ARTICLE

Family History of Hematopoietic Malignancy and Risk of Lymphoma

Ellen T. Chang, Karin Ekström Smedby, Henrik Hjalgrim, Anna Porwit-MacDonald, Göran Roos, Bengt Glimelius, Hans-Olov Adami

Affiliations of authors: Department of Medical Epidemiology and Biostatistics (ETC, KES, H-OA) and Department of Oncology and Pathology (AP-M, BG), Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology Research, Danish Epidemiology Science Center, Statens Serum Institut, Copenhagen, Denmark (HH); Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden (GR); Department of Oncology, Radiology and Clinical Immunology, University of Uppsala, Uppsala, Sweden (BG)

Correspondence to: Ellen T. Chang, ScD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, SE-171 77, Stockholm, Sweden (e-mail: ellen.chang{at}meb.ki.se).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: A family history of hematopoietic malignancy is associated with an increased risk of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL), although the magnitude of the relative risk is unclear. We estimated the association between familial hematopoietic cancer and risk of lymphoma using validated, registry-based family data, and we also investigated whether associations between some environmental exposures and risk of lymphoma vary between individuals with and without such a family history. Methods: In a population-based case–control study of malignant lymphoma, 1506 case patients and 1229 control subjects were linked to the Swedish Multi-Generation Register and then to the Swedish Cancer Register to ascertain history of cancer in first-degree relatives of patients with malignant lymphoma. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations with the risk of lymphoma. Results: A history of hematopoietic malignancy in any first-degree relative was associated with an increased risk of all NHL (OR = 1.8, 95% CI = 1.2 to 2.5), common B-cell NHL subtypes, and HL. Relative risks were generally stronger in association with sibling hematopoietic cancer (OR for all NHL = 3.2, 95% CI = 1.3 to 7.6) than with parental hematopoietic cancer (OR = 1.6, 95% CI = 1.1 to 2.3). A family history of NHL or chronic lymphocytic leukemia (CLL) was associated with an increased risk of several NHL subtypes and HL, whereas familial multiple myeloma was associated with a higher risk of follicular lymphoma. There was no statistically significant heterogeneity in NHL risk associations with environmental factors between individuals with and without familial hematopoietic malignancy. Conclusions: The increased risk of NHL and HL among individuals with a family history of hematopoietic malignancy was approximately twofold for both lymphoma types. There was no evidence that etiologic associations varied between familial NHL and nonfamilial NHL.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The risk of malignant lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL), appears to be elevated among individuals with a family history of cancer, especially hematopoietic cancer. Although the causes of lymphoma are mostly unknown (15), the association with family history of malignancy, especially hematopoietic malignancy, suggests that genetic factors may play an important etiologic role. The risk of NHL is estimated to be doubled in first-degree relatives of NHL patients (615), whereas the excess risk of HL in first-degree relatives of HL patients is reportedly even higher (7,11,1620). Two other studies (21,22) have examined whether exposure–disease associations vary between individuals with and without a family history of hematopoietic cancer. In these studies, homosexual behavior, drug use, exposure to pesticides and other occupational contaminants, history of liver diseases (21), and alcohol consumption (22) were more strongly associated with NHL risk among men with a family history of hematopoietic cancer than among those without such a history; these results indicate that an interaction between genetic susceptibility and some non-genetic risk factors may influence lymphoma risk. However, most previous studies of the risk associated with a family history of malignant lymphoma have been constrained either by limited sample size (6,8,13,1618) or by registry-based data (911,15,20) that lacked detailed, individualized information on potential confounders or modifiers of the association. Furthermore, many prior studies have relied on self-reported family history of cancer, which is prone to both misclassification and recall bias.

To investigate risk factors for malignant lymphoma, we assembled a large population-based case–control study of NHL and HL. By linking our case–control study, the largest such study to date, to the Swedish Multi-Generation Register and the Swedish Cancer Register, we obtained high-quality data on confirmed cancer diagnoses in first-degree relatives of study participants. To our knowledge, no other population-based case–control study of lymphoma has used confirmed registry-based data on family history of malignancy. The unique combination of detailed, individualized exposure data and validated information on cancer in first-degree relatives enabled us to examine the associations between family history of cancer and risk of malignant lymphoma, including major NHL subtypes, and also to investigate whether associations of lymphoma risk with environmental exposures varied between individuals with and without a family history of hematopoietic malignancy.


    PATIENTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study Population

The Scandinavian Lymphoma Etiology (SCALE) study is a population-based case–control study of newly diagnosed malignant lymphoma case patients and population control subjects in Denmark and Sweden [previously described (23)]. For this analysis, however, we included only Swedish residents. The study base included all persons between 18 and 74 years living in Sweden between October 1, 1999, and April 15, 2002. To be eligible, individuals were required to speak Swedish and to have no history of organ transplantation, human immunodeficiency virus infection, or prior hematopoietic malignancy.

Case patients were diagnosed with incident, morphologically verified NHL (International Classification of Diseases, Tenth Revision [ICD-10] codes C82–C85, C88.0, C91.3–5, and C91.7), chronic lymphocytic leukemia (CLL; ICD-10 code C91.1), or HL (ICD-10 code C81) (24). HL case patients diagnosed in 1999 but before the start of enrollment on October 1 were also included but as prevalent case patients. Incident case patients were identified through a rapid case ascertainment network of contact physicians from all departments in which malignant lymphomas are diagnosed and treated and also through continuous collaboration with the Swedish regional cancer registries, with an estimated coverage close to 100% (25).

Control subjects were randomly sampled from the Swedish population by use of a continuously updated, computerized population registry. A subset of control subjects was sampled every 6 months during the study period and was frequency matched to the expected final distribution of NHL case patients on 10-year age intervals and sex.

Within the study base and time period, 85% of all Swedish case patients diagnosed with malignant lymphoma (n = 2347) and 75% of potential control subjects (n = 2001) consented to participate in the study. All participants granted informed consent before the interview. This study was approved by all regional ethics committees in Sweden.

Histopathologic Classification of Case Patients

All specimens from case patients were histopathologically evaluated by one of six senior hematopathologists or cytologists and classified according to the current World Health Organization specifications (26). Those specimens with indeterminate results (8%) were referred to the panel of hematopathologists for final evaluation. Overall, 2312 (98.5%) of the 2347 original tumor slides were reevaluated; for the 35 (1.5%) remaining case patients, the written results of the primary morphologic and immunohistochemical investigation were evaluated.

Registry-Based Data Collection

The Swedish Multi-Generation Register was created by Statistics Sweden in the early 1990s from national registration records and includes individuals (index persons) who were born in 1932 or later and who were still alive in 1961 or who were born in 1961 or later (27). The Register contains information on index persons and their parents, full or half-siblings, and children. Non-biologic (e.g., adoptive) relations are indicated. At present, the Multi-Generation Register includes more than 11 million individuals and approximately 3.2 million nuclear families.

The population-based Swedish Cancer Register, established in 1958, contains individual data on all newly diagnosed malignant tumors in Sweden (25). Tumors are required to be reported to the Cancer Register by both the diagnosing clinician and the responsible pathologist or cytologist, so that nearly 100% of diagnosed cancers are reported.

Using the individually unique national registration number of each study participant, we linked all participants in the SCALE study born in 1932 or later (1841 case patients [78%] and 1498 control subjects [75%]) to the Multi-Generation Register to identify their first-degree relatives. We then linked all individuals and their relatives, again by national registration number, to the Swedish Cancer Register to identify all cancer diagnoses in first-degree relatives of primary case patients and control subjects. Based on ICD-7 codes (28), we identified all hematopoietic cancers (ICD-7 codes 200–209), including NHL (ICD-7 codes 200, 202, 204.0 [CLL], and 205), HL (ICD-7 code 201), multiple myeloma (ICD-7 code 203), and leukemia (ICD-7 codes 204–207, excluding 204.0 and 205). Malignant skin neoplasms were identified by ICD-7 codes 190–191.

We restricted our study population to individuals for whom both parents were identified within the Multi-Generation Register (n = 1506 case patients and 1229 control subjects, or 82% of both groups) to ensure that we had full information on cancer history in parents and siblings.

