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1.  Epstein Barr virus: a prime candidate of breast cancer aetiology in Sudanese patients 
Breast cancer is the commonest cancer in Sudanese women. Reported genetic alterations in the form of mutations in tumor suppressors are low in frequencies and could not explain the peculiarities of the diseases including its focal nature. Potential contributors disease aetiology include oncogenic viruses such as Epstein-Barr virus (EBV), an established culprit of nasopharyngeal carcinoma, one of the most frequent cancers in Sudan.
In this study, DNA was extracted from malignant tissue samples and healthy tumour-free tissue from the same breast. Polymerase chain Reaction (PCR) was used to amplify two genes encoding for EBV viral proteins. The presence of Epstein-Barr virus and its cellular localization was confirmed by in situ hybridization (ISH) for Epstein-Barr encoded small RNAs (EBERs). Given the reported low frequency of mutations in BRCA1 and BRCA2 in Sudanese breast cancer patients, the methylation status of six tumor suppressor genes was investigated using methylation specific PCR. EBV genome was detected in 55.5% (n = 90) of breast cancer tissues as compared to 23% in control tissue samples (p = 0.0001). Using ISH, EBV signal was detected in all 18 breast cancer biopsies examined while all five normal breast tissue biopsies tested were negative for EBV. Of six tumour suppressor genes investigated BRCA1, BRCA2, and p14 appeared to be under strong epigenetic silencing.
In conclusion, we present evidence of a strong association between EBV and breast carcinoma in Sudanese patients, and considerable epigenetic silencing of tumor suppressors that may likely be an outcome or an association with viral oncogenesis.
PMCID: PMC3975647  PMID: 24607238
Sudan; Epstein Barr virus (EBV); Breast cancer; DNA methylation
2.  Cancer burden among HIV-positive persons in Nigeria: preliminary findings from the Nigerian AIDS-cancer match study 
Although Nigeria has a large HIV epidemic, the impact of HIV on cancer in Nigerians is unknown.
We conducted a registry linkage study using a probabilistic matching algorithm among a cohort of HIV positive persons registered at health facilities where the Institute of Human Virology Nigeria (IHVN) provides HIV prevention and treatment services. Their data was linked to data from 2009 to 2012 in the Abuja Cancer Registry. Match compatible files with first name, last name, sex, date of birth and unique HIV cohort identification numbers were provided by each registry and used for the linkage analysis. We describe demographic characteristics of the HIV clients and compute Standardized Incidence Ratios (SIRs) to evaluate the association of various cancers with HIV infection.
Between 2005 and 2012, 17,826 persons living with HIV (PLWA) were registered at IHVN. Their median age (Interquartile range (IQR)) was 33 (27–40) years; 41% (7246/17826) were men and 59% (10580/17826) were women. From 2009 to 2012, 2,029 clients with invasive cancers were registered at the Abuja Cancer Registry. The median age (IQR) of the cancer clients was 45 (35–68) years. Among PLWA, 39 cancer cases were identified, 69% (27/39) were incident cancers and 31% (12/39) were prevalent cancers. The SIR (95% CI) for the AIDS Defining Cancers were 5.7 (4.1, 7.2) and 2.0 (0.4, 3.5), for Kaposi Sarcoma and Cervical Cancer respectively.
The risk of Kaposi Sarcoma but not Cervical Cancer or Non-Hodgkin’s Lymphoma, was significantly increased among HIV positive persons, compared to the general population in Nigeria.
PMCID: PMC3942812  PMID: 24597902
HIV; Cancer; AIDS-cancer match; Registry linkage; Nigeria
3.  Epstein-Barr virus and telomerase: from cell immortalization to therapy 
Overcoming cellular senescence is strictly required for virus-driven tumors, including those associated with Epstein-Barr virus (EBV). This critical step is successfully accomplished by EBV through TERT expression and telomerase activation in infected cells. We herein review the complex interplay between EBV and TERT/telomerase in EBV-driven tumorigenesis. Evidence accumulated so far clearly indicates that elucidation of this issue may offer promising opportunities for the design of innovative treatment modalities for EBV-associated malignancies. Indeed, several therapeutic strategies for telomerase inhibition have been developed and are being investigated in clinical trials. In this respect, our recent finding that TERT inhibition sensitizes EBV+ lymphoma cells to antivirals through activation of EBV lytic replication is particularly promising and provides a rationale for the activation of clinical studies aimed at assessing the effects of combination therapies with TERT inhibitors and antivirals for the treatment of EBV-associated malignancies.
PMCID: PMC3943417  PMID: 24572088
Epstein-Barr virus; Telomerase; Cancer; Lymphoma; Lytic replication; Antivirals
4.  Infectious Agents and Cancer reviewer acknowledgement 2013 
Contributing reviewers
The editor of Infectious Agents and Cancer would like to thank all our reviewers who have contributed to the journal in Volume 32 (2013).
