95% CI 3.99-8.85], p < 0.001; I2 = 0%) (Supplementary Figure 1 and 2). On subgroup analysis, JCV infection was significantly associated with increased risk of colorectal cancer when compared with adjacent tissues (Peto OR 4.01 [95% CI 3.06-5.25], P < 0.001; I2 = 73%) and with non-adjacent tissues (Peto OR 4.19 [95% CI 2.96-5.92], p < 0.001; I2 = 0%) (Supplementary Figure 3). Similarly, significant association was also found between JCV infection and increased risk of colorectal adenoma compared with adjacent (Peto OR 6.63 [95% CI 3.41-12.92], p < 0.001) and non-adjacent tissues (Peto OR 5.59 [95% CI 3.40-9.19], p < 0.001; I2 = 21%) (Supplementary Figure 4).

Supplementary Figure 1 Meta-analysis of JCV infection incidence in colorectal cancer compared with controls.

Supplementary Figure 2 Meta-analysis of JCV infection incidence in colorectal adenoma compared with controls.

Supplementary Figure 3 Subgroup analysis of JCV infection incidence in colorectal cancer compared with adjacent and non-adjacent tissue control.

Supplementary Figure 4 Subgroup analysis of JCV infection incidence in colorectal adenoma compared with adjacent and non-adjacent tissue control.

Association between JCV and EO-CRC

Of the 18 studies included in this analysis, 6 were conducted in a high-prevalence setting[11,13,15,17,47,49], and 12 in a low-prevalence setting for EO-CRC[9,10,12,14,16,42-46,48]. Stratifying studies by the incidence trend of EO-CRC, 6[9,10,16,17,46,47], 8[11-15,45,48,49], and 4 studies[42-44] were conducted in a rising-trend, stable-trend, and decreasing-trend setting, respectively (Table 1). The pooled OR for JCV infection in colorectal tumors (ie. cancer and/or adenoma) compared to controls was significantly higher in the high-prevalence settings compared to the low-prevalence settings (Peto OR 6.38 [95% CI 4.53-9.01] vs. 3.61 [95% CI 2.78-4.68], p = 0.01; Figure 2). This difference was also noted when analysis was restricted to studies testing paired samples of colorectal tumors and adjacent colorectal tissues (Peto OR 8.26 [95% CI 5.31-12.85] vs. 2.78 [95% CI 1.96-3.96], p = 0.0002; Figure 3). Likewise, the pooled OR for JCV infection in colorectal tumors compared to controls and adjacent tissues trended to be higher in the rising-trend settings compared to the stable -trend settings (Peto OR 5.95 [95% CI 4.16-8.51] vs. 3.83 [95% CI 2.97-4.94], p = 0.05) and (Peto OR 5.62 [95% CI 3.46-9.13] vs. 3.73 [95% CI 2.67-5.21], p = 0.17), respectively (Figure 4 and 5). No JCV infection was detected in both colorectal tumors and controls in the decreasing-trend settings[42-44].

Figure 2 JCV infection incidence in colorectal tumors vs. controls according to the prevalence settings

Figure 3 JCV infection incidence in colorectal tumors vs. adjacent tissues according to the prevalence settings.

Figure 4 JCV infection incidence in colorectal tumors vs. controls according to the incidence trend settings.

Figure 5 JCV infection incidence in colorectal tumors vs. adjacent tissues according to the incidence trend settings.

Sensitivity analysis and Publication bias

On sensitivity analysis of association between JCV infection and colorectal cancer and adenoma, leaving out one study at a time did not significantly alter the effect size, indicating that the results were stable and reliable. For the comparisons (colorectal cancer vs. controls and colorectal adenoma vs. controls), the funnel plot appeared symmetric (Supplementary Figure 5 and 6), and egger’s test did not detect publication bias (p = 0.27 and p = 0.70, respectively).

Supplementary Figure 5 Funnel plot for studies detecting JCV infection in colorectal cancer vs. controls.