Exposure Assessment

All SCALE participants completed a comprehensive telephone interview evaluating known and suspected risk factors for lymphoma, including age, height, normal weight, family background, UV exposure, smoking history, past medication use, occupation, and sexual behavior. Body mass index was calculated as usual weight (in kilograms) divided by height (in meters) squared and categorized as normal weight (<25 kg/m2), overweight (25 to <30 kg/m2), or obese (≥30 kg/m2), in accordance with World Health Organization standards for adults (29). Family background included country of birth, age at immigration if born elsewhere, and country of mother's and father's birth. Measures of UV exposure, categorized according to the distribution among control subjects, included number of beach and/or sun vacations abroad (0, 1–5, 6–20, or ≥21 total vacations), frequency of sunbathing 5–10 years ago or at age 20 years (0, ≤1, 2–3, or ≥4 times per week), frequency of sunburns 5–10 years ago, at age 20 years, or before age 15 years (0, <1, 1, or ≥2 times per year), and frequency of solarium visits (0, <10, 10–49, or ≥50 times). Smoking was classified as never, former, or current smoking of any cigarettes daily for at least 1 year. Medication use evaluated included total frequency of antibiotic use during adulthood (0, 1–2, 3–5, 6–10, 11–20, 21–30, 31–40, or ≥41 courses of treatment) and use of immunosuppressive drugs (ever/never use of azathioprine, cyclosporine, methotrexate, cyclophosphamide, or chlorambucil) for conditions other than lymphoma at least 2 years prior to the interview. Occupational data included history of working at a paper factory or sawmill, regular occupational exposure to organic solvents for at least 1 year, and occupational exposure to pesticides at least twice a year for 2 years or more. Sexual behavior included history of heterosexual and/or homosexual intercourse and sexually transmitted disease.

After completing the telephone interview, residents of seven Swedish counties (about half of the country's population) were asked to complete a semiquantitative food-frequency questionnaire. Details of the questionnaire, including its contents and validity, have been described elsewhere (30,31). Individuals were asked how often, on average, they had consumed 137 food and drink items 2 years before the interview. Intake of all food groups and items was converted into number of servings per day and then categorized into tertiles by the distribution in the control population. Alcohol intake overall or from beer, wine, or liquor was converted into grams of ethanol consumed per day (31) and similarly categorized into tertiles by the distribution in the control group, excluding former drinkers. Among eligible participants who were asked to complete the food-frequency questionnaire, 613 (89%) case patients and 480 (85%) control subjects did so. After exclusion of those who were born before 1932, had at least one unidentified parent, and/or left more than half of the food-frequency questionnaire blank, a total of 442 case patients (374 NHL case patients) and 384 control subjects had information on dietary intake. These participants were included in analyses of the association between diet and risk of NHL, stratified by family history of hematopoietic malignancy.

Statistical Analysis

We used unconditional logistic regression to estimate the relative risks, approximated by odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for associations between family history of malignancy and risk of overall NHL, NHL subtypes, and HL. All models were adjusted for 5-year age group, sex, and number of full siblings in the family (none, 1, 2, or ≥3). Birthplaces of the subject (Sweden or other) and of his/her parents (both born in Sweden or not) were also considered as possible confounders. Tests for linear trend were conducted with the exposure coded as an ordinal variable, with each level defined by the median value within each category. Estimates were stratified by age (<60 years or ≥60 years for NHL; <45 or ≥45 years for HL) or sex; heterogeneity of the stratified associations was evaluated by using a likelihood ratio test for the statistical significance of an interaction term between family history of cancer and either age or sex. All statistical tests were two-sided. Analyses were performed with SAS System software, release 8.2 (SAS Institute Inc., Cary, NC, 1999–2001).


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The numbers of case patients and control subjects with a first-degree family member (including fathers, mothers, and full siblings) with a history of any cancer or hematopoietic cancer are listed in Table 1. We initially examined younger HL case patients (those younger than age 45 years) separately from older case patients because of epidemiologic evidence suggesting that the etiology of HL differs by age group (3234). However, because there were no major differences between the groups and to increase statistical power, we analyzed all HL case patients together.


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Table 1.  Frequency of family history of malignancy among case patients and control subjects

 
The relative risks of malignant lymphoma associated with having a father, mother, parent, sibling, or any family member with cancer, especially with a hematopoietic cancer, are shown in Table 2. There were several marginally positive, but mostly statistically non-significant, associations between a family history of any cancer and risk of NHL and its most common subtypes. However, when we considered family history of non-hematopoietic cancers or of skin malignancies in particular, we found no association with risk of NHL, any subtype, or HL (data not shown), other than a positive association between paternal history of non-hematopoietic cancer and risk of follicular lymphoma (OR = 1.5, 95% CI = 1.1 to 2.1). In contrast, a history of hematopoietic malignancy in any first-degree relative, including a father, mother, or sibling, was associated with an increased risk of overall NHL (OR for NHL associated with having any family member with hematopoietic malignancy = 1.8, 95% CI = 1.2 to 2.5; OR associated with having parental hematopoietic cancer in particular = 1.6, 95% CI = 1.1 to 2.3; and OR associated with sibling hematopoietic cancer = 3.2, 95% CI = 1.3 to 7.6).


