Genetic factors, as well as environmental factors, play a role in development of nasopharyngeal carcinoma (NPC). A number of single nucleotide polymorphisms (SNPs) have been reported to be associated with NPC. To confirm these genetic associations with NPC, two independent case-control studies from Southern China comprising 1166 NPC cases and 2340 controls were conducted. Seven SNPs in ITGA9 at 3p21.3 and 9 SNPs within the 6p21.3 HLA region were genotyped. To explore the potential clinical application of these genetic markers in NPC, we further evaluate the predictive/diagnostic role of significant SNPs by calculating the area under the curve (AUC). Results. The reported associations between ITGA9 variants and NPC were not replicated. Multiple loci of GABBR1 , HLA-F , HLA-A , and HCG9 were statistically significant in both cohorts (Pcombinedrange from 5.96 × 10 −17 to 0.02). We show for the first time that these factors influence NPC development independent of environmental risk factors. This study also indicated that the SNP alone cannot serve as a predictive/diagnostic marker for NPC. Integrating the most significant SNP with IgA antibodies status to EBV, which is presently used as screening/diagnostic marker for NPC in Chinese populations, did not improve the AUC estimate for diagnosis of NPC.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA -B, and HLA -C class I genes (P(HLA-A-aa-site-62) = 7.4 × 10(-29); P (HLA-B-aa-site-116) = 6.5 × 10(-19); P (HLA-C-aa-site-156) = 6.8 × 10(-8) respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China.

BACKGROUND The presence and origin of endemic foci of human T-lymphotropic virus type 2 (HTLV2) infection in Africa remain a matter of debate. METHODS To better appreciate such determinants, we performed a survey of 1918 inhabitants from Cameroon forest areas, including 1051 Bakola Pygmies and 867 Bantus. RESULTS The overall HTLV-1/2 seroprevalence was 4% (49 cases of HTLV-1 and 27 cases of HTLV-2 infection). Both infections were mainly restricted to the Bakola Pygmies, with surprisingly no HTLV-2 infections in the Bantu population. Both HTLV-1 and HTLV-2 seroprevalences increased with age. There was evidence of ongoing HTLV-2 transmission in this population. Lymphoid T cell lines producing HTLV-2 were established. HTLV-2 long terminal repeat sequences (672 base pairs) obtained from 7 infected Bakola were highly similar to each other (<1% nucleotide divergence), as well as to Amerindian HTLV-2B strains. Analyses on a complete sequence (8954 base pairs) confirmed that it was a typical HTLV-2 subtype B strain. Along with molecular clock analysis, these data strongly suggest that HTLV-2 has been endemic in the Bakola Pygmy population for a long time. CONCLUSIONS This study demonstrates clearly an HTLV-2 endemicity with ongoing transmission in an African population. Furthermore, it give insights into central questions regarding the origins and evolution rate of HTLV-2 and the migrations of infected populations.

HTLV-2 in Central Africa: HTLV-2 subtype B strains similar to those found in Amerindian tribes are endemic in Bakola Pygmies from south Cameroon but not in surrounding Bantus and Baka Pygmies Philippe Mauclere, Laurent Meertens, Philippe Afonso, Sabine Plancoulaine, Claudia Filippone, Edouard Betsem, Sara Calattini, Alain Froment, Monique Van Beveren, Guy de The, Luis Quintana-Murci, Renaud Mahieux, Antoine Gessain

Objective: To perform a quantitative estimate of the proportion of cancers attributable to occupational exposures in France in 2000. Methods: Exposure data for established carcinogens were obtained from a 1994 survey and other sources. Relative risks for 23 exposure-cancer combinations were derived from meta-analyses and pooled analyses. Results: A total of 4335 cases of cancer among men (2.7% of all cancers) and 403 cases among women (0.3% of all cancers) were attributed to occupational exposures. Asbestos, polycyclic aromatic hydrocarbons, and chromium VI were the main occupational carcinogens in men, and asbestos and involuntary smoking were the main carcinogens in women. Corresponding proportions for cancer deaths were 4.0% and 0.6% in men and women, respectively. Lung cancer represented 75% of deaths attributable to occupational exposures. Conclusion: Our estimates are comparable with those obtained for other countries in studies based on similar methodology.