PMCID: PMC3909281  PMID: 24484901
5.  Upscaling human papillomavirus vaccination in high-income countries: impact assessment based on transmission model 
The decrease in human papillomavirus (HPV) vaccine prices may allow upscale already started vaccination programmes but the advantages of different options are unclear.
Using a mathematical model of HPV16 and 18 transmission and data on vaccination coverage from Italy, we compared 3 options to upscale an already started programme targeting 11-year old girls (coverage 65%): a) coverage improvement (from 65% to 90%); b) addition of 11-year-old boys (coverage 65%); or c) 1-year catch-up of older girls (coverage 50%).
The reduction of cervical HPV16/18 infection as compared to no vaccination (i.e. effectiveness against HPV16/18) increased from 76% to 98% with coverage improvement in girls and to 90% with the addition of boys. With higher coverage in girls, HPV16/18 infection cumulative probability by age 35 decreased from 25% to 8% with a 38% increase in vaccine number. The addition of boys decreased the cumulative probability to 18% with a 100% increase in the number of vaccinees. For any coverage in girls, the number of vaccinees to prevent 1 woman from being infected by HPV16/18 by age 35 was 1.5, whereas it was 2.7 for the addition of boys. Catch-up of older girls only moved forward the vaccination effectiveness by 2–5 years.
Increasing vaccination coverage among girls is the most effective option for decreasing HPV16/18. If not achievable, vaccinating boys is justifiable if vaccine cost has at least halved, because this option would almost double the number of vaccinees.
PMCID: PMC3901332  PMID: 24438317
Human papillomavirus; Vaccination; High-income; Mathematical model
6.  Implication of human herpesviruses in oncogenesis through immune evasion and supression 
All human herpesviruses (HHVs) have been implicated in immune system evasion and suppression. Moreover, two HHV family members, i.e. EBV and KSHV, are recognised as oncogenic viruses. Our literature review summarises additional examples of possible oncogenic mechanisms that have been attributed to other HHVs. In general, HHVs affect almost every cancer-implicated branch of the immune system, namely tumour-promoting inflammation, immune evasion, and immunosuppression. Some HHVs accomplish these effects by inhibiting apoptotic pathways and by promoting proliferation. Mechanisms related to immunosupression and low grade chronic inflammation could eventually result in the initiation and progression of cancer. In this article we open a discussion on the members of Herpesviridae, their immune evasion and suppression mechanisms, and their possible role in cancer development. We conclude that discerning the mechanisms of interplay between HHV, immune system, and cancer is essential for the development of novel preventative and therapeutic approaches for cancer treatment and prophylaxis.
PMCID: PMC3904197  PMID: 24438207
Herpesviruses; Cancer; Immune system; Antigen presentation; Natural killer cells; Cytokine
7.  Escherichia coli-derived outer membrane vesicles are genotoxic to human enterocyte-like cells 
Colorectal cancers are the third most common type in the world. The causes of the disease are poorly understood, but since the discovery of Helicobacter pylori as a causative agent of gastric cancer, attention has turned to bacteria as a possible trigger for colorectal cancer. Recently H. pylori outer membrane vesicles (OMVs) were revealed as potentially genotoxic which can be important first step in carcinogenesis. We therefore investigated whether OMVs from intestinal Escherichia coli could be genotoxic.
OMVs from the avirulent DH5α strain, a pathogenic adherent-invasive E. coli (AIEC) and an enterohaemolytic (EHEC) strain of E. coli were enriched by ultracentrifugation. The effect on the growth and viability of human enterocyte-like Caco-2 cells by OMVs was determined by trypan blue exclusion, MTT and BrdU incorporation assays. The ability of OMVs to induce DNA damage was assayed by single-cell gel electrophoresis, and 8-oxo-dG and γH2Ax immunofluorescence staining. Cytopathological changes were assessed by microscopy. The induction of aneuploidy by the OMVs was measured by flow cytometry in Caco-2 and LoVo cells.
We found that OMVs derived were internalised by Caco-2 cells, increased cell numbers, induced double-stranded DNA breaks, recruited γH2Ax to the nucleus, initiated DNA rereplication, and produced distended multinucleate cells. DH5α and AIEC OMVs caused free radical generation as indicated by the reduction of glutathione in cells, leading to the development of mutagenic 8-oxo-dG adducts in DNA. Flow cytometry revealed that DH5α and EHEC OMVs increased aneuploidy in p53 mutant Caco-2 cells, but not in p53 wild type LoVo cells.
We conclude that E. coli derived OMVs, whether from avirulent or pathogenic strains are potentially genotoxic.