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Table 2.  ORs (with 95% CIs) for the risk of malignant lymphoma in association with family history of malignancy*

 
When we analyzed by lymphoma subtype, we found that, for diffuse large B-cell lymphoma, follicular lymphoma, T-cell lymphoma, and HL, there was a stronger positive association with hematopoietic malignancy in a father than in a mother, although the association with paternal hematopoietic cancer was statistically significant only for diffuse large B-cell lymphoma (OR = 2.2, 95% CI = 1.1 to 4.2) (Table 2). In contrast, there was a statistically significant positive association between maternal but not paternal hematopoietic cancer and risk of CLL. When data from both parents were combined, a parental history of hematopoietic malignancy was associated with a statistically significantly increased risk of the three most common B-cell NHL subtypes and of HL but not of T-cell lymphoma. As with total NHL, the association between a sibling history of hematopoietic cancer and risk of CLL or follicular lymphoma was stronger than the association with a parental history. This pattern did not hold for diffuse large B-cell lymphoma, T-cell lymphoma, or HL, although the numbers of case patients with a sibling history of hematopoietic cancer were low for these lymphoma subtypes. Overall, having any first-degree relative with hematopoietic malignancy was associated with an increased risk of the major B-cell NHL subtypes and HL but not T-cell NHL. All associations were essentially unchanged after additional adjustment for the birth country of the subject or his/her parents (data not shown).

We performed a secondary analysis limited to participants who were born in Sweden that included 1468 case patients and 1197 control subjects (97% of both groups), because Multi-Generation Register data are incomplete for immigrants. There were no substantial changes in the estimates of association among Swedish-born participants only (data not shown). In another analysis, we restricted the population to those born in 1948 or later, that is, 641 case patients (43%) and 575 control subjects (47%), based on the assumption that their parents would have been born in 1908 or later and would thus have had a diagnosis of cancer after age 50 years recorded in the Cancer Register beginning in 1958. Again, although estimates were less stable due to a smaller sample size, there were no differences in the overall associations between family history of total or hematopoietic malignancy and risk of NHL (data not shown).

To examine whether associations between family history of total or hematopoietic cancer and risk of NHL varied by age or sex, we stratified analyses by age (individuals younger than 60 years old and those 60 years or older) or by sex. There was no statistically significant heterogeneity in the association between family history of any, hematopoietic, or non-hematopoietic cancer and risk of NHL between age groups or between sexes (data not shown), with one exception: the relative risk of NHL associated with having a father with a history of hematopoietic cancer was increased among individuals younger than 60 years of age (OR = 3.0, 95% CI = 1.4 to 6.1) but not among those aged 60 years or older (OR = 0.8, 95% CI = 0.4 to 1.7) (P for test of heterogeneity = .02).

To examine whether risk associations with family history varied by the type of hematopoietic malignancy in family members, we divided all such hematopoietic malignancies into NHLs (including CLL), CLL, HL, multiple myeloma, and leukemias (Table 3). Although numbers were small, it appeared that a family history of NHL was associated with an increased risk of all NHL subtypes and of HL. Similarly, a family history of CLL, in particular, was associated with a statistically significantly elevated risk of overall NHL and especially of CLL and HL. HL was too rare among family members for reliable relative risks to be estimated, although having a family history of HL was statistically non-significantly associated with a threefold-higher risk of HL. Neither a family history of multiple myeloma nor a family history of leukemia was statistically significantly associated with increased risk of NHL, HL, or most NHL subtypes, although relative risk estimates were unstable because multiple myeloma and leukemia were uncommon in family members. However, the risk of follicular lymphoma was increased by more than threefold among those with familial multiple myeloma (OR = 3.6, 95% CI = 1.5 to 8.7).


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Table 3.  Risk of malignant lymphoma in association with family history of specific hematopoietic malignancy

 
Because of previous findings that NHL risk associations with occupational exposures (including paper or wood products, pesticides, or organic solvents) (21), homosexual intercourse (21), or alcohol intake (22) vary between individuals with and without a family history of hematopoietic malignancy, we tested for heterogeneity between individuals with and without such a family history. We found no statistically significant variation in the associations with any of these exposures or with body mass index or cigarette smoking status (data not shown). We also examined differences in associations of NHL risk with UV exposure or dietary intake of fruits and vegetables, both of which we found to be associated with a decreased risk of NHL (23,30), or with use of antibiotics or immunosuppressive drugs, which were associated with an increased risk of NHL (Chang et al., in press; Ekström Smedby et al., unpublished data); or with dietary intake of dairy products, fried or red meat, or coffee, which were also associated with increased NHL risk in our study population (30). Again, we observed no heterogeneity in the associations of familial versus nonfamilial NHL risk with these exposures (Table 4, some data not shown).