Supplementary Figure 6 Funnel plot for studies detecting JCV infection in colorectal adenoma vs. controls.


This meta-analysis demonstrated that JCV infection was associated with increased risk of colorectal cancer and adenoma, regardless of the type of control, suggesting a possible causal role for JCV in colorectal carcinogenesis. Additionally, JCV infection increased the odds for colorectal adenoma development (6-fold) more than colorectal cancer (4.1-fold). Our findings corroborate the results of recent meta-analyses indicating that the presence of JCV in colorectal tissues increased the odds of colorectal tumors by 4.4 to 4.7 times compared to the absence of the virus[50,51]. In these studies, however, colorectal cancer and adenoma were not looked at individually, and the association of JCV infection with EO-CRC was not assessed.

According to our results, it is clearly evident that the presence of JCV increased the odds of CRC in countries with high prevalence of EO-CRC significantly more than in their low-prevalence counterparts. This difference was further substantiated when tumor-adjacent colorectal tissues were used as the sole control. Tumor-adjacent colorectal tissues are more valid controls as they share the same genetic conditions and environmental exposures with the tumors. These results indicate that JCV may play a key role in the higher prevalence of EO-CRC observed in certain parts of the world, notably developing countries. Indeed, JCV-associated CRC has a strong predilection for the distal colorectum[52], a pattern analogous to that described in the context of CRC in developing countries[5,24,26,31]. Further evidence supporting this hypothesis was a recent study employing the Next Generation Sequencing technology from Sudan, where EO-CRC represents almost 40-50% of CRC cases. Whole-exome sequencing of CRC disclosed significant centrality of NFKB1 and ELAVL1 pointing to a possible underlying viral etiology in these tumors[53].

Virus association with cancer may be influenced by geographic and ethnic factors, as clearly illustrated by the Epstein-Barr virus.[54] Infection with JCV is endemic in almost all populations, often acquired during late childhood, and is caused by different genotypes in different geographical regions[55]. Furthermore, viral DNA sequence variability was detected in normal colorectal mucosa between and within subjects in the same population, suggesting that the same individuals are infected by different JCV strains[7]. Recently, the International Agency for Research on Cancer has classified JCV as a probable, class 2B, biological carcinogen in humans[56]. It has been proposed that JCV induces malignant transformation through “hit and run” mechanism, during early stage of carcinogenesis, which is often followed by genome silencing or loss of the T-Ag sequence as a consequence of viral integration. Our analysis showed that the association with JCV was stronger for colorectal adenoma compared to CRC, which supports this concept. The JCV T-Ag, a multi-potent virally-encoded oncoprotein, promotes carcinogenesis by inactivating tumor suppressor proteins p53 and pRb, and inducing chromosomal instability[52]. The latter is frequently implicated in the early stages of carcinogenesis in EO-CRC[4].

In another aspect, there has been a rising trend in the incidence of EO-CRC, particularly rectal cancer, in several countries over the last two decades, often against a backdrop of rapidly declining rates in older individuals[3,38]. In some countries like the USA and Korea, the cohort effect, lifestyle changes, antibiotic use, and dietary transitions, have been pointed as likely and plausible culprits[3]. In Taiwan, a recent large-scale population-based study, using serological markers to diagnose infection, has evidenced that chronic hepatitis B virus was significantly associated with the risk of CRC, particularly in young patients[57], nevertheless, isolation of the viral DNA from the tumor cell nuclei is necessary to indicate causality. In other regions, such as Europe, the causes of this rising trend are yet to be determined. Considering that the inclines in the incidence of EO-CRC pertains predominantly to distal cancers, and the association between CRC and JCV infection in our analysis was stronger in the rising-trend settings, we postulate that JCV may contribute to the development of a subset of EO-CRC in this rising trend.