PMCID: PMC3898235  PMID: 24405746
Escherichia coli; Outer membrane vesicles; Genotoxicity; Colorectal cancer
8.  Clustering patterns of human papillomavirus infections among HIV-positive women in Kenya 
HIV-positive women are at increased risk of human papillomavirus (HPV) infection, and, especially, multiple infections compared to HIV-negative women. Whether certain HPV types have a tendency to cluster in multiple infections beyond or below what would be expected by shared risk factors (e.g., sexual behavior and the degree of immunosuppression) is unclear. We, therefore, investigated clustering patterns of 44 HPV types in HIV-positive women from Kenya.
HPV status was assessed on cervical scrapings from 498 women using GP5+/6+ PCR and reverse line blot. Logistic regression was used to model type-specific HPV positivity, adjusted for age, specific HPV type prevalence, CD4, combination antiretroviral therapy, and, in the Full Model, individual-level random effects that represent unobservable risk factors common to all HPV types. We found a modest excess of women with co-infections with 2 HPV types (1.12; 95% credible intervals: 1.03-1.21) in the Full Model but no significant associations of individual types. No significant deviations of observed/expected counts were observed for any 2-way combination of HPV types at either the chosen level of significance, p = 0.00005, or at p = 0.01. Findings were substantially similar when women with CIN2/3 were excluded and when they were stratified by use of anti-retroviral therapy or CD4 count.
HPV co-infections occurred at random in the cervix of HIV-positive women as previously found in HIV-negative women. The removal of HPV types through vaccination should not result, therefore, in an increase or decrease in the prevalence of HPV types not targeted by vaccination in immunosuppressed women.
PMCID: PMC3878246  PMID: 24355034
Human papillomavirus; HIV; Prevalence; Women; Multiple infections
9.  Prevalence and predictors of Cervical Intraepithelial Neoplasia among HIV infected women at Bugando Medical Centre, Mwanza-Tanzania 
Cancer of the cervix rank the second most common cause of cancer related deaths among women in Sub-Saharan Africa. It is estimated that 529, 409 new cases are diagnosed annually with a mortality rate approaching 274,883 per year. Cervical Intraepithelial Neoplasia (CIN) precedes almost all cervical cancers. The incidence rate of CIN among HIV infected women is five times higher as compared to the rate in HIV negative women. The screening for cervical dysplasia and an appropriate management in women with CIN are effective methods for preventing cervical cancer. This study was done to determine the prevalence and predictors of CIN among a HIV infected women attending Care and Treatment centre (CTC) at Bugando Medical Centre (BMC).
A cross sectional survey was undertaken among HIV infected women aged 18 years and above attending at BMC CTC clinic between February and March 2013. Visual Inspection with Acetic acid (VIA) was used as the screening method for detection of CIN. Socio-demographic, reproductive and clinical information was obtained from participants and the blood was collected for CD4 lymphocyte count. Cervical punch biopsy for histological examination was performed for those who had VIA positive test. Data were entered and analyzed using STATA Version 12.0 soft ware.
A total number of 95 (26.8%) participants had positive VIA test among three hundred and fifty-five (355) HIV infected women. Histology results showed; 4(4.2%) were normal, 26 (27.4%) had an inflammatory lesion, 58(61.1%) had CIN and 7(7.3%) had invasive cervical cancer. CIN was found to be associated with a history of multiple sexual partners (P<0.001), a history of genital warts (P<0.001), and a history of STI (P = 0.010).
The Cervical Intraepithelial Neoplasia is a problem among HIV infected women. A history of multiple sexual partners, a history of genital warts, a history STI and a low baseline CD4 T lymphocyte were significant predictors for CIN. Screening for Cervical Intraepithelial Neoplasia is recommended for all women with HIV.
PMCID: PMC3833176  PMID: 24228805
Cervical intraepithelial Neoplasia; HIV; Mwanza
10.  Learning lessons from cancer centers in low- and middle-income countries 
Infectious Agents and Cancer is introducing a new section on Cancer Centers in Low- and Middle-Income Countries intended to provide the oncology community with detailed information about lessons learned in cancer control in resource-limited settings. The growing burden of cancer and the high rates of infection-related cancers in Low- and Middle-Income Countries (LMICs) argue for exploring the successes and challenges of cancer centers in low-resource settings. Detailed analyses are needed on how successful cancer centers have developed and managed such key components as strategic partnerships, trained cancer professionals, sustainable funding, appropriate technology, and research capacity. Many examples exist wherein local cancer centers have made significant progress and as such, the series will provide a platform to showcase detailed features of cancer institutes in LMICs and provide valuable information for those seeking to replicate successful models and to help invigorate efforts to build cancer capacity.
