Summary: Hodgkin's Lymphoma (HL) is a common malignancy in early adulthood with a complex etiology. In a cohort of 2.3 million Jewish adolescent males and females followed for up to 45 years, being born in Israel was associated with a much elevated risk for nodular sclerosis HL. Higher risks were found among Israeli-born subjects compared to European, Asian and North African immigrants; higher risks were also found for women, those born more recently, those with higher BMI and taller stature. The findings suggest that exposure to as yet unidentified elements of the Israeli environment increase the risk of nodular sclerosis HL, and should aid in directing research efforts. The data support a rapidly-acquired environmental component in the etiology of HL, possibly due to preconception, prenatal or early life exposures to a changing lifestyle and environment and its interaction with susceptibility genes.
Hodgkin's Lymphoma (HL) is a common malignancy in early adulthood, accounting for approximately 30 percent of all lymphomas (cancers of the lymph system). The incidence of HL in Israel is among the highest in the world: based on GLOBOCAN estimates for 2012, Israeli females have the highest age-standardized incidence rate of HL worldwide, and Israeli males have the second highest worldwide. From 1960 through 2005, Israel experienced a sharp rise in the incidence of HL among Israeli-born Jews of both sexes, with similar rates in the Jewish and non-Jewish populations.
Despite evidence for an environmental etiology, very few risk factors have been identified. Epstein-Barr virus (EBV) infection is causally associated with development of EBV-positive HL, which is common in tropical regions but less common in Israel and other developed countries. Studying immigrant populations provides a means of investigating the relative importance of genetic factors as compared to environmental factors in disease development. Since Israel is a multi-ethnic society to which extensive immigration took place since the establishment of the state in 1948, and in which extensive population data is available over the course of several decades, it provides a unique setting to conduct a large-scale, population-based migrant cohort study.
For this reason, researchers at the Hebrew University-Hadassah Braun School of Public Health and Community Medicine, led by Dr. Hagai Levine and Prof. Jeremy Kark, in collaboration with Dr. Merav Leiba from the Sheba Medical Center, conducted a migrant cohort study to assess what impact immigration status and origin have on the development of HL in Israelis.
The study, which appears today in the journal Leukemia and Lymphoma, included Jewish men and women aged 16 to 19 at examination, with no history of a cancer diagnosis. Nationwide data on 2,285,009 adolescents, collected from 1967-2011, were linked to Israel's Cancer Registry to obtain the incidence of HL until 2012. The study protocol was approved by the Institutional Review Board of the IDF Medical Corps.
During 47 million person-years of follow-up, 2,093 HL cases were detected. Among the cohort of 2.3 million men and women, an association was found between being born in Israel and subsequent occurrence of HL. This association was independent of paternal country of origin, year of birth, sex, socio-demographic characteristics, BMI and height.
Risk of HL was greater for more recent year of birth, higher BMI, taller stature, and apparently for women. These findings suggest that exposure to as yet unidentified elements of the Israeli environment increase the risk of nodular sclerosis HL, and should aid in directing research efforts.
Remarkably, the elevated risk appeared within one generation; the low incidence of HL observed for immigrants from Western Asia was no longer evident among Israeli-born individuals of Asian origin. Among immigrants, there was no difference by age at migration.
The higher risk was driven largely by an elevated risk for the predominant NS subtype of HL (there are four main subtypes as defined by the World Health Organization classification: nodular sclerosis (NS), mixed cellularity (MC), lymphocyte-rich and lymphocyte-depleted).
Thus, the researchers suggest that immigration from a low-risk to a high-risk location, mostly to locales with a modern lifestyle and environment, is associated with an increase in HL incidence (mainly the NS subtype) within short periods, making genetic drift unlikely as a causal explanation. However, the Israeli life-style and environment, either independently or by gene-environment interaction, may pose exceptional risks for HL, as suggested by the very high and increasing incidence in Israel and the increased risk even among Israeli-born of European origin compared to European-born immigrants.
Dr. Hagai Levine, Head of the Environmental Health Track at the Hebrew University-Hadassah Braun School of Public Health and Community Medicine, explains: "While we still need further studies to identify the specific causes of the high rates of Hodgkin lymphoma among native Israelis, our findings direct us to search for possible environmental causes in Israel and the neighboring countries. These causes could be not only environmental exposures, but also diet, climate, social environment and stress that may be related to chronic regional conflict."
"There is increasing evidence for developmental origins of health and disease, with different possible mechanisms, including epigenetic changes or endocrine disruption. There is also increasing evidence on the role of prenatal stress in offspring development, including cancer development, especially for hematological malignancies. These data suggest that risk of HL (the nodular sclerosis subtype) is possibly increased due to preconception, prenatal or early life exposures to a changing lifestyle and environment and its interaction with susceptibility genes," adds Dr. Levine.
PARTICIPATING INSTITUTIONS include the Hebrew University-Hadassah Braun School of Public Health and Community Medicine, Jerusalem, Israel; Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Multiple Myeloma Service, Division of Hematology, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel; The National Cancer Registry, Israel Center for Disease Control, Ministry of Health, Jerusalem, Israel; School of Public Health, University of Haifa, Haifa, Israel; The Israel Defense Forces Medical Corps, Jerusalem, Israel; Department of Medicine and Medical Education, Mount Auburn Hospital, Harvard Medical School, Boston, MA, USA.
The Hebrew University-Hadassah Braun School of Public Health and Community Medicine (link), in the Hebrew University's Faculty of Medicine, is the first school of public health in Israel. Since its inception in 1961, the Braun School has cultivated and sustained an integrated multidisciplinary environment that facilitates excellence in teaching, research, and creative academic activity. It offers curricula that promote interdisciplinary approaches to public health and prepare public health researchers, practitioners and teachers to identify, quantify and effectively address the complex public health challenges at the community level - be it a village, country, or the global community. Its world-renowned International Master's in Public Health (IMPH) (link) is comprehensive multi-disciplinary 12-month training experience prepares graduates to take up key positions as leaders and teachers of public health in their home countries, and to initiate and participate in the promotion and development of public health practices and develop capacity-building programs for training public health personnel.
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