Correspondence

Genetic Predisposition to Hodgkin's Disease

N Engl J Med 1995; 333:64-65July 6, 1995

Article

To the Editor:

From their study of Hodgkin's disease in monozygotic and dizygotic twins, Mack et al. (Feb. 16 issue)1 concluded that genetic susceptibility underlies certain subtypes of Hodgkin's disease. We have studied the familial aggregation of hematologic neoplasms among 4061 relatives of 189 patients with any kind of hematologic neoplasm.2 Fifty-six of the relatives (1.4 percent) had a hematologic neoplasm, with a calculated odds ratio of 3.62 (95 percent confidence interval, 1.44 to 9.07; P<0.01) as compared with two control groups and after adjustment for age, sex, ethnic group, number of relatives in the family, and degree of familial linkage. Furthermore, only 6 of these 56 subjects had the same type of neoplastic disease as the index patients (12 relatives had an undefined hematologic neoplasm). We concluded that the familial aggregation we observed was consistent with a genetic predisposition to hematologic neoplasms, and hypothesized that a genetic lesion in a pluripotent hematopoietic stem cell accounts for the diversity of hematologic neoplasms in the families.

In our study, the same pattern of familial aggregation was observed in a subgroup of patients with Hodgkin's disease. We would have expected such a tendency in the twins studied by Mack et al. The twins they analyzed had a median age at diagnosis of 26 years. Since young case patients usually have young siblings, an age-related bias might have caused an underestimation of the aggregation of hematologic neoplasms in the twins, because the median age at onset of most kinds of hematologic neoplasms is in the sixth and seventh decades. Moreover, since only living patients with Hodgkin's disease were analyzed, a selective mortality bias is possible. It is still unclear whether the degree of familial aggregation of hematologic neoplasms differs between patients with a short, fatal disease and those with a disease of long duration. It would therefore be interesting to examine the familial aggregation of all hematologic neoplasms in all first-degree relatives of the pairs of twins, without limiting the index patients to a certain age group or vital status.

Ofer Shpilberg, M.D.
Avner Shahar, M.D.
University of Pittsburgh, Pittsburgh, PA 15261

2 References

1. 1

   Mack TM, Cozen W, Shibata DK, 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;332:413-418
   Full Text | Web of Science | Medline

2. 2

   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
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. Shpilberg and Shahar are concerned about the exclusion of rapidly fatal cases of Hodgkin's disease, about the undercounting of other hematologic neoplasms, and about our general failure to confirm the global familiality of hematologic neoplasms reported by Dr. Shpilberg and his colleagues.1

Few cases of Hodgkin's disease were rapidly fatal during this period, dead probands were reported to us by the surviving twins, and as described, our findings were unaffected by the exclusion of the less successfully treated probands given a diagnosis before 1970. Neither ascertainment nor follow-up was done on a disease-specific basis, and no hematologic neoplasm occurred at any age in any first- or second-degree relative of the concordant twins.

Although the retrospective ascertainment of concordant pairs was probably incomplete for those with different tumors, a comparison of the observed and expected numbers of pairs affected by the same and by different tumors, identified retrospectively and prospectively, leads us to estimate that we missed about one third of the pairs of twins affected by different malignant conditions, relative to those with the same malignant condition. If the risks of Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and leukemia were each to be increased by the same genetic factor, the cumulative incidence rates for these categories of neoplastic disease from 20 to 60 years of age in the United States2 permit us to estimate that for every twin in whom the same condition developed as in his or her identical proband, three would have a different hematologic neoplasm. Assuming that we identify two of every three of these, only a third of the twins in identified pairs that were concordant for hematologic neoplasms would be expected to have the same type of neoplasm. In fact, 38 of the 44 affected identical pairs (86 percent)(10 pairs with Hodgkin's disease, 8 with non-Hodgkin's lymphoma, 1 with multiple myeloma, and 19 with leukemia) were concordant for the type of neoplasm.

Shpilberg et al.1 compared the occurrence of hematologic neoplasms in relatives (mostly second-degree) of case patients with that in relatives of patients referred for other conditions. If there is assumed to be no selective bias in recall, compliance, or referral, their findings suggest the global familiality of hematologic neoplasms (but do not address heritability). We have not systematically collected information on the non-twin relatives, but 15 fraternal twins (all ages) of probands also went on to have a hematologic neoplasm, in seven instances the same type as in the proband. Of these, six were cases of non-Hodgkin's lymphoma, suggesting that some families are prone specifically to non-Hodgkin's lymphoma, but not necessarily on a genetic basis. For Hodgkin's disease and leukemia,3 familiality is less obvious but more likely to be genetic. Although we cannot rule out an additional common genetic basis for hematologic neoplasms, this evidence rather suggests separate genetic mechanisms.

Thomas M. Mack, M.D.
Wendy Cozen, D.O.
University of Southern California School of Medicine, Los Angeles, CA 90033

3 References

1. 1

   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
   CrossRef | Web of Science | Medline

2. 2

   Miller BA, Reis LAG, Hankey BF, et al., eds. SEER cancer statistics review, 1973-1990. Bethesda, Md.: National Institutes of Health, 1993. (NIH publication no. 93-2789.)
   

3. 3

   Buckley JD, Versteeg CM, Breslow N, et al. Concordance for childhood cancer in twins. Med Pediatr Oncol (in press).
   

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