PMCID: PMC3882881  PMID: 24228782
11.  Potential role of gastrointestinal microbiota composition in prostate cancer risk 
Among men in the U.S., prostate cancer is the most common cancer and the second leading cause of cancer death. Despite its prevalence, there are few established risk factors for prostate cancer. Some studies have found that intake of certain foods/nutrients may be associated with prostate cancer risk, but few have accounted for how intake and metabolic factors may interact to influence bioavailable nutrient levels and subsequent disease risk.
Presentation of the hypothesis
The composition of the gastrointestinal (GI) microbiome may influence metabolism of dietary compounds and nutrients (e.g., plant phenols, calcium, choline) that may be relevant to prostate cancer risk. We, therefore, propose the hypothesis that GI microbiota may have a markedly different composition among individuals with higher prostate cancer risk. These individuals could have microbial profiles that are conducive to intestinal inflammation and/or are less favorable for the metabolism and uptake of chemopreventive agents.
Testing the hypothesis
Because very little preliminary data exist on this potential association, a case–control study may provide valuable information on this topic. Such a study could evaluate whether the GI microbial profile is markedly different between three groups of individuals: healthy men, those with latent prostate cancer, and those with invasive prostate cancer. Any findings could then be validated in a larger study, designed to collect a series of specimens over time.
Implications of the hypothesis
Given the plethora of information emerging from the Human Microbiome Project, this is an opportune time to explore associations between the microbiome and complex human diseases. Identification of profiles that alter the host’s risk for disease may clarify inconsistencies in the literature on dietary factors and cancer risk, and could provide valuable targets for novel cancer prevention strategies.
PMCID: PMC3826836  PMID: 24180596
Human microbiome; Metagenome; Prostate cancer; Metabolic process
12.  Differences in the mutation of the p53 gene in exons 6 and 7 in cervical samples from HIV- and HPV-infected women 
Human Papillomavirus (HPV) infection is a serious problem for human immunodeficiency virus (HIV)-infected women, increases their risk of cervical lesions and cancer. In cervical carcinogenesis, mutations in the p53 gene occur most frequently within exons 5–8. To our knowledge, no previous studies have analyzed mutations in exons 5–8 of the p53 gene in HIV- and HPV-infected women. In our study, we verified these mutations in women with and without cervical abnormalities.
The study included 160 women, divided into three groups: (1) 83 HPV- and HIV-infected women (HIV group); (2) 37 HPV-infected/HIV-uninfected (control group); and (3) 40 normal cytology/DNA-HPV negative/HIV-uninfected women (negative control p53 reactions). HPV-DNA was detected using polymerase chain reaction (PCR) and genotyping by PCR-restriction fragment length polymorphism analysis. Using primers for exons 5–8, the mutation of the p53 gene was verified by PCR-single strand conformational polymorphism. The total mutation of the p53 gene in exons 5–8 was not significantly associated with the HIV and control groups. The mutations in exon 7 were the highest in the HIV group (43.8%) and in exon 6 in the control group (57.2%) (p = 0.0793) suggesting a tendency toward differential mutation in exon 7 in the HIV group.
Our study provides preliminary evidence that the mutation in exon 7 might be an important differentiating factor for cervical carcinogenesis in HIV-infected women. This aspect deserves an additional cross-sectional and longitudinal study using a larger sample size with a higher number of High-grade squamous intraephitelial lesion (HSIL) to observe the evolution of cervical lesions.
PMCID: PMC3851445  PMID: 24098975
HIV; HPV; Cervical lesions; p53 gene; Mutations; Exons 5–8
13.  Mentoring future Kenyan oncology researchers 
This is a summary of the 1st Academic Model Providing Access to Healthcare (AMPATH) Oncology Institute research grant writing workshop organized in collaboration with the Kenya Medical Research Institute (KEMRI) and held in Kisumu, Kenya from January 16th to 18th, 2013. The goal of this meeting was to mentor future Kenyan scientists and prioritize research topics that would lead to improved cancer care and survival for the citizens of Kenya.
PMCID: PMC3851568  PMID: 24099090
Cancer; Kenya; Grant writing workshop; Provocative research questions
14.  Clinical oncology in resource-limited settings 
Infectious Agents and Cancer is introducing a new section of Clinical Oncology with the main objective of stimulating debate through articles published in the section. Infectious diseases have been the major causes of morbidity and mortality in human populations, and have dominated the medical approach to clinical and public health. Successful efforts to control mortality from acute infections have paved the way for chronic, mostly indolent, infections to become major causes of morbidity. Cancer, hitherto thought to be rare in resource-limited settings, is becoming a major contributor. The changes in mortality patterns are due, in part, to diseases linked to rapid changes in lifestyle, urbanization, and pollution. These diseases include many of the non-infection associated cancers. However, there is a dearth of information about the burden, pathogenesis, and therapeutic approaches about cancer in resource-limited countries. There are also substantial other challenges, including economic, infrastructure, technology, and personnel. The Journal advocates for interactive local–global (lo-bal) efforts to generate relevant knowledge about cancer burden, pathogenesis, and therapeutic approaches using a bottom-up approach to sharpen the focus on local and global relevance of research and clinical and public practice, particularly in resource-limited countries. The section on Clinical Oncology in Infectious Agents and Cancer will harness these “lo-bal” strategies to reduce substantially the time from concept, discovery, and development and implementation of locally and globally applicable diagnostic and therapeutic technologies.
