Ruth F. Jarrett

Epstein-Barr virus-associated Hodgkin's disease: Epidemiologic characteristics in international data

Hodgkins disease (HD) has long been suspected to have an infectious precursor, and indirect evidence has implicated Epstein‐Barr virus (EBV), a ubiquitous herpesvirus, as a causal agent. Recent molecular studies using EBER in situ hybridization or latency membrane protein‐1 (LMP‐1) immunohisto‐chemistry have identified EBV latent infection in up to 50% of HD tumors. However, the epidemiologic features of these cases have not been examined in detail. To explore the epidemiology of EBV‐positive HD so as to understand the role of EBV in HD etiology more clearly, this project accumulated patient data from 14 studies that had applied these EBV assays to HD tumors. With information on age at diagnosis, sex, ethnicity, histologic subtype, country of residence, clinical stage and EBV tumor status from 1,546 HD patients, we examined risk for EBV‐positive disease using logistic regression. Forty percent of subjects had EBV‐positive tumors, and EBV prevalence varied significantly across groups defined by the study variables. Odds ratios (OR) for EBV‐associated HD were significantly elevated for Hispanics vs. whites (OR = 4.1), mixed cellularity vs. nodular sclerosis histologic subtypes (OR = 7.3, 13.4, 4.9 for ages 0–14, 15–49, 50+ years), children from economically less‐developed vs. more‐developed regions and young adult males vs. females (OR = 2.5). These findings suggest that age, sex, ethnicity and the physiologic effects of poverty may represent biologic modifiers of the EBV association and confirm that this association is strongly but variably linked to histologic subtype. The data augment biologic evidence that EBV is actively involved in HD pathogenesis in some cases but describe epidemiologic complexity in this process. Int. J. Cancer, 70:375–382, 1997.

Human Tissues Contain CD141hi Cross-Presenting Dendritic Cells with Functional Homology to Mouse CD103+ Nonlymphoid Dendritic Cells

Summary Dendritic cell (DC)-mediated cross-presentation of exogenous antigens acquired in the periphery is critical for the initiation of CD8+ T cell responses. Several DC subsets are described in human tissues but migratory cross-presenting DCs have not been isolated, despite their potential importance in immunity to pathogens, vaccines, and tumors and tolerance to self. Here, we identified a CD141hi DC present in human interstitial dermis, liver, and lung that was distinct from the majority of CD1c+ and CD14+ tissue DCs and superior at cross-presenting soluble antigens. Cutaneous CD141hi DCs were closely related to blood CD141+ DCs, and migratory counterparts were found among skin-draining lymph node DCs. Comparative transcriptomic analysis with mouse showed tissue DC subsets to be conserved between species and permitted close alignment of human and mouse DC subsets. These studies inform the rational design of targeted immunotherapies and facilitate translation of mouse functional DC biology to the human setting.

Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IκBα

The NF-κB/Rel family of transcription factors regulates a wide variety of genes whose products play a fundamental role in inflammatory and immune responses. The implication of NF-κB/Rel proteins and their IκB regulatory subunits in the control of cellular growth and oncogenesis, was suggested by the induction of fatal lymphomas in birds by the v-rel oncoprotein, and the rearrangement and amplification of several genes encoding the NF-κB/Rel/IκB signal transduction factors in human malignancies, primarily of lymphoid origin. Hodgkins disease (HD) is a lymphoma characterized by a low frequency of malignant Hodgkin and Reed – Sternberg (H/RS) cells in a reactive background of non-neoplastic cells. The peculiar activated phenotype of Hodgkin and Reed – Sternberg cells and their pattern of cytokine secretion are believed to be a consequence of constitutive activation of the NF-κB transcription factor. Here, we report the detection of mutations of the IkBa gene, in two HD-derived cell lines and in two out of eight biopsy samples from patients with relapsed Hodgkins disease. The presence of defective IκBα is thus likely to explain the constitutive activation of NF-κB in these cells and suggests that IκBα is a tumour suppressor controlling the oncogenic activation of NF-κB in Hodgkin and Reed – Sternberg cells.

