1 Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois-Chicago, Chicago, IL.
2 National Institute of Environmental Health Sciences, Research Triangle Park, NC.
3 Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.
4 Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, MN.
5 Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
6 Cancer and Leukemia Group B, The Ohio State University, Columbus, OH.
Received for publication January 3, 2002; accepted for publication May 7, 2002.
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ABSTRACT |
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case-control studies; leukemia; proxy; risk factors
Abbreviations: Abbreviations: CALGB, Cancer and Leukemia Group B; CI, confidence interval.
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INTRODUCTION |
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Family history of cancer may serve as a marker for shared genetic and environmental risk factors for adult acute leukemia. Family histories of breast (3), colon (4), lung (57), and other cancers have been shown to be associated with same-site cancer risk, consistent with a shared etiology within families. Incidence of (adult) chronic lymphocytic leukemia has well-established associations with family histories of leukemia and other hematoproliferative diseases (810). With respect to acute leukemia, childhood twins with leukemia tend to be the same sex (and therefore possibly monozygotic) (11, 12), leading some investigators to suspect an inherited genetic link to acute leukemia in children. However, there are very few data specific to acute leukemia in adults (13). Associations have been examined for leukemia as a whole (14, 15); these studies have found a two- to threefold higher leukemia incidence in persons with family histories of leukemia (13, 14) or hematopoietic cancer (15). Family history of cancer at other sites might also be associated with adult acute leukemia (16), if these sites have familially shared risk factors in common with leukemia.
Because acute leukemia is often rapidly fatal in adults, proxy respondents become an important source of information on family history and exposure history. In a large case-control study of adult acute leukemia, we estimated the relative risk of leukemia related to cancer history in first-degree relatives, separately in patients and patient proxies. The primary purpose of this investigation was to search for clues that family histories might provide regarding the etiology of adult acute leukemia. A secondary goal was to understand the influence of proxy reporting, which is likely to continue to be a vital part of exposure assessment in studies of this disease.
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MATERIALS AND METHODS |
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Cases were recruited for the epidemiology study (CALGB 8661) when they were recruited to participate in a CALGB treatment clinical trial, most often within a day of confirmation of diagnosis. Patients were excluded from the clinical trials (and therefore the case-control study) if their disease was known to be secondary to chemotherapy or radiotherapy or to be the result of a preleukemic condition such as myelodysplasia.
From January 1986 through June 1989, 610 of 743 eligible adult acute leukemia patients (82 percent response) were enrolled. Enrollment was extended through September 1990 to increase the number of acute myeloid leukemia patients for whom cytogenetic data were available and to enroll myelodysplasia patients for related studies. Of 159 apparent myelodysplasia patients, 15 were subsequently determined to have acute myeloid leukemia and all were enrolled in the present study; of 210 acute myeloid leukemia patients eligible during the extended enrollment period, 186 were interviewed (89 percent response). In all, 811 confirmed adult acute leukemia patients were included in the analyses presented here (84 percent total response).
Patients were subtyped with respect to morphology by using the French-American-British classification system (18, 19) and the presence or absence of specific cytogenetic abnormalities (CALGB 8461). Cases were assigned to French-American-British type after central review of their slides at the CALGB Hematopathology Laboratory at the State University of New York Health Sciences Center at Syracuse.
Hospitalized patients were contacted by telephone within a few days of registration and completed the interview at either that time or a later arranged time. In all, next of kin participated in 274 (34 percent) of the case interviews; 170 (21 percent) interviews were conducted without patient involvement, and the remaining 104 (13 percent) included the patient. Next of kin were consulted if the patient died before an interview could be conducted (9 percent), was too ill to be interviewed (13 percent), or could not be interviewed for another reason (11 percent). Interviews were conducted with a patients spouse (16 percent), a parent (4 percent), a sibling (2 percent), a child (7 percent), or another person (5 percent). The median interval between registration and completion of the interview was 8 days (90 percent within 2 months) for self-interviewed patients and 37 days (90 percent within 5 months) for proxy-interviewed patients.
Controls were selected by using a two-stage random digit dialing procedure (20), with the sampling frame restricted to the area code and first three digits of patients telephone numbers. Every 6 months, controls were selected and were frequency matched to cases with respect to age (10-year intervals), sex, race, and region of residence (one of six in the United States and Canada). Of those telephone numbers found to belong to residences, screening was completed for 83 percent. Of 792 potential controls screened, 637 (80 percent) completed interviews, for an overall response rate of 66 percent. Proxies were involved in 83 (13 percent) of the control interviews, and most of these (83 percent) were conducted by proxy only. Proxies were usually spouses (70 percent), and proxy interviews were rarely due to illness of the control (5 percent).