PMCID: PMC3852095  PMID: 24099039
15.  Detection of Chlamydophila pneumoniae and human herpesvirus 8 in primary cutaneous anaplastic large-cell lymphoma: a case report 
The etiology of primary cutaneous anaplastic large-cell CD30+ lymphoma is largely unknown, and although an infectious involvement has been suspected, the implication of infectious agents in its pathogenesis is still unclear.
We report the case of a HIV-negative patient referred to our hospital with a rapidly enlarging skin tumor on her upper eyelid. Surgical excision was performed and histological analysis evidenced a primary cutaneous anaplastic large-cell lymphoma. Due to the ocular localization and to the prominent angiogenic component of the lesion, molecular analyses for the detection of Chlamydophila pneumoniae and HHV8 were performed, revealing the presence of an infection by both pathogens in surgical biopsy and in peripheral blood mononuclear cells.
These findings suggest for the first time a possible association of C. pneumoniae and/or HHV8 infection, or both together, with primary cutaneous anaplastic large-cell lymphoma in non-immunocompromised and HIV-negative subjects. This potential pathogenic association, if confirmed, could provide potential indications for future therapy.
PMCID: PMC3852251  PMID: 24099147
Primary cutaneous anaplastic large-cell lymphoma; Chlamydophila pneumoniae; Human herpesvirus 8; Infection-related carcinogenesis; Eyelid
16.  Factors influencing time to diagnosis and initiation of treatment of endemic Burkitt Lymphoma among children in Uganda and western Kenya: a cross-sectional survey 
Survival rates for children diagnosed with Burkitt lymphoma (BL) in Africa are far below those achieved in developed countries. Late stage of presentation contributes to poor prognosis, therefore this study investigated factors leading to delays in BL diagnosis and treatment of children in Uganda and western Kenya.
Guardians of children diagnosed with BL were interviewed at the Jaramogi Oginga Odinga Teaching and Referral Hospital (JTRH) and Uganda Cancer Institute (UCI) from Jan-Dec 2010. Information on sociodemographics, knowledge, attitudes, illness perceptions, health-seeking behaviors and prior health encounters was collected using a standardized, pre-tested questionnaire.
Eighty-two guardians were interviewed (20 JTRH, 62 UCI). Median "total delay" (1st symptoms to BL diagnosis) was 12.1 weeks [interquartile range (IQR) 4.9-19.9] in Kenya and 12.9 weeks (IQR 4.3-25.7) in Uganda. In Kenya, median "guardian delay" (1st symptoms to 1st health encounter) and "health system delay" (1st health encounter to BL diagnosis) were 9.0 weeks (IQR 3.6-15.7) and 2.0 weeks (IQR 1.6-5.8), respectively. Data on guardian and health system delay in Uganda were only available for those with < 4 prior health encounters (n = 26). Of these, median guardian delay was 4.3 weeks (range 0.7-149.9), health system delay 2.6 weeks (range 0.1-16.0), and total delay 10.7 weeks (range 1.7-154.3). Guardians in Uganda reported more health encounters than those in Kenya (median 5, range 3–16 vs. median 3, range 2–6). Among Kenyan guardians, source of income was the only independent predictor of delay, whereas in Uganda, guardian delay was influenced by guardians’ beliefs on the curability of cancer, health system delay, by guardians’ perceptions of cancer as a contagious disease, and total delay, by the number of children in the household and guardians’ role as caretaker. Qualitative findings suggest financial costs, transportation, and other household responsibilities were major barriers to care.
Delays from symptom onset to BL treatment were considerable given the rapid growth rate of this cancer, with guardian delay constituting the majority of total delay in both settings. Future interventions should aim to reduce structural barriers to care and increase awareness of BL in particular and cancer in general within the community, as well as among health professionals.