An important issue related to this meta-analysis is that two of the studies conducted in high-prevalence and rising-trend settings failed to detect JCV DNA in cancerous or noncancerous colorectal tissues[46,47]. This could be ascribed in large part to the method employed for JCV testing. In these studies, formalin-fixed specimens were used. Formalin fixation breaks the DNA and makes it more difficult to recover sufficient quantities for amplification[58]. In addition, one of these studies used PCR assay for JCV DNA testing rather than nested PCR, which is known to have lower sensitivity. In this setting, the use of topoisomerase I treatment before PCR amplification may enhance the sensitivity of JCV DNA detection[8].

In conclusion, JCV may play a role in the international variations and the rising trend of EO-CRC in some parts of the world. The current meta-analysis is limited by the relatively small number of studies. Further studies, comparing the prevalence of JCV in EO-CRC and average-onset CRC, and including larger numbers of patients with colorectal adenomas with special reference to the different JCV rearranged genotypes, are warranted to elucidate the role of JCV in colorectal tumorogenesis.


1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394-424. [PMID: 30207593]; [DOI: 10.3322/caac.21492]

2. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11. Lyon, France: International Agency for Research on Cancer, 2013.

3. Siegel RL, Torre LA, Soerjomataram I, Hayes RB, Bray F, Weber TK, Jemal A. Global patterns and trends in colorectal cancer incidence in young adults. Gut 2019; 68: 2179-2185. [PMID: 31488504]; [DOI: 10.1136/gutjnl-2019-319511]

4. Cavestro GM, Mannucci A, Zuppardo RA, Di Leo M, Stoffel E, Tonon G. Early onset sporadic colorectal cancer: Worrisome trends and oncogenic features. Dig Liver Dis 2018; 50: 521-532. [PMID: 29615301]; [DOI: 10.1016/j.dld.2018.02.009]

5. Abou-Zeid AA, Jumuah WA, Ebied EF, Karim Atia KSA, El Ghamrini Y, Dina A Somaie DA. Hereditary factors are unlikely behind unusual pattern of early - Onset colorectal cancer in Egyptians: A study of family history and pathology features in Egyptians with large bowel cancer (cross-sectional study). Int J Surg 2017; 44: 71-75. [PMID: 28624559]; [DOI: 10.1016/j.ijsu.2017.06.028]

6. Hamid HKS, Mustafa YM. The role of infectious agents in colorectal carcinogenesis. Colorectal cancer biology - from Genes to Tumor Rijeka: INTECH publisher Ettarh R 2012, 16:341-374.

7. Ricciardiello L, Laghi L, Ramamirtham P, Chang CL, Chang DK, Randolph AE, Boland CR. JC virus DNA sequences are frequently present in the human upper and lower gastrointestinal tract. Gastroenterology 2000; 119: 1228-1235. [PMID: 11054380]; [DOI: 10.1053/gast.2000.19269]

8. Laghi L, Randolph AE, Chauhan D, Marra G, Major EO, Neel JV, C R Boland CR. JC virus DNA is present in the mucosa of the human colon and in colorectal cancers. Proc Nat Acad Sci 1999; 96: 7484-7489. [PMID: 10377441]; [DOI: 10.1073/pnas.96.13.7484]

9. Coelho TR, Gaspar R, Figueiredo P, Mendonça C, Lazo PA, Almeida L. Human JC polyomavirus in normal colorectal mucosa, hyperplastic polyps, sporadic adenomas, and adenocarcinomas in Portugal. J Med Virol 2013; 85: 2119-2127. [PMID: 24009184]; [DOI: 10.1002/jmv.23705]

10. Goel A, Li MS, Nagasaka T, Shin SK, Fuerst F, Ricciardiello L, Wasserman L, Boland CR. Association of JC virus T antigen expression with the methylator phenotype in sporadic colorectal cancers. Gastroenterology 2006; 130: 1950-1961. [PMID: 16762618]; [DOI: 10.1053/j.gastro.2006.02.061]