We have conducted a comprehensive case–control study of a nasopharyngeal carcinoma (NPC) population cohort from Guangxi Province of Southern China, a region with one of the highest NPC incidences on record. A total of 1407 individuals including NPC patients, healthy controls, and their adult children were examined for the human leukocyte antigen (HLA) association, which is so far the largest NPC cohort reported for such studies. Stratified analysis performed in this study clearly demonstrated that while NPC protection is associated with independent HLA alleles, most NPC susceptibility is strictly associated with HLA haplotypes. Our study also detected for the first time that A * 0206, a unique A2 subtype to South and Southeast Asia is also associated with a high risk for NPC. HLA-A * 0206, HLA-B * 3802 alleles plus the A * 0207–B * 4601 and A * 3303–B * 5801 haplotypes conferred high risk for NPC showing a combined odds ratio (OR) of 2.6 ( P <0.0001). HLA alleles that associate with low risk for NPC include HLA-A * 1101, B * 27, and B * 55 with a combined OR of 0.42 ( P <0.0001). The overall high frequency of NPC-susceptible HLA factors in the Guangxi population is likely to have contributed to the high-NPC incidence in this region.

PURPOSE: Human herpesvirus 8 (HHV-8, or Kaposi sarcoma [KS]-associated herpesvirus, KSHV) is a necessary but insufficient cause of KS, as KS develops in few HHV-8-infected persons. In sub-Saharan Africa, marked differences in the geographic distribution of HHV-8 and KS suggest that environmental cofactors influence HHV-8 transmission, control, and progression to KS. However, a direct comparison of HHV-8 prevalence estimates is complicated because studies used different serologic assays and analytic methods. We assessed HHV-8 seropositivity in several African countries with heterogeneous environments and varying KS incidence using a unified approach.METHODS: HHV-8 antibodies were measured among 3196 adults (aged 20+ years) and 2404 children (aged < 20 years) from five studies in four sub-Saharan countries in Africa. Serum samples were tested by the same laboratory using K8.1 and orf73 enzyme immunoassays.RESULTS: Children's HHV-8-seropositivity ranged from 18.1% in Kampala, Uganda, to 33.8% in North Mara, Tanzania, increasing steeply with age in all populations. Among adults, HHV-8-seropositivity ranged from 23.5% in Nigeria to 70.6% in rural West Nile, Uganda. It was higher in males and rural areas.CONCLUSIONS: Our data indicate that geographical exposures, gender, age, and factors correlated with rural residence impact HHV-8 seropositivity in sub-Saharan Africa. Ann Epidemiol 2010;20:958-963. (C) 2010 Elsevier Inc. All rights reserved.

To understand the role of environmental and genetic influences on nasopharyngeal carcinoma (NPC) in populations at high risk of NPC, we have performed a case‐control study in Guangxi Province of Southern China in 2004–2005. NPC cases ( n = 1,049) were compared with 785 NPC‐free matched controls who were seropositive for IgA antibodies (IgA) to Epstein‐Barr virus (EBV) capsid antigen (VCA)—a predictive marker for NPC in Chinese populations. A questionnaire was used to capture exposure and NPC family history data. Risk factors associated with NPC in a multivariant analysis model were the following: ( i ) a first, second or third degree relative with NPC [attributable risk (AR)= 6%, odds ratio (OR) = 3.1, 95% confidence interval (CI) = 2.0–4.9, p < 0.001]; ( ii ) consumption of salted fish 3 or more than 3 times per month (AR = 3%, OR = 1.9, 95% CI = 1.1–3.5, p = 0.035); ( iii ) exposure to domestic wood cooking fires for more than 10 years (AR = 69%, OR = 5.8, 95% CI = 2.5–13.6, p < 0.001); and ( iv ) exposure to occupational solvents for 10 or less years (AR = 4%, OR = 2.6, 95% CI = 1.4–4.8, p = 0.002). Consumption of preserved meats or a history of tobacco smoking were not associated with NPC ( p > 0.05). We also assessed the contribution of EBV/IgA/VCA antibody serostatus to NPC risk—32.2% of NPC can be explained by IgA+ status. However, family history and environmental risk factors cumulatively explained only 2.7% of NPC development in NPC high risk population. These findings should have important public health implications for NPC risk reduction in endemic regions. © 2009 UICC