PMCID: PMC3849966  PMID: 24079452
Africa; Kenya; Uganda; Cancer; Children; Burkitt lymphoma; Delay; Delayed diagnosis
17.  MYC chromosomal aberration in differential diagnosis between Burkitt and other aggressive lymphomas 
Myc oncogenetic deregulation is abundantly described in several solid human cancer and lymphomas. Particularly, Burkitt's lymphoma belongs to the family of B Non Hodgkin aggressive lymphomas. Although it is morphologically characterized, immunophenotypic and cytogenetic diagnosis remains complex. In 2008, the WHO has introduced a new diagnostic class of aggressive B-cell lymphomas with features intermediate between BL and DLBCL. This diagnostic class represents a temporary container of aggressive B-cell lymphomas, not completely belonging to the BL and DLBCL categories. The importance of establishing a correct diagnosis would allow a better prognostic classification and a better therapeutic approach. In this review, we summarize the main diagnostic approaches necessary for appropriate diagnoses and we emphasize the importance of cytogenetic analysis of the oncogene Myc in the histopathological diagnosis and the prognostic/predictive stratification. In this contest, Myc represents the more involved gene in the development of these lymphomas. Therefore, we analyze the genetic aberrations causing its over-expression and the concomitant deregulation of molecular pathways related to it. We also propose a FISH approach useful in the diagnosis of these lymphomas.
PMCID: PMC3850004  PMID: 24079473
Burkitt Lymphoma; FISH; MYC; Aggressive non-Hodgkin B-cell lymphoma; Diffuse large B cell lymphoma; B-cell lymphoma unclassifiable
18.  Burkitt Lymphoma: beyond discoveries 
First described in 1958 in Uganda, Burkitt lymphoma (BL) attracted interest worldwide following reports of its uneven geographic distribution and rapidly fatal clinical course. Both suggested infectious etiology and curability. Seminal discoveries followed in quick succession. Viral etiology – due to Epstein-Barr virus (EBV) – was confirmed. Chromosomal translocations, involving cellular MYC, a protooncogene, were discovered, shown to be a hallmark of BL, and central to the genetic basis of cancer. Cure of BL using combination chemotherapy was demonstrated. Unfortunately, civil disturbance in Africa disrupted BL research and blunted its impact on education and oncology care in Africa. Important questions went unanswered. The risk of BL due to malaria or EBV was not quantified. Efforts to answer whether BL could be prevented – by preventing malaria or early EBV infection – were abandoned. The mechanism of malaria in BL is unknown. In Africa, BL remains mostly fatal and diagnosis is still made clinically. Unprecedented advances in molecular, genomics and proteomic technologies, promising to unlock mysteries of cancers, have re-awakened interest in BL. With return of stability to Africa, the unanswered questions about BL are re-attracting global interest. This interest now includes exploiting the knowledge gained about genetics, proteomics, and bioinformatics to enable the development of targeted less toxic treatment for BL; and simpler methods to diagnose BL with high accuracy and sensitivity. The articles in the Burkitt Lymphoma (BL): Beyond Discoveries in Infectious Agents and Cancer highlight BL as priority. Authors explore etiology, pathology, pathogenesis of BL, and whether knowledge gained in the studies of BL can catalyze sustainable cancer services in one of the world’s poorest served regions.
PMCID: PMC3852287  PMID: 24079372
19.  Identification of a novel variant of LMP-1 of EBV in patients with endemic Burkitt lymphoma in western Kenya 
Epstein Barr virus (EBV) is a gammaherpesvirus that is associated with nasopharyngeal carcinoma (NPC) and endemic Burkitt lymphoma (eBL). EBV carries several latent genes that contribute to oncogenesis including the latent membrane protein 1 (LMP-1), a known oncogene and constitutively active CD40 homolog. Variation in the C terminal region of LMP-1 has been linked to NPC pathogenesis, but little is known regarding LMP-1 variation and eBL.
In the present study, peripheral blood samples were obtained from 38 eBL patients and 22 healthy controls in western Kenya, where the disease is endemic. The LMP-1 C-terminal region from these samples was sequenced and analyzed. The frequency of a 30 base pair deletion of LMP-1 previously linked to NPC was not associated with eBL compared to healthy controls. However a novel LMP-1 variant was identified, called K for Kenya and for the G318K mutation that characterizes it. The K variant LMP-1 was found in 40.5% of eBL sequences and 25.0% of healthy controls. All K variant sequences contained mutations in both of the previously described minimal T cell epitopes in the C terminal end of LMP-1. These mutations occurred in the anchor residue at the C-terminal binding groove of both epitopes, a pocket necessary for MHC loading.
Overall, our results suggest that there is a novel K variant of LMP-1 in Kenya that may be associated with eBL. Further studies are necessary to determine the functional implications of the LMP-1 variant on early events in eBL genesis.
PMCID: PMC3847075  PMID: 24016332
20.  Human papillomavirus, high-grade intraepithelial neoplasia and killer immunoglogulin-like receptors: a Western Australian cohort study 
Human papillomavirus (HPV) is the causative agent in cervical cancer and HPV genotypes 16 and 18 cause the majority of these cancers. Natural killer (NK) cells destroy virally infected and tumour cells via killer immunoglobulin-like receptors (KIR) that recognize decreased MHC class I expression. These NK cells may contribute to clearance of HPV infected and/or dysplastic cells, however since KIR controls NK cell activity, KIR gene variation may determine outcome of infection.