11. Toumi W, Ripalti A, Ricciardiello L, Cherif A, Gargouri D, Bouhafa A, Kharrat J, Jarboui S, Benrhouma H, Zili M, Khelifa R. Detection of a new JCV strain of genotype A in a subpopulation of colorectal adenocarcinomas in Tunisia. New Microbiologica 2017; 40: 99-106. [PMID: 28255604]

12. Hori R, Murai Y, Tsuneyama K, Abdel-Aziz HO, Nomoto K, Takahashi H, Cheng C, Kuchina T, Harman BV, Takano Y. Detection of JC virus DNA sequences in colorectal cancers in Japan. Virchows Arch 2005; 447: 723-730. [PMID: 16021515]; [DOI: 10.1007/s00428-005-0014-3]

13. Ksiaa F, Allous A, Ziadi S, Mokni M, Trimeche M. Assessment and biological significance of JC polyomavirus in colorectal cancer in Tunisia. J Buon 2015; 20: 762-769. [PMID: 26214628]

14. Mou X, Chen L, Liu F, Lin J, Diao P, Wang H, Li Y, Lin J, Teng L, Xiang C. Prevalence of JC virus in Chinese patients with colorectal cancer. PLoS One 2012; 7: e35900. [PMID: 22606241]; [DOI: 10.1371/journal.pone.0035900]

15. Matalka I, Swedan S, Khabaz MN, Barahmeh M. JC virus in colorectal cancer: where do we stand? Future Virol 2013; 8: 607-615. [DOI: /10.2217/fvl.13.36]

16. Selgrad M, Koornstra JJ, Fini L, Blom M, Huang R, Devol EB, Ek BW, Dijkstra G, Verdonk RC, de Jong S, Goel A, Williams SL, Meyer RL, Haagsma EB, Ricciardiello L, Boland CR. JC virus infection in colorectal neoplasia that develops after liver transplantation. Clin Cancer Res. 2008; 14: 6717-6721. [PMID: 18927316]; [DOI: 10.1158/1078-0432.CCR-08-0961]

17. Lin PY, Fung CY, Chang FP, Huang W-S, Chen W-C, Wang J-Y, Chang D. Prevalence and genotype identification of human JC virus in colon cancer in Taiwan. J Med Virol 2008; 80: 1828-1834. [PMID: 18712832]; [DOI: 10.1002/jmv.21296]

18. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535. [PMID: 19622551]; [DOI: 10.1136/bmj.b2535]

19. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25: 603-605. [PMID: 20652370]; [DOI: 10.1007/s10654-010-9491-z]

20. Castillo JJ, Mull N, Reagan JL, Nemr S, Mitri J. Increased incidence of non-hodgkin lymphoma, leukemia, and myeloma in patients with diabetes mellitus type 2: A meta-analysis of observational studies. Blood 2012; 119: 4845-4850. [PMID: 22496152]; [DOI: 10.1182/blood-2011-06-362830]

21. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: A systematic review and meta-analysis. Gastroenterology 2013; 144: 323-332. [PMID: 23063971]; [DOI: 10.1053/j.gastro.2012.10.005]

22. Loomans-Kropp HA, Umar A. Increasing Incidence of Colorectal Cancer in Young Adults. J Cancer Epidemiol 2019; 2019: 9841295. [PMID: 31827515]; [DOI: 10.1155/2019/9841295]

23. Nagai Y, Hata K, Kawai K, Murono K, Yasuda K, Otani K, Nishikawa T, Tanaka T, Kiyomatsu T, Nozawa H, Yamaguchi H, Ishihara S, Watanabe T. Clinicopathological Features of Colorectal Cancer Patients Under the Age of 50: Recent Experience and Case-Control Study of Prognosis in a Japanese Cohort. Digestion 2016; 93: 272-279. [PMID: 27188463]; [DOI: 10.1159/000446344]