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Table 4.  Risk of malignant lymphoma in association with selected behavioral and environmental exposures, stratified by family history of hematopoietic malignancy

 

    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In this large population-based case–control study that used validated data on cancer diagnoses in family members, we confirmed the increased risk of NHL and HL in first-degree relatives of patients with hematopoietic malignancies. The risk of NHL, HL, and NHL subtypes, including diffuse large B-cell lymphoma, CLL, and follicular lymphoma, was approximately doubled. We observed no excess risk of T-cell NHL, but analyses of this outcome were limited by small numbers. A family history of NHL or CLL in particular was associated with a statistically significantly increased risk of most lymphoma subtypes, including HL. The incidence of HL, multiple myeloma, and leukemia among first-degree relatives was too low for stable estimates. Although most point estimates were greater than 1.0, most were not statistically significant, and the one statistically significant positive association—between familial multiple myeloma and risk of follicular lymphoma—may have been due to chance. Risk associations with family history of any type of cancer were generally weaker, not statistically significant, and almost entirely attributable to the association with hematopoietic cancer. In contrast to the positive association between previous skin cancer and risk of NHL in an individual (3539), there was no association between skin cancer in a family member and risk of lymphoma.

We also found a stronger association of NHL risk with sibling rather than with parental history of hematopoietic malignancy. This observation suggests that a shared environment in childhood and adolescence may contribute to NHL risk, beyond the increased risk conferred by a shared genetic background. In addition, there was an apparently stronger association of paternal, than of maternal, history of hematopoietic malignancy with risk of several lymphoma subtypes and vice versa for risk of CLL. This difference could be explained by sex-linked susceptibility genes. For example, a susceptibility gene on the Y chromosome would be transmitted only from father to son. However, there was no heterogeneity of associations with paternal or maternal history of hematopoietic malignancy between males and females in our study. Alternatively, these differences could be explained by genomic imprinting, by which the expression, and therefore phenotype, of a susceptibility gene in the offspring depends on whether it was inherited from the father or the mother (40). Both of these phenomena could help to explain the approximately 2-to-1 male-female ratio in NHL incidence that is consistently observed worldwide (41). The association with paternal history of malignancy could also arise if risk factors in the offspring's environment, including exposures in childhood and/or adulthood, are more strongly influenced by fathers than by mothers. Finally, the differences in strength of association could be due to chance. In fact, any of the associations that we observed, most of which were modest, could be explained by chance, although the consistency across studies of the positive association between familial hematopoietic cancer and risk of lymphoma argues for a true association.

Likewise, we observed a heterogeneity of the association with paternal history of hematopoietic malignancy between older and younger individuals. This difference could be explained either by chance or by under-ascertainment of cancer in fathers of older individuals. That is, a positive association between paternal hematopoietic malignancy and risk of lymphoma in older persons could have been obscured if their fathers' cancer diagnoses occurred before 1958 and, therefore, were not registered. It is also possible that offspring of fathers with a history of hematopoietic cancer tend to develop malignant lymphoma at an earlier age than do offspring of fathers with no such history, leading to a positive association with paternal hematopoietic cancer only in the younger age group. Such a phenomenon, known as anticipation, has been hypothesized to occur in both familial NHL and HL (42,43).

The estimated twofold increase in risk of NHL among first-degree relatives of individuals with hematopoietic malignancy is similar to that reported in other studies (615). However, the magnitude of increased HL risk in those with a family history was also twofold in our study, whereas the estimated relative risk has generally been higher in other studies (7,11,1620). This discrepancy could be due to the low numbers of HL case patients in our study, especially those with a family history of hematopoietic malignancy, which limited our ability to estimate the relative risk precisely. The association of HL risk with a family history of NHL or CLL has been reported previously (20), whereas the association of follicular lymphoma risk with a family history of multiple myeloma has not. One other study corroborates our finding of increased risks of overall NHL, diffuse large B-cell lymphoma, and follicular lymphoma among individuals with familial NHL, as well as an increased risk of CLL among those with a family history of CLL (15).