Family history of cancer
Cases and controls (or their proxies) were asked to report separately for their mothers, fathers, each sibling, and each child any history of 1) aplastic anemia; 2) leukemia; 3) any other "cancer, tumor, or growth such as lymphoma or lung cancer" and the specific sites involved; and 4) any other blood disorder as well as vital status and the cause of death, if deceased. Responses were written as text and were coded later with respect to site. Hematopoietic cancers were defined as cancers that included International Classification of Diseases, Ninth Revision, codes 200208 (first three digits). Reports of "blood cancer" or "bone marrow cancer" were coded as leukemia, although such a report could potentially refer to circulating lymphoma or multiple myeloma.
Only gynecologic reports with definitive wording such as "cancer," "invasive," or "malignancy" were included (8 of 72 reports were excluded) to reduce misclassification of benign tumors such as fibroids as cancer. A report of skin cancer in a living relative that was not specifically reported as melanoma was assumed to be nonmelanoma (23 exclusions), whereas any skin cancer reported as a cause of death was included (12 reports). Any cancer reported in the "intestines" was coded as colorectal cancer since cancer of the small intestine is rare. Liver (8/15 excluded) and brain (6/29 excluded) cancers were excluded as metastatic sites if they accompanied another cancer report.
A total of 10,819 first-degree relatives (6,045 of cases and 4,774 of controls) were identified. We excluded 71 siblings and 17 children for whom information on the persons sex was missing (excluding five cancer reports in the process) because we considered these reports to be unreliable. For another 319 relatives, data on cancer history were missing. In all, data were missing for 407 relatives (3.8 percent) (260 relatives of cases and 147 relatives of controls). No difference was found between cases and controls regarding the mean number of parents, siblings, or children for whom data on cancer history were available (an average of 1.9 parents, 3.4 siblings, and 1.9 children with data for each case or control). For the 724 relatives with a positive cancer history, cancer site was unknown for the relatives of 50 cases and 34 controls.
Data on cancer history were reported for all first-degree relatives by 675 cases (83 percent) and 557 controls (87 percent). Another 128 cases (16 percent) and 76 controls (12 percent) reported cancer histories for at least one relative (usually for all but one relative). Of these, data on matching factors were complete for 779 cases and 625 controls, and they were included in our analyses.
Analytic approach
We examined demographic characteristics associated with case-control status. We defined a positive family history as the presence of a cancer history for all sites combined and for specific sites, for all first-degree relatives and for specific relatives (parents and siblings). We also estimated relative risks for older (aged 60 years) and younger (aged <60 years) persons and for different leukemia morphologies. We analyzed French-American-British subtypes M1 and M2 (myeloblastic leukemia); M3 (promyelocytic leukemia); M4 and M5 (monocytic leukemia); and L1, L2, and L3 (lymphoblastic leukemia) in separate, adjusted models. Finally, we examined demographic characteristics associated with patient versus patient-proxy reporting.
We estimated relative risks of leukemia as exposure odds ratios in logistic regression. The matching factors age (10-year intervals), sex, race (White, non-White), and geographic region were included as category indicator variables in all models. Number of first-degree relatives, while associated with family history, was not associated with case-control status and therefore was not included in these analyses. Estimated relative risks were similar when site-specific variables were modeled together compared with when each family history variable was modeled separately; thus, only the separate models are presented here.
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RESULTS |
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Relative risk for all sites combined
For all interviews combined, any first-degree family history of cancer was associated with a relative risk of 1.2 (95 percent confidence interval (CI): 1.0, 1.6). Family history of cancer did not appear to be a risk factor for adult acute leukemia when analyses were restricted to self-interviewed cases. In contrast, family history of cancer was associated with a 70 percent increased risk when analyses were restricted to proxy-interviewed cases (table 2).
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Older versus younger patients
For both self-interviewed and proxy-interviewed patients, relative risks tended to be larger for older (aged 60 years) than for younger (aged <60 years) persons. With respect to family history of cancer at any site, for proxy-interviewed patients, we estimated relative risks of 2.2 for older patients and 1.4 for younger patients (ratio of odds ratios = 1.6, 95 percent CI: 0.8, 3.1). For self-interviewed patients, we estimated relative risks of 1.4 and 0.9 for older and younger patients, respectively (ratio of odds ratios = 1.6, 95 percent CI: 0.9, 2.8).