24. Khader YS, Sharkas GF, Arkoub KH, Alfaqih MA, Nimri OF, Khader AM. The Epidemiology and Trend of Cancer in Jordan, 2000-2013. J Cancer Epidemiol 2018; 2018: 2937067. [PMID: 30416523]; [DOI: 10.1155/2018/2937067]

25. Chou CL, Tseng CJ, Shiue YL. The impact of young age on the prognosis for colorectal cancer: a population-based study in Taiwan. Jpn J Clin Oncol 2017; 47: 1010-1018. [PMID: 29048580]; [DOI: 10.1093/jjco/hyx110]

26. Missaouia N, Jaidaine L, Ben Abdelkader A, Beizig N, Anjorin A, Yaacoubi MT, Hmissa S. Clinicopathological patterns of colorectal cancer in Tunisia. Asian Pac J Cancer Prev 2010; 11: 1719-1722. [PMID: 21338221]

27. Lemmens V, van Steenbergen L, Janssen-Heijnen M, Martijn H, Rutten H, Coebergh JW. Trends in colorectal cancer in the south of the Netherlands 1975-2007: rectal cancer survival levels with colon cancer survival. Acta Oncol 2010; 49: 784-796. [PMID: 20429731]; [DOI: 10.3109/02841861003733713]

28. Russo AG, Andreano A, Sartore-Bianchi A, Mauri G, Decarli A, Siena S. Increased incidence of colon cancer among individuals younger than 50 years: A 17 years analysis from the cancer registry of the municipality of Milan, Italy. Cancer Epidemiol 2019; 60: 134-140. [PMID: 31005829]; [DOI: 10.1016/j.canep.2019.03.015]

29. Yang J, Du XL, Li ST, Wang BY, Wu YY, Chen ZL, Lv M, Shen YW, Wang X, Dong DF, Li D, Wang F, Li EX, Yi M, Yang J. Characteristics of Differently Located Colorectal Cancers Support Proximal and Distal Classification: A Population-Based Study of 57,847 Patients. PLoS One 2016; 11: e0167540. [PMID: 27936129]; [DOI: 10.1371/journal.pone.0167540]

30. Rozen P, Liphshitz I, Barchana M. The changing epidemiology of colorectal cancer and its relevance for adapting screening guidelines and methods. Eur J Cancer Prev 2011; 20: 46-53. [PMID: 21102339]; [DOI: 10.1097/CEJ.0b013e328341e309]

31. Rahimi Z, Kasraei R, Najafi F, Tanhapoor M, Abdi H, Rahimi Z, Vaisi-Raygani A, Aznab M, Moradi M. Cancer notification at a referral hospital of Kermanshah, Western Iran (2006-2009). Asian Pac J Cancer Prev 2015; 16: 133-137. [PMID: 25640340]; [DOI: 10.7314/apjcp.2015.16.1.133]

32. Antunes L, Mendonça D, Bento MJ, Rachet B. No inequalities in survival from colorectal cancer by education and socioeconomic deprivation - a population-based study in the North Region of Portugal, 2000-2002. BMC Cancer 2016; 16: 608. [PMID: 27495309]; [DOI: 10.1186/s12885-016-2639-9]

33. Ramos M, Montaño J, Esteva M, Barceló A, Franch P. Colorectal cancer survival by stage of cases diagnosed in Mallorca, Spain, between 2006 and 2011 and factors associated with survival. Cancer Epidemiol 2016; 41: 63-70. [PMID: 26828896]; [DOI: 10.1016/j.canep.2016.01.001]

34. Vuik FE, Nieuwenburg SA, Bardou M, Lansdorp-Vogelaar I, Dinis-Ribeiro M, Bento MJ, Zadnik V, Pellisé M, Esteban L, Kaminski MF, Suchanek S, Ngo O, Májek O, Leja M, Kuipers EJ, Spaander MC. Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years. Gut 2019; 68: 1820-1826. [PMID: 31097539]; [DOI: 10.1136/gutjnl-2018-317592]