KIR gene frequencies were compared between 147 patients with a history of high-grade cervical intraepithelial neoplasia (CIN) and a control population of 187, to determine if any KIR genes are associated with high-grade CIN. In addition a comparison was also made between cases of high grade CIN derived from 30 patients infected with HPV 16/18 and 29 patients infected with non-16/18 HPV to determine if KIR variation contributes to the disproportional carcinogenesis derived from HPV 16/18 infection.
High-grade CIN was weakly associated with the absence of KIR2DL2 and KIR2DS2 (p = 0.046 and 0.049 respectively, OR 0.6; 95% CI 0.4 – 0.9) but this association was lost after correction for multi-gene statistical analysis. No difference in KIR gene frequencies was found between high-grade CIN caused by HPV 16/18 and non-16/18.
No strong association between KIR genes, high-grade CIN and HPV genotype was found in the Western Australian population.
PMCID: PMC3846821  PMID: 24011088
Cervical cancer; High-grade CIN; KIR; Natural killer cells; Human papillomavirus
21.  Role of viruses in the development of breast cancer 
The most common cancer worldwide among women is breast cancer. The initiation, promotion, and progression of this cancer result from both internal and external factors. The International Agency for Research on Cancer stated that 18-20% of cancers are linked to infection, and the list of definite, probable, and possible carcinogenic agents is growing each year. Among them, biological carcinogens play a significant role. In this review, data covering infection-associated breast and lung cancers are discussed and presented as possible involvements as pathogens in cancer. Because carcinogenesis is a multistep process with several contributing factors, we evaluated to what extent infection is significant, and concluded that members of the herpesvirus, polyomavirus, papillomavirus, and retrovirus families definitely associate with breast cancer. Detailed studies of viral mechanisms support this conclusion, but have presented problems with experimental settings. It is apparent that more effort needs to be devoted to assessing the role of these viruses in carcinogenesis, by characterizing additional confounding and synergistic effects of carcinogenic factors. We propose that preventing and treating infections may possibly stop or even eliminate certain types of cancers.
PMCID: PMC3765990  PMID: 24138789
Carcinogenesis; Infectious agents; Breast cancer
22.  HLA-DRB1 Class II antigen level alleles are associated with persistent HPV infection in Mexican women; a pilot study 
Persistent infection with high-risk human papillomavirus (HPV) is a major risk factor for malignant lesions and cervical cancer. A widely studied element in the search for genetic factors influencing risk HPV infection diseases is allelic variation of the human leukocyte antigen (HLA) locus. The study was designed to search for HLA susceptibility alleles contributing to the persistence of HPV infection in Mexican women.
A total of 172 subjects were divided into three groups: 1) HPV–persistent patients; 2) HPV–cleared; and 3) HPV–reinfected patients. They were screened for HPV types using a polymerase chain reaction (PCR). PCR-sequence specific oligonucleotide probes (PCR-SSOP) was used for HLA DRB1 and DQB1 typing.
We observed that HLA-DQB1*0501 allele might be associated with susceptibility of reinfection with HPV (p = 0.01, OR = 4.9, CI 95% = 1.3 -18.7). Allele frequency of HLA-DRB1*14 was particularly reduced in patients with cancer when compared with the HPV–persistent group (p = 0.04), suggesting that this allele is a possible protective factor for the development of cervical cancer (OR = 2.98). HLA-DRB1*07 might be associated with viral clearance (p = 0.04).
Genetic markers for HPV infection susceptibility are different in each population, in Mexicans several HLA-DQB1 alleles might be associated with an enhanced risk for viral persistence. In contrast, DRB1*14, seems to confer protection against cervical cancer.
PMCID: PMC3766142  PMID: 24000898
HPV; HLA class II; Susceptibility; Persistent infection; DRB1
23.  Oncogenic human papillomavirus-associated nasopharyngeal carcinoma: an observational study of correlation with ethnicity, histological subtype and outcome in a UK population 
Nasopharyngeal carcinoma (NPC) accounts for 0.6% of all cancers worldwide with the highest prevalence in South East Asia, Southern China and Northern Africa but the disease is uncommon in Europe with an annual incidence in this region of less than 1 per 100 000. Although the Epstein-Barr virus (EBV) is a well known causative agent in NPC, recent reports have implicated oncogenic Human Papillomavirus (HPV) in a subgroup of these tumours. The recent striking rise of oropharyngeal carcinoma has been attributed to HPV, but little is known about the prevalence and clinical significance of the virus in NPC. The aim of this study was to determine the prevalence of oncogenic HPV in NPC from tissue archives of two head and neck cancer centres in the UK.