In regard to family history of leukemia, for proxy-interviewed patients, we estimated relative risks of 4.5 and 1.4 in older and younger persons, respectively (ratio of odds ratios = 3.2, 95 percent CI: 0.8, 12). For self-interviewed patients, we estimated relative risks of 1.9 and 0.4, respectively (ratio of odds ratios = 4.6, 95 percent CI: 1.1, 19).
Parental and sibling cancer histories
For proxy-interviewed patients, both parental and sibling cancers at any site, hematopoietic cancer, and leukemia were associated with increased incidence (table 3). For self-interviewed patients, parental colorectal and prostate cancers were associated with increased incidence.
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Morphologic subtypes
For proxy-interviewed cases, family history of cancer at any site was positively associated with myeloblastic, monocytic, and possibly promyelocytic leukemia, whereas family history of hematopoietic cancer was positively associated with myeloblastic and monocytic leukemia (table 4). For self-interviewed cases, neither family history of cancer at any site nor hematopoietic cancer was associated with incidence of any leukemia subtype.
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DISCUSSION |
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Results for family history of breast cancer displayed a different pattern of associations. Sibling breast cancer was associated with increased incidence regardless of patient interview type, as was familial breast cancer with early-onset leukemia morphologies. Whereas associations for other family histories tended to be stronger in older persons, familial breast cancer associations tended to be stronger in younger persons. These associations between leukemia and breast cancer could be explained in part by specific genetic mechanisms associated with early-onset cancers of both types.
Control and patient selection
The response rate among controls was 66 percent, raising concern about selection bias (2123). Because family history is not a well-known risk factor for leukemia, and because our study was introduced as one focused on environment and health, selection bias seems unlikely. Still, controls selected by random telephone screening are often of higher socioeconomic status than the pool of eligible controls (24). Furthermore, patients recruited for clinical trials are not necessarily a representative sample of patients (25), and those who agree to participate may also be of higher socioeconomic status (25). Overrepresentation of controls or cases of higher socioeconomic status may inflate the prevalence of a family cancer history if persons with higher incomes or more years of schooling are better able to report a history or if their family members have increased access to screening or treatment. However, neither income nor education was more than marginally associated with family history of cancer in either participating controls or participating cases (results not shown), making nonparticipation related to socioeconomic status less of a concern.
We compared the distribution of cases in the present study with a complete sample of adult acute leukemia patients (n = 76) diagnosed during the study period from a single participating facility. From these analyses, it seemed that the elderly (7 percent vs. 18 percent aged 75 years or older) might have been underrepresented in the present study. Controls were matched to cases on age; therefore, preferential selection of younger patients would have attenuated associations with family history, since relative risk estimates were greater for older cases and controls.
Validity of self-reports
We know of no validation studies of reported family history of leukemia or hematopoietic cancers. Validations for the major cancer sites have suggested that a large percentage (85 percent or higher) of self-reported family histories of any cancer, breast cancer, colorectal cancer, and lung cancer can be confirmed through medical records (2633). However, most validations have not examined underreporting, and reported confirmation rates from previous studies may not generalize well to the specific patient group in the present study.
To our knowledge, there are no publications on the validity of proxy reporting of family histories of cancer in adults. One study of children diagnosed with soft tissue or bone sarcoma found that parents report their own cancer diagnoses accurately as part of their childs family history, including 20 of 21 reported breast cancers (34).
Patient versus proxy associations
There are several possible explanations for the discrepancy between self-interviewed and proxy-interviewed patient reporting of family histories. Patients requiring a proxy interview tended to be considerably older than patients who were interviewed themselves, providing more opportunity for cancer occurrence in their first-degree relatives (table 5). This finding could explain the stronger family history of cancer associations for patient proxies than for patients. However, although patient proxies reported more family history of cancer than patients did (odds ratio = 2.1, 95 percent CI: 1.6, 2.8), an association remained after adjusting for age (odds ratio = 1.6), suggesting that differences in age did not fully explain the differences in results. Patient proxies were also less likely to have any college education and less likely to come from the northeastern United States (table 5).