35. Missaoui N, Jaidaine L, Abdelkader AB, Trabelsi A, Mokni M, Hmissa S. Colorectal cancer in Central Tunisia: increasing incidence trends over a 15-year period. Asian Pac J Cancer Prev 2011; 12: 1073-1076. [PMID: 21790254]

36. Abdifard E, Amini S, Bab S, Masroor N, Khachian A, Heidari M. Incidence trends of colorectal cancer in Iran during 2000-2009: A population-based study. Med J Islam Repub Iran 2016; 30: 382. [PMID: 27493926]

37. Ismail SI, Soubani M, Nimri JM, Al-Zeer AH. Cancer incidence in Jordan from 1996 to 2009--a comprehensive study. Asian Pac J Cancer Prev 2013; 14: 3527-3534. [PMID: 23886140]; [DOI: 10.7314/apjcp.2013.14.6.3527]

38. Sung JJY, Chiu HM, Jung KW, Jun JK, Sekiguchi M, Matsuda T, Kyaw MH. Increasing Trend in Young-Onset Colorectal Cancer in Asia: More Cancers in Men and More Rectal Cancers. Am J Gastroenterol 2019; 114: 322-329. [PMID: 30694865]; [DOI: 10.14309/ajg.0000000000000133]

39. Theodoropoulos G, Panoussopoulos D, Papaconstantinou I, Gazouli M, Perdiki M, Bramis J, Lazaris AC. Assessment of JC polyoma virus in colon neoplasms. Dis Colon Rectum 2005; 48: 86-91. [PMID: 15690663]; [DOI: 10.1007/s10350-004-0737-2]

40. Brockhaus AC, Grouven U, Bender R. Performance of the Peto odds ratio compared to the usual odds ratio estimator in the case of rare events. Biom J 2016; 58: 1428-1444. [PMID: 27546483]; [DOI: 10.1002/bimj.201600034]

41. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629-634. [PMID: 9310563]; [DOI: 10.1136/bmj.315.7109.629]

42. Militello V, Trevisan M, Squarzon L, Biasolo MA, Rugge M, Militello C, Palù G, Barzon L. Investigation on the presence of polyomavirus, herpesvirus, and papillomavirus sequences in colorectal neoplasms and their association with cancer. Int J Cancer 2009; 124: 2501-2503. [PMID: 19170205]; [DOI: 10.1002/ijc.24224]

43. Fiorina L, Ricotti M, Vanoli A, Luinetti O, Dallera E, Riboni R, Paolucci S, Brugnatelli S, Paulli M, Pedrazzoli P, Baldanti F, Perfetti V. Systematic analysis of human oncogenic viruses in colon cancer revealed EBV latency in lymphoid infiltrates. Infect Agent Cancer 2014; 9: 18. [PMID: 24936208]; [DOI: 10.1186/1750-9378-9-18]

44. Campello C, Comar M, Zanotta N, Minicozzi A, Rodella L, Poli A. Detection of SV40 in colon cancer: a molecular case-control study from northeast Italy. J Med Virol 2010; 82: 1197-1200. [PMID: 20513084]; [DOI: 10.1002/jmv.21798]

45. Hernández Losa J, Fernandez-Soria V, Parada C, Sanchez-Prieto R, Cajal SRY, Fedele CG, Tenorio A. JC virus and human colon carcinoma: an intriguing and inconclusive association. Gastroenterology 2003; 124: 268-269. [PMID: 12512060]; [DOI: 10.1053/gast.2003.50033]

46. Newcomb PA, Bush AC, Stoner GL, Lampe JW, Potter JD, Bigler J. No evidence of an association of JC virus and colon neoplasia. Cancer Epidemiol Prev Biomarker 2004; 13: 662-666. [PMID: 15066935]