Samples were available for 67 patients with clinically validated NPC. The detection of high-risk HPV was carried out by screening all cases for p16 using immunohistochemistry and HPV DNA by polymerase chain reaction (PCR) using GP5+/6+ primers. All cases with p16 over-expression or positive for HPV by PCR were then examined by high-risk HPV DNA in-situ hybridisation and genotype analysis by PCR.
Eleven cases (11/67, 16.4%) showed concurrent over-expression of p16 and evidence of high-risk HPV DNA by in-situ hybridisation; the majority were HPV16 positive. Of these 11 cases, nine occurred in Whites and two in Blacks. Histologically, there were two keratinising squamous cell carcinoma and nine non-keratinising carcinomas (eight differentiated and one undifferentiated). None of the HPV-positive cases showed any co-infection with EBV. There was no statistically significant difference in overall survival outcome between patients with HPV-positive and HPV-negative NPC.
The results of this study show that oncogenic HPV is associated with a subgroup of NPCs and is more likely to occur in Whites. However, unlike oropharyngeal carcinoma there was no significant difference in overall survival between patients with HPV-positive and HPV-negative NPC.
PMCID: PMC3751535  PMID: 23938045
Nasopharyngeal carcinoma; Human papillomavirus; Epstein-Barr virus
24.  Complete genomic sequence of Epstein-Barr virus in nasopharyngeal carcinoma cell line C666-1 
Nasopharyngeal carcinoma is a distinct type of head and neck cancer which is consistently associated with Epstein-Barr virus (EBV). The C666-1 cell line is the only in vitro native EBV-infected NPC cell model commonly used for study of the viral-host interaction. Nevertheless, the complete EBV genome sequence in this in vitro EBV-infected NPC model has not been characterized.
To determine the complete EBV genome sequence in C666-1 cells.
The C666-1 genome was sequenced by 100-bases pair-end massive parallel sequencing. Bioinformatics analysis was performed to extract the EBV sequences and construct an EBV consensus sequence map. PCR amplification and Sanger DNA sequencing were used for sequence validation and gap filling. A phylogenetic analysis of EBV strain in C666-1 cells and other reported EBV strains was performed.
A 171,317 bp complete EBV genome of C666-1 was successfully constructed (GenBank accession number: KC617875). Phylogenetic analysis of EBV genome in C666-1 revealed that the C666-1 EBV strain is closely related to the reported strains in NPC primary tumors.
C666-1 contains a representative NPC-associated EBV genome and might serve as an important model for studying the roles or function of viral proteins in NPC tumorigenesis.
PMCID: PMC3734220  PMID: 23915735
Epstein-Barr virus; Nasopharyngeal carcinoma; Whole-genome deep sequencing; Single-nucleotide variations; Indels; Phylogenetic analysis; BNRF
25.  Epstein Barr virus DNA analysis in blood predicts disease progression in a rare case of plasmablastic lymphoma with effusion 
In HIV-1-infected patients a long lasting CD4+ cell decline influences the host-EBV balance and thereby increases the risk for EBV related malignancies. In spite of a world-wide access to combination antiretroviral therapy (cART) there are still a considerable number of HIV-1-infected patients who will develop severe immunodeficiency. These undiagnosed HIV-1 infected patients, so called late testers, demonstrate an increased lymphoma risk, compared to patients diagnosed early. Consecutive individual screening for EBV DNA-load in late testers might be a useful predictor of emerging EBV-malignancy.
Patient biopsies and ascites were analyzed morphologically, by immuncyto-histochemistry and in-situ hybridization. Viral DNA and RNA load were quantified by PCR. Cell lines from primary tumor and from ascites, were established in vitro and further analyzed.
We here report on a case of EBV-positive lymphoma in an AIDS patient, first presenting with pleural effusion and ascites and was thus initially considered a primary effusion lymphoma (PEL) but was later diagnosed as a plasmablastic lymphoma (PBL). The patient had responded to cART with undetectable HIV-RNA and increased CD4 cell count one year prior to lymphoma presentation. At the time of lymphoma diagnosis the HIV-RNA values were <50 RNA-copies per mL blood (undetectable) and the CD4-positive cell count 170 ×106/L. The lymphoma was CD45-negative and weakly CD22- and CD30-positive. The patient had a history of Kaposi sarcoma and HHV-8 seropositivity. The lymphoma biopsies, and three cell lines derived on different occasions from the tumor cell effusion, were all EBV-positive but HHV-8 negative.
A noticeable EBV-DNA load decline was observed during the remission of the lymphoma following CHOP-therapy. The EBV-DNA load increased dramatically at the time of recurrence.
EBV DNA load might be useful in monitoring the effect of lymphoma treatment as well as in estimating the risk of EBV-associated lymphoma in HIV-1 infected patients with pronounced immunosuppression.
PMCID: PMC3726497  PMID: 23880011
EBV; HIV-1; HHV-8; DNA load; Plasmablastic lymphoma

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