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Another possibility (which we consider likely) is that patients and patient proxies have similar family histories but report them differently. In patients, symptoms of leukemia and the shock of the diagnoses may have reduced recall, possibly explaining inverse associations for family history of leukemia and hematopoietic cancers. Proxies, on the other hand, had considerably more time to complete the interview and to reconstruct the cases family history. This extra time could have resulted in more sensitive (although perhaps less specific) reporting of true positive family histories. Although proxy-reported exposures are usually assumed to be less accurate than patient-reported exposures (3739), proxies who are first-degree relatives of the patient are reporting on their own history of cancer and on many of the same relatives as the case or control. Although a spouse may have less knowledge, relative risks in this study did not differ materially when spouse-reporters were compared with blood relatives (results not shown).
Death certificate review
Medical record validation of relatives cancer histories was not feasible given the national sampling of cases and controls. In a convenience sample of 314 death certificates, we confirmed 83 percent of all cancer reports, 89 percent of cancers reported as a cause of death, and 96 percent of negative reports. In sensitivity analyses of family history of cancer misclassification based on the death certificate comparison, the crude odds ratios for patients and patient proxies (0.9 and 1.9, respectively) were not materially changed by adjusting for potential misclassification of family history (40). However, the death certificate validation was based solely on data from cases and controls able to provide detailed identifying information on their relatives and may have produced overly optimistic patient, patient-proxy, and control sensitivities and specificities; larger reporting differences could still exist.
Setting aside the death certificate comparisons, if proxies were in fact overreporting their family history of any cancer at a false-positive rate of 20 percent, and patients were underreporting at a rate of 20 percent, both odds ratio estimates would converge at about 1.2 or 1.3. Therefore, it is possible that the true odds ratio for leukemia related to any family history of cancer is slightly above one.
Because we did not know which associations might be more valid, those for patients or for patient proxies, associations found for both patients and patient proxies were considered evidence in favor of a true association. Such associations could not be the result of both patient underreporting and proxy overreporting, which we believe to be the most likely scenarios for misclassification. On the basis of these criteria, we concluded that the positive associations for sibling breast cancer and leukemia overall, and for breast cancer with leukemia types characterized by earlier onset, might provide etiologic clues to adult acute leukemia incidence.
Previous leukemia studies have reported modest associations with familial breast cancer. One study of all leukemia types combined estimated a relative risk for sibling breast cancer of 1.4 (95 percent CI: 0.8, 2.2) (15); another study of chronic lymphocytic leukemia reported a roughly twofold relative risk (relative risk = 1.9, 95 percent CI: 0.9, 4.0) with sibling breast cancer (10). Neither of these studies reported associations separately by patient interview type; 39 percent of patients in the former study and 60 percent of patients in the latter study were interviewed through proxies. The American Cancer Society Prevention Study I estimated a relative risk of 1.3 (95 percent CI: 0.9, 1.9) for a first-degree family history of breast cancer and subsequent leukemia mortality in female volunteers (16). The only known published family history study specifically of adult acute (myeloid) leukemia (161 cases) did not report an association for breast cancer (13). Finally, in one study in which breast cancer was the outcome, twin pairs discordant for breast cancer reported a higher-than-expected family history of leukemia (41). Breast cancer case-control studies have not reported on family histories of leukemia, probably because the number of positive leukemia family histories is so small that associations would be very unstable.
Associations between family histories of breast cancer and leukemia incidence could have a genetic basis. Two familial cancer syndromes are associated with clustering of both breast cancer and leukemia and are the result of rare, but highly penetrant germline mutations in p53 (Li-Fraumeni cancer syndrome) and ataxia telangiectasia (42). Although these syndromes are too rare to account for much of the association observed in the present study, they may be indicative of more prevalent, but less penetrant defects in these genes, resulting in a more general association between leukemia and breast cancer. Many other genetic factors could be related to incidence at both sites, including common polymorphisms in DNA repair genes (43, 44) and carcinogen-metabolizing genes (45, 46).
In conclusion, the divergent results for self-interviewed and proxy-interviewed cases obscured the relations between family histories of cancer and risk of adult acute leukemia in this study. Results suggest that family history of breast cancer is associated with adult acute leukemia incidence and that this association is stronger for earlier-onset cancers of both types. These results could be due to an etiologic mechanism common to both cancer types. Future studies should also examine the impact of patient interview type on the associations between family histories of cancer and leukemia incidence.
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ACKNOWLEDGMENTS |
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Special thanks to Dr. David Shore, Glenn Heartwell, and staff at WESTAT, Inc. and CODA, Inc. and to participating CALGB facilities.
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NOTES |
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REFERENCES |
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