47. Sarvari J, Mahmoudvand S, Pirbonyeh N, Safaei A, Hosseini SY. The very low frequency of Epstein-Barr JC and BK Viruses DNA in colorectal cancer tissues in Shiraz, Southwest Iran. Pol J Microbiol 2018; 67: 73-79. [PMID: 30015427]; [DOI: 10.5604/01.3001.0011.6146]

48. Vilkin A, Ronen Z, Levi Z, Morgenstern S, Halpern M, Niv Y. Presence of JC virus DNA in the tumor tissue and normal mucosa of patients with sporadic colorectal cancer (CRC) or with positive family history and Bethesda criteria. Dig Dis Sci 2012; 57: 79-84. [PMID: 21830098]; [DOI: 10.1007/s10620-011-1855-z]

49. Casini B, Borgese L, Del Nonno F, Galati G, Izzo L, Caputo M, Donnorso RP, Castelli M, Risuleo G, Visca P. Presence and incidence of DNA sequences of human polyomaviruses BKV and JCV in colorectal tumor tissues. Anticancer Res 2005; 25: 1079-1085. [PMID: 15868949]

50. Shavaleh R, Kamandi M, Feiz Disfani H, Mansori K, Naseri SN, Rahmani K, Kanrash FA. Association between JC virus and colorectal cancer: systematic review and meta-analysis. Infect Dis (Lond) 2020; 52: 152-160. [PMID: 31766929]; [DOI: 10.1080/23744235.2019.1692145]

51. Shoraka HR, Abobakri O, Tahami AN, Mollaei HR, Bagherinajad Z, Afshar RM, Shahesmaeili A. Prevalence of JC and BK viruses in Patients with Colorectal Cancer: A Systematic Review and Meta- Analysis. Asian Pac J Cancer Prev 2020; 21: 1499-1509. [PMID: 32592342]; [DOI: 10.31557/APJCP.2020.21.6.1499]

52. Nosho K, Shima K, Kure S, Irahara N, Baba Y, Chen L, Kirkner GJ, Fuchs CS, Ogino S. JC virus T-antigen in colorectal cancer is associated with p53 expression and chromosomal instability, independent of CpG island methylator phenotype. Neoplasia 2009; 11: 87-95. [PMID: 19107235]; [DOI: 10.1593/neo.81188]

53. Suleiman SH, Koko ME, Nasir WH, Elfateh O, Elgizouli UK, Abdallah MOE, Alfarouk KO, Hussain A, Faisal S, Ibrahim FMA, Romano M, Sultan A, Banks L, Newport M, Baralle F, Elhassan AM, Mohamed HS, Ibrahim ME. Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways. Front Genet 2015; 6: 288. [PMID: 26442106]; [DOI: 10.3389/fgene.2015.00288]

54. Abdel-Hamid M, Chen JJ, Constantine N, Massoud M, Raab-Traub N. EBV strain variation: Geographical distribution and relation to disease state. Virology 1992; 190: 168-175. [PMID: 1356286]; [DOI: 10.1016/0042-6822(92)91202-6]

55. Agostini HT, Jobes DV, Stoner GL (2001) In: Khalili K, Stoner GD (eds) Molecular evolution and epidemiology of JC virus: molecular and clinical perspectives. Wiley-Liss, New York, pp 491-526

56. IARC, IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2013. Infection with malaria and some polyomaviruses (SV40, BK, JC, and Merkel Cell Viruses). IARC Monogr Eval Carcinog Risks Hum 104:261-307

57. Su FH, Le TN, Muo CH, Te SA, Sung F-C, Yeh C-C. Chronic Hepatitis B Virus Infection Associated with Increased Colorectal Cancer Risk in Taiwanese Population. Viruses 2020; 12: E97. [PMID: 31947702]; [DOI: 10.3390/v12010097]

58. Boland CR, Bigler J, Newcomb PA, et al. Evidence for an association between JC virus and colorectal neoplasia. Cancer Epidemiol Biomarkers Prev 2004; 13: 2285-2286. [PMID: 15598796]


  • There are currently no refbacks.

Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.