Contrary to prior reports, in this large study, we found no evidence that associations with a range of environmental risk factors vary between familial and nonfamilial NHL. Our results indicate that body mass index, cigarette smoking, occupational contaminants, homosexual activity, and alcohol intake play no role in either type of NHL and that the roles of UV exposure, medication use, and diet are the same in both familial and nonfamilial NHL. These findings suggest that putative susceptibility genes do not interact with these exposures in the pathogenesis of NHL. Previous studies that detected statistically significant heterogeneity in risk associations between NHL case patients with and without a family history of hematopoietic malignancy relied on self-reported data of familial cancer (12,21,22). It could be that individuals who reported a family history of hematopoietic cancer were also more or less likely to report certain other risk factors. If, as expected, more case patients than control subjects reported a family history of hematopoietic malignancy and if those reporting such a history had a greater tendency to recall harmful exposures, this tendency could lead to spurious positive associations with risk of familial, but not nonfamilial, NHL.

Although our study was relatively large, there were only 166 diagnoses of hematopoietic malignancy among relatives of our study participants, and fewer than one-third of these familial diagnoses were among control subjects. The low prevalence of familial hematopoietic cancer limited the precision of our relative risk estimates, especially for NHL subtypes and HL, and for associations with family history of NHL, HL, multiple myeloma, and leukemia. Sample size restrictions also prevented us, for example, from examining whether family history of a particular NHL subtype was specifically associated with an increased risk of the same subtype.

One factor that reduced our study sample size was the restriction of the analysis to individuals with both parents who could be identified in the Multi-Generation Register, which enabled us to identify all siblings and then all parent and sibling cancer diagnoses. This restriction should not have introduced any bias to our analysis, because an equal proportion of case patients and control subjects had identifiable parents. Likewise, an equal proportion of case patients and control subjects were born in Sweden, making it unlikely that differences in immigration influenced our results; indeed, there were no changes in our findings when we restricted the analysis to individuals born in Sweden. Although the percentages of case patients and control subjects born after 1948 were different, with a higher percentage of case patients being born earlier, our overall results also remained the same when we restricted the analysis to persons born after 1948. Thus, the positive association between parental history of hematopoietic malignancy and risk of lymphoma is probably not due to more complete recording of diagnoses among the parents of case patients after the Swedish Cancer Registry was established in 1958. If anything, the case patients—who were on average older than the control subjects—should have had older parents, whose diagnoses would be less likely to be registered, which would bias the association downward toward the null.

Because we used validated, registry-based data on family history of cancer, our results were not vulnerable to the problem of recall bias that can invalidate case–control studies of self-reported family medical history. By combining confirmed family history data with detailed interview-based data, we were able to examine the association between family history of hematopoietic malignancy and risk of lymphoma in further depth than would be possible in a study using registry data alone. In summary, we substantiated the positive association between family history of hematopoietic cancer and risk of malignant lymphoma and estimated the increase in relative risk to be about twofold for both NHL and HL. Furthermore, we found no differences in the associations between certain environmental exposures and risk of familial versus nonfamilial NHL. The particular genes that account for the increased genetic risk of NHL, and any other environmental factors with which they may interact, remain to be identified.


    NOTES
 Top
 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We thank Leila Nyrén (Karolinska Institutet) for her capable coordination of the project, Marie Reilly (Karolinska Institutet) for her expertise with using Multi-Generation Register data, and Fang Fang (Karolinska Institutet) for discussing research ideas. We are also grateful to Christer Sundström (Akademiska Hospital, Uppsala), Edneia Tani (Karolinska University Hospital), Måns Åkerman (Lund University Hospital), and Åke Öst (Medilab, Stockholm) for their extensive histopathologic and cytologic review of tumor material. We sincerely thank all of the contact doctors and nurses throughout Sweden who contributed to our rapid case ascertainment system. The SCALE study in Denmark and Sweden was funded by the National Institutes of Health (#1 R01 CA069269–01). Funding was also provided by the Swedish Cancer Society (#02 6661) and the Stockholm Cancer Foundation (Cancerföreningen).


    REFERENCES
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 Notes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

(1) Obrams GI, O'Conor G. The emerging epidemic of non-Hodgkin's lymphoma: current knowledge regarding etiological factors. Time trends and pathological classification: a summary. Cancer Res 1992;52:5570s.[Medline]

(2) Banks PM. Changes in diagnosis of non-Hodgkin's lymphomas over time. Cancer Res 1992;52:5453s–5s.[Abstract]

(3) Hartge P, Devesa SS. Quantification of the impact of known risk factors on time trends in non-Hodgkin's lymphoma incidence. Cancer Res 1992;52:5566s–9s.[Abstract]

(4) Vose JM, Chiu BC, Cheson BD, Dancey J, Wright J. Update on epidemiology and therapeutics for non-Hodgkin's lymphoma. Hematology (Am Soc Hematol Educ Program) 2002:241–62.