Detection of Epstein-Barr virus (EBV) genomes in the serum of patients with EBV-associated Hodgkin's disease

DNA from malignant cells is present in the serum/plasma of cancer patients and DNA from this source is amenable to analysis by polymerase chain reaction (PCR). In the present study, we evaluated whether Epstein‐Barr virus (EBV) DNA is present in the serum of patients with EBV‐associated Hodgkins disease (HD). Using conventional PCR, EBV DNA was detected in serum from 30/33 patients with EBV‐associated HD but in only 6/26 patients with non‐EBV‐associated disease (p < 0.001). Samples from healthy individuals were negative and only 5/12 infectious mononucleosis samples were positive. Real‐time quantitative PCR was subsequently employed to determine the concentration of EBV DNA present in serum; among positive samples the level ranged from 1 to 705 copies per 125 μl of serum. Post‐treatment samples from 5/14 cases with EBV‐associated HD contained detectable EBV DNA; analysis of this small group of cases suggests that positivity in post‐treatment samples correlates with risk factors indicative of a poor prognosis. Overall, our results are consistent with the notion that DNA from Reed‐Sternberg cells is present in the serum of HD patients, and further suggest that serum EBV should be evaluated as a prognostic marker. Int. J. Cancer (Pred. Oncol.) 84:442–448, 1999.

Detection of Epstein-Barr virus genomes in Hodgkin's disease: relation to age.

An investigation as to whether any particular subgroup of patients with Hodgkins disease was particularly likely to be Epstein-Barr virus (EBV) genome positive was made on samples from 95 patients. These were grouped according to age and Hodgkins disease subtype, and analysed using Southern blot analysis. Most samples from children or adults aged 50 years or over contained detectable EBV genomes; samples from young adults were only rarely positive. The differences in EBV positivity by age were highly significant, but there was no significant association between EBV and histological subtype after allowing for the effect of age. The results support the hypothesis that Hodgkins disease in different age groups may have different aetiologies, and suggest that EBV does have a pathogenetic role in Hodgkins disease in children and older age groups.

Epstein-Barr virus and Hodgkin's disease: further evidence for the three disease hypothesis

The epidemiology of Hodgkin’s disease suggests that it is a heterogeneous condition comprising more than one disease entity. The Epstein–Barr virus (EBV) is present in the Reed–Sternberg cells of a proportion of cases and is likely to play a role in the pathogenesis of these cases. In this study we show that EBV association rates vary with age at diagnosis. We suggest that Hodgkin’s disease can be divided into three disease entities on the basis of EBV association and age, thereby providing biological support for the multiple aetiology hypothesis proposed by MacMahon (Cancer Res 1966; 26: 1189–1290).

The epidemiology of Hodgkin's disease.

Summary Much of the epidemiological heterogeneity of HD incidence reflects the behaviour of the NS subtype, at least in the USA. Incidence variation across races (except Asians) and time periods is most marked in this subtype. In young adults with HD, there is compelling evidence for social class modification of risk consistent with an infectious aetiology; limited data suggest that this effect occurs within the NS subtype, but considerable evidence indicates that it does not primarily involve EBV infection. Findings from familial aggregation studies and HLA associations point to inherited susceptibility to this subtype. Despite little sex difference for NS in young adulthood in the latest incidence data, parity nevertheless appears to be protective against this subtype for women. Therefore, the greater increase for females than males in the incidence of young-adult NS in recent years may reflect the impact of population trends towards later childbearing and lower parity. This change, as well as the concomitant smaller family sizes and growing affluence, could explain part of the burgeoning incidence of NS in young adults in the USA. These observations suggest that NS in young adults constitutes a separate disease, probably of infectious origin. The incongruous occurrence of this subtype in older adults, and the presence of EBV in some NS cases, could reflect heterogeneity within NS, for example, representing features of the cellular phase of NS ( Cozen et al, 1992 ; Medeiros and Greiner, 1995 ). For the non-NS subtypes, many of the factors that predict risk of NS may also be relevant. Patterns of social class determinants in children and older adults, the age groups at risk for MC, support involvement of an infectious precursor given intense exposure, and EBV is a likely candidate, based on its high prevalence in these groups. However, little aetiological research has been directed explicitly at the non-NS subtypes. Considerable effort has gone into exploring an infectious aetiology of HD. Recently, this line of investigation has moved beyond social class determinants to molecular epidemiological studies of EBV and, to a lesser degree, other potentially involved viruses. The roles of genetic susceptibility and sex hormones also represent promising areas for exploration, particularly in their possible interaction with infectious agents and other environmental factors. Ultimately, clearer epidemiological understanding of HD will be aided by more precise classification of this disease at the molecular level.