BACKGROUND:While external factors are responsible for many human cancers, precise estimates of the contribution of known carcinogens to the cancer burden in a given population have been scarce.METHODS:We estimated the proportion of cancer deaths which occurred in France in 2000 attributable to known risk factors, based on data on frequency of exposure around 1985.RESULTS:In 2000, tobacco smoking was responsible for 23.9% of cancer deaths (33.4% in men and 9.6% in women), alcohol drinking for 6.9% (9.4% in men and 3.0% in women) and chronic infections for 3.7%. Occupation is responsible for 3.7% of cancer deaths in men; lack of physical activity, overweight/obesity and use of exogenous hormones are responsible for 2%-3% of cancer deaths in women. Other risk factors, including pollutants, are responsible for <1% of cancer deaths. Thus, known risk factors explain 35.0% of cancer deaths, and 15.0% among never smokers.CONCLUSIONS:While cancer mortality is decreasing in France, known risk factors of cancer explain only a minority of cancers, with a predominant role of tobacco smoking.

Received 16 March 2007; accepted 2 April 2007; electronically published 28 June 2007. Potential conflicts of interest: none reported. Reprints or correspondence: Dr. Guy de Thé, Unité d’Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France (dethe@pasteur.fr). The Journal of Infectious Diseases 2007;196:499–501 2007 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2007/19604-0002$15.00 DOI: 10.1086/519172 The migrations of human populations are matters of great interest and hot debates in evolutionary biology, inasmuch as they relate to the rise and fall of civilizations. Multidisciplinary analyses of archeological, physical anthropological, and molecular genetic data has resulted in a near consensus view that the original human migrations out of East Africa took place some 100 thousand years ago (KYA), moving toward the middle East and then to Europe and Asia independently [1]. In contrast, Oceanic settlement via sea travel over very long distances in the myriad islands in Melanesia, Micronesia, and Polynesia in the South Pacific remain a matter of controversy and intense recent investigation [2]. Can microbiological agents, which accompanied these migrating populations as “cellular parasites,” be used as indirect but reliable markers of humans migrations [3]? We shall briefly review the data concerning 3 much-studied oncogenic agents—namely, an RNA retrovirus, a small DNA virus, and the bacterium Helicobacter pylori—as privileged markers of human migrations. Human T lymphotropic virus type 1 (HTLV-1) was initially isolated from cell cultures of a patient with an adult T cell leukemia in the United States and then in Japan. This oncogenic retrovirus was later found to be neurotropic and to be etiologically associated with a progressive degenerative neuromyelopathy called “tropical spastic paraparesis/HTLV-1–associated myelopathy” (TSP/HAM) [4]. Epidemiologically, HTLV-1 is mainly restricted to areas of endemicity such as the southern islands of the Japanese archipelago, the Caribbean region, tropical Africa, certain areas of South America, and regions of the Middle East and Melanesia. This retrovirus is transmitted through prolonged breast-feeding, sexual contact, and blood transfusion. In early 1991, our group pioneered the molecular epidemiology of HTLV-1, showing that the few genetic mutations observed in the U3 region of the HTLV-1 long terminal repeat as well as in the env gene and the Px region of a series of HTLV-1 isolates from the Ivory Coast, the Caribbean, and Japan were linked to geography but not to any associated pathology [5]. Soon after, 3 major geographical HTLV-1 genotypes were characterized: the cosmopolitan subtype A, the Central African subtype B, and the Melanesian subtype C [6, 7]. Later, a restricted subtype D was discovered in Pygmies of Central Africa. HTLV-1 exhibits high genetic stability, a quite surprising feature for a retrovirus. Such a low genetic variability appears to be linked to its replication mode, which occurs mainly during mitosis of infected lymphocytes, thus not involving reverse transcription [8]. The idea that such low genetic drift could be used as a molecular means of monitoring viral transmission and the movements of ancient human infected populations was raised in 1992 [9] and has been largely used since then for both HTLV-1 and simian T lymphotropic virus type 1 (STLV-1), which shares with HTLV-1 the same mode of replication and has similar genetic stability. The origin of most geographic HTLV1 subtypes appears to be linked to episodes of interspecies transmission between STLV1–infected monkeys and humans. However, some unanswered questions remain regarding the origin of HTLV-1 in certain areas of the world. Although it is generally accepted that the great majority of the HTLV-1 isolates from Central and South America originated via the dispersion of HTLV-1 subtype A from infected African slaves during the 16th–18th centuries, the origin of HTLV-1 cosmopolitan subtype A present in some remote Amerindian groups in the Andes remains highly debated [10]. The pathogenic HTLV1 cluster in the city of Mashadd in northern Iran also remains an enigma [11], although it is probably linked to ethnic migrations. In contrast to the human population genetics–based hypothesis of an African root for HTLV-1, the best basal clade for HTLV-1 phylogeny is to be found in the Melanesian inhabitants of the Sol-