(5) Mueller NE, Grufferman S. The epidemiology of Hodgkin's disease. In: Mauch PM, Armitage JO, Diehl V, Hoppe RT, Weiss LM, editors. Hodgkin's disease. Philadelphia: Lippincott Williams & Wilkins; 1999. p. 61–77.

(6) Cuttner J. Increased incidence of hematologic malignancies in first-degree relatives of patients with chronic lymphocytic leukemia. Cancer Investig 1992;10:103–9.[ISI][Medline]

(7) Linet MS, Pottern LM. Familial aggregation of hematopoietic malignancies and risk of non-Hodgkin's lymphoma. Cancer Res 1992;52:5468s–73s.[Abstract]

(8) Shpilberg O, Modan M, Modan B, Chetrit A, Fuchs Z, Ramot B. Familial aggregation of haematological neoplasms: a controlled study. Br J Haematol 1994;87:75–80.[ISI][Medline]

(9) Paltiel O, Schmit T, Adler B, Rachmilevitz EA, Polliack A, Cohen A, et al. The incidence of lymphoma in first-degree relatives of patients with Hodgkin disease and non-Hodgkin lymphoma: results and limitations of a registry-linked study. Cancer 2000;88:2357–66.[CrossRef][ISI][Medline]

(10) Hemminki K, Mutanen P. Parental cancer as a risk factor for nine common childhood malignancies. Br J Cancer 2001;84:990–3.[CrossRef][ISI][Medline]

(11) Hemminki K, Czene K. Attributable risks of familial cancer from the Family-Cancer Database. Cancer Epidemiol Biomarkers Prev 2002;11:1638–44.[Abstract/Free Full Text]

(12) Chiu BC, Weisenburger DD, Zahm SH, Cantor KP, Gapstur SM, Holmes F, et al. Agricultural pesticide use, familial cancer, and risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 2004;13:525–31.[Abstract/Free Full Text]

(13) Chatterjee N, Hartge P, Cerhan JR, Cozen W, Davis S, Ishibe N, et al. Risk of non-Hodgkin's lymphoma and family history of lymphatic, hematologic, and other cancers. Cancer Epidemiol Biomarkers Prev 2004;13:1415–21.[Abstract/Free Full Text]

(14) Domingo-Domenech E, Benavente Y, Alvaro T, Hernandez M, de Sevilla AF, de Sanjose S. Family clustering of blood cancers as a risk factor for lymphoid neoplasms. Haematologica 2005;90:416–8.[ISI][Medline]

(15) Altieri A, Bermejo JL, Hemminki K. Familial risk for non-Hodgkin lymphoma and other lymphoproliferative malignancies by histopathologic subtype: the Swedish Family-Cancer Database. Blood 2005;106:668–72.[Abstract/Free Full Text]

(16) Razis DV, Diamond HD, Craver LF. Familial Hodgkin's disease: its significance and implications. Ann Intern Med 1959;51:933–71.[ISI][Medline]

(17) Grufferman S, Cole P, Smith PG, Lukes RJ. Hodgkin's disease in siblings. N Engl J Med 1977;296:248–50.[Abstract]

(18) Grufferman S, Barton JW III, Eby NL. Increased sex concordance of sibling pairs with Behcet's disease, Hodgkin's disease, multiple sclerosis, and sarcoidosis. Am J Epidemiol 1987;126:365–9.[ISI][Medline]

(19) Mack TM, Cozen W, Shibata DK, Weiss LM, Nathwani BN, Hernandez AM, et al. Concordance for Hodgkin's disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease. N Engl J Med 1995;332:413–8.[Abstract/Free Full Text]

(20) Goldin LR, Pfeiffer RM, Gridley G, Gail MH, Li X, Mellemkjaer L, et al. Familial aggregation of Hodgkin lymphoma and related tumors. Cancer 2004;100:1902–8.[CrossRef][ISI][Medline]

(21) Zhu K, Levine RS, Brann EA, Gu Y, Caplan LS, Hall I, et al. Risk factors for non-Hodgkin's lymphoma according to family history of haematolymphoproliferative malignancies. Int J Epidemiol 2001;30:818–24.[Abstract/Free Full Text]