A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 ( REL ), 8q24.21 and 10p14 ( GATA3 )

To identify susceptibility loci for classical Hodgkins lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10−8), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10−13) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10−8). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10−50). These data provide new insight into the pathogenesis of cHL.

Cytomegalovirus disease in renal allograft recipients: is human herpesvirus 7 a co-factor for disease progression?

Fifty‐six renal allograft recipients were studied prospectively for 3 months or longer after transplant. The polymerase chain reaction (PCR) was used to screen peripheral blood leucocyte (PBL) specimens for CMV, human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7) DNA (DNAemia) in 67 healthy controls and in serial (fortnightly) PBL specimens from the 56 allograft recipients. None of the healthy controls had detectable CMV DNAemia, although HHV6 and HHV7 DNAemia was found in 7% and 9% of individuals respectively. In contrast, DNAemia due to CMV, HHV6 and HHV7 was found in 50%, 36% and 39% of patients respectively, at some time during the post‐transplant period. Of the 28 patients who had CMV DNAemia, eight developed “CMV disease.” The risk of progression to “CMV disease” was increased in patients with concurrent DNAemia to all three viruses (relative risk 3.7; 95% CI 1.3–10.5). The relative risk of “CMV disease” for patients with concurrent CMV and HHV7 was also increased (RR = 3.5; 95% CI = 1.1–11.6), while the association between CMV and HHV6 was inconclusive (RR = 2.1; 95% CI = 0.7–6.6). The first 26 patients recruited to the study also had serial serum samples tested for antibody responses to the three viruses. “CMV disease” was associated with rising antibody titres to HHV7 (Fishers exact test, P = 0.02), and weakly so with HHV6 (P = 0.07). It is concluded that in patients with CMV DNAemia, concurrent infection/reactivation of HHV7 (and possibly HHV6) is associated with an increased risk of progression to “CMV disease.”

Risk factors for Hodgkin's disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents

A UK population-based case–control study of Hodgkin’s disease (HD) in young adults (16–24 years) included 118 cases and 237 controls matched on year of birth, gender and county of residence. The majority (103) of the cases were classified by Epstein–Barr virus (EBV) status (EBV present in Reed–Stenberg cells), with 19 being EBV-positive. Analyses using conditional logistic regression are presented of subject reports of prior infectious disease (infectious mononucleosis (IM), chicken pox, measles, mumps, pertussis and rubella). In these analyses HD cases are compared with matched controls, EBV-positive cases and EBV-negative cases are compared separately with their controls and formal tests of differences of association by EBV status are applied. A prior history of IM was positively associated with HD (odds ratio (OR) = 2.43, 95% confidence interval (CI) = 1.10–5.33) and with EBV-positive HD (OR = 9.16, 95% CI = 1.07–78.31) and the difference between EBV-positive and EBV-negative HD was statistically significant (P = 0.013). The remaining infectious illnesses (combined) were negatively associated with HD, EBV-positive HD and EBV-negative HD (in the total series, for ≥2 episodes compared with ≤1, OR = 0.45, 95% CI = 0.25–0.83). These results support previous evidence that early exposure to infection protects against HD and that IM increases subsequent risk; the comparisons of EBV-positive and EBV-negative HD are new and generate hypotheses for further study.