Nasopharyngeal carcinoma (NPC) is a complex disease caused by an interaction of EBV chronic infection, environment and host genes, in a multi-step process of carcinogenesis. However, which genetic factors play an important role in the development of chronic EBV infection and NPC remain elusive. The objective of this study is to identify genetic variations associated with two key clinical stages of NPC development: persistent Epstein-Barr virus (EBV) infection of nasopharyngeal epithelia and progression to NPC. We inspected a NPC-associated region on the short arm of chromosome 4 previously implicated by a genome-wide linkage analysis of familial NPC. We determined genotypes for 319 alleles in 34 microsatellite markers spanning an 18 Mb region in 350 NPC cases, 288 individuals with IgA antibodies to EBV capsid antigen (IgA/VCA+) and 346 controls seronegative for IgA antibodies to EBV capsid antigen (IgA/VCA-). The cases and controls were Han Chinese from Wuzhou city and Cangwu County, Guangxi province where the incidence of NPC is as high as 25-50 per 100,000 individuals. Comparing NPC cases to IgA/VCA+ subjects, we found 9 alleles marginally associated with developing NPC from IgA+ status, 5 for risk (OR=1.51-5.36, P=0.01-0.03) and 4 for restrictive (OR=0.3-0.71, P=0.02-0.045). Comparing IgA/VCA+ subjects and IgA/VCA- controls, and comparing all IgA seropositives with and without NPC to IgA seronegatives revealed 12 significant and 3 highly significant (P<0.01) alleles associated with IgA+ serostatus in the two comparing groups. Alleles D4S3241-136 (P=0.004, OR=1.91, 95% CI=1.2-3.0) and D4S3347-213 (P=0.001, OR=1.6, 95% CI=1.2-2.1) were for risk. Allele D4S174-202 (P=0.001, OR=0.5, 95%CI=0.3-0.7) was restrictive. However, statistical significance was lost for all when corrected for multiple comparisons test. Our study could not affirm the genetic association within this region with NPC as did another pedigree study, but provide an opportunity for further gene discovery in this highly endemic NPC population and suggest that this region warrants further study.

Nasopharyngeal carcinoma (NPC) is a complex disease caused by a combination of Epstein-Barr virus chronic infection, the environment and host genes in a multi-step process of carcinogenesis. The identity of genetic factors involved in the development of chronic Epstein-Barr virus infection and NPC remains elusive, however. Here, we describe a two-phase, population-based, case-control study of Han Chinese from Guangxi province, where the NPC incidence rate rises to a high of 25-50 per 100,000 individuals. Phase I, powered to detect single gene associations, enrolled 984 subjects to determine feasibility, to develop infrastructure and logistics and to determine error rates in sample handling. A microsatellite screen of Phase I study participants, genotyped for 319 alleles from 34 microsatellites spanning an 18-megabase region of chromosome 4 (4p15.1-q12), previously implicated by a linkage analysis of familial NPC, found 14 alleles marginally associated with developing NPC or chronic immunoglobulin A production (p = 0.001-0.03). These associations lost significance after applying a correction for multiple tests. Although the present results await confirmation, the Phase II study population has tripled patient enrolment and has included environmental covariates, offering the potential to validate this and other genomic regions that influence the onset of NPC.

A squirrel monkey model of human T-cell leukemia virus type 1 (HTLV-1) infection was used to evaluate the immunogenicity and protective efficacy of a chimeric peptide vaccine composed of a B-cell epitope from the envelope region (aa 175-218) and three HLA-A*0201-restricted cytotoxic T-lymphocyte epitopes derived from Tax protein (Tri-Tax). These selected Tax peptides induced secretion of gamma interferon (IFN-gamma) in peripheral blood mononuclear cells obtained from monkeys chronically infected with HTLV-1. After immunization, a high titre of antibodies and a high frequency of IFN-gamma-producing cells were detected against the Env and the Tri-Tax immunogens, but not against the individual Tax peptides. This might indicate that epitope(s) distinct from those recognized by humans are recognized by responder monkeys. After challenge, it was shown by competitive PCR that partial protection against HTLV-1 infection could be raised in immunized animals. Further studies should be developed to determine the duration of this protection.