(22) Chiu BC, Weisenburger DD, Cantor KP, Zahm SH, Holmes F, Burmeister LF, et al. Alcohol consumption, family history of hematolymphoproliferative cancer, and the risk of non-Hodgkin's lymphoma in men. Ann Epidemiol 2002;12:309–15.[CrossRef][ISI][Medline]

(23) Ekström Smedby K, Hjalgrim H, Melbye M, Torrång A, Rostgaard K, Munksgaard L, et al. Ultraviolet radiation exposure and risk of malignant lymphomas. J Natl Cancer Inst 2005;97:199–209.[Abstract/Free Full Text]

(24) International statistical classification of diseases and related health problems, 1989 revision. Geneva (Switzerland): World Health Organization; 1992.

(25) Swedish Cancer Register. Cancer incidence in Sweden 1998. Stockholm (Sweden): Centre for Epidemiology; 2000.

(26) Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. WHO classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon (France): International Agency for Research on Cancer (IARC) Press; 2001.

(27) Statistics Sweden. The multi-generation register. Örebro (Sweden): Statistics Sweden; 2004.

(28) Report of the International Conference for the Seventh Revision of the International Lists of Diseases and Causes of Death. Geneva (Switzerland): World Health Organization; 1955.

(29) Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 1995;854:1–452.[ISI][Medline]

(30) Chang ET, Ekström Smedby K, Zhang SM, Hjalgrim H, Melbye M, Öst Å, et al. Dietary factors and risk of non-Hodgkin lymphoma in men and women. Cancer Epidemiol Biomarkers Prev 2005;14:512–20.[Abstract/Free Full Text]

(31) Chang ET, Ekström Smedby K, Zhang SM, Hjalgrim H, Melbye M, Öst Å, et al. Alcohol intake and risk of non-Hodgkin lymphoma in men and women. Cancer Causes Control 2004;15:1067–76.[CrossRef][ISI][Medline]

(32) MacMahon B. Epidemiology of Hodgkin's disease. Cancer Res 1966;26:1189–201.[ISI][Medline]

(33) Gutensohn NM. Social class and age at diagnosis of Hodgkin's disease: new epidemiologic evidence for the "two-disease hypothesis." Cancer Treatment Rep 1982;66:689–95.[ISI][Medline]

(34) Alexander FE, McKinney PA, Williams J, Ricketts TJ, Cartwright RA. Epidemiological evidence for the ‘two-disease hypothesis’ in Hodgkin's disease. Int J Epidemiol 1991;20:354–61.[Abstract]

(35) Adami J, Frisch M, Yuen J, Glimelius B, Melbye M. Evidence of an association between non-Hodgkin's lymphoma and skin cancer. BMJ 1995;310:1491–5.[Abstract/Free Full Text]

(36) Frisch M, Melbye M. New primary cancers after squamous cell skin cancer. Am J Epidemiol 1995;141:916–22.[Abstract]

(37) Swerdlow AJ, Storm HH, Sasieni PD. Risks of second primary malignancy in patients with cutaneous and ocular melanoma in Denmark, 1943–1989. Int J Cancer 1995;61:773–9.[ISI][Medline]

(38) Frisch M, Hjalgrim H, Olsen JH, Melbye M. Risk for subsequent cancer after diagnosis of basal-cell carcinoma. A population-based, epidemiologic study. Ann Intern Med 1996;125:815–21.[Abstract/Free Full Text]

(39) Levi F, Randimbison L, Te VC, La Vecchia C. Non-Hodgkin's lymphomas, chronic lymphocytic leukaemias and skin cancers. Br J Cancer 1996;74:1847–50.[ISI][Medline]

(40) Reik W, Walter J. Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001;2:21–32.[CrossRef][ISI][Medline]

(41) Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB, editors. Cancer incidence in five continents. IARC scientific publication no. 155. Vol VIII. Lyon (France): International Association for Research on Cancer (IARC); 2003.

(42) Shugart YY. Anticipation in familial Hodgkin lymphoma. Am J Hum Genet 1998;63:270–2.[Medline]

(43) Shugart YY, Hemminki K, Vaittinen P, Kingman A. Apparent anticipation and heterogeneous transmission patterns in familial Hodgkin's and non-Hodgkin's lymphoma: report from a study based on Swedish cancer database. Leuk Lymphoma 2001;42:407–15.[ISI][Medline]

Manuscript received March 29, 2005; revised July 18, 2005; accepted August 5, 2005.


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