Families With Both Hodgkin Lymphoma and Multiple Myeloma in Their Pedigrees

Peter H. Wiernik, MD, Dona Wickramasinghe, MD, and Janice P. Dutcher, MD

Clinical Advances in Hematology & Oncology

April 2015, Volume 13, Issue 4


Families With Both Hodgkin Lymphoma and Multiple Myeloma in Their Pedigrees

Peter H. Wiernik, MD, Dona Wickramasinghe, MD, and Janice P. Dutcher, MD

The authors are affiliated with the Cancer Research Foundation of New York in Chappaqua, New York. Dr Wiernik is the director, Dr Wickramasinghe is a research associate, and Dr Dutcher is an associate director.

Corresponding author: Peter H. Wiernik, MD, Cancer Research Foundation of New York, 43 Longview Lane, Chappaqua, NY 10514, Tel: 914-241-7242, E-mail: pwiernik@aol.com

Abstract: Reports of familial clustering of hematologic malignancies have appeared for decades, but the cause of this uncommon observation is still unknown. Most modern investigations support a genetic rather than an environmental explanation. Clinically, most pedigrees of families with familial hematologic malignancies demonstrate age of onset anticipation (ie, diagnosis at an earlier age in successive generations). The cause of anticipation is clear in some familial neurologic disorders (eg, trinucleotide repeat expansion in Huntington disease) but unclear in familial hematologic malignancies. In preparation for molecular studies on familial clustering of hematologic malignancies, we collected pedigrees on 738 families. In these families, we observed anticipation in those with familial multiple myeloma, chronic lymphocytic leukemia, or non-Hodgkin lymphoma. Here we present preliminary data on 26 families with both multiple myeloma and Hodgkin lymphoma in their pedigrees, and demonstrate strong evidence for anticipation and predominantly male transmission of these neoplasms. We encourage all health care personnel to ask patients about their family’s medical history, to take careful family histories from individuals with uncommon illnesses, and to refer families with clustering of such illnesses for investigation.

Introduction and Methods

The study of familial hematologic malignancies is important because it may lead to the discovery of underlying genetic causes, or of genes that enhance susceptibility to an etiologic agent. To begin such studies, we collected pedigree information and medical records—including pathology reports and other material when possible—on 738 families with multiple hematologic malignancies. Many of the patients were referred to us by physicians and genetic counselors. Other patients were acquired through online support groups, patient chat rooms, and our own practices. Of note, we found that most of the family history data in the hospital charts of patients from other practices were partially or entirely inaccurate. Obtaining accurate data required questioning the propositus repeatedly, even when the propositus was a physician. All members of each family studied gave written informed consent to participate, whether affected by a neoplasm or not.


This paper concerns 26 families that have both multiple myeloma (MM) and Hodgkin lymphoma (HL) with or without other hematologic malignancies in their pedigrees (Table 1). To our knowledge, such families have not been previously reported in detail. In 14 of the 26 pedigrees, a parent and child were affected (11 father-child pairs; 3 mother-child pairs). These pairs included 9 father-son, 2 father-daughter, 2 mother-daughter, and 1 mother-son pairs. Eight of the 26 pedigrees had only 1 affected pair and 18 had multiple affected individuals. Male transmission was evident in 19 pedigrees, and female transmission was evident in 7 pedigrees. There were 5 sibling pairs in these families; four were sex concordant (2 MM-MM, 1 HL-HL, 1 MM-HL), and one was a brother-sister pair with MM and HL, respectively. HL and MM cases had at least 1 generation separating them in 7 pedigrees, occurred in sequential generations in 14 pedigrees, and occurred in the same generation in 5 pedigrees. In the youngest affected generation, MM was found in 8 pedigrees, HL in 13 pedigrees, and both in 5 pedigrees. The median age at diagnosis for HL was 30.8 years (range, 17-80 years), which is older than expected, and the median age at diagnosis for MM was 64.2 years (range, 31-81 years) as expected.1
The presence or absence of anticipation could be assessed in 20 of the 26 pedigrees. Nineteen of those 20 pedigrees demonstrated evidence of age of onset anticipation (median difference in age at diagnosis, 26 years; range, 3-61 years). More advanced and aggressive disease, another feature of anticipation, was observed in 15 of 21 families. However, the presentation of disease and response to therapy in these families did not appear to be different from that of sporadic cases. Details of anticipation in parent-child pairs in these families are given in Table 2.

Anticipation has been previously documented in familial MM,2,3 HL,4 chronic lymphocytic leukemia (CLL),5 and non-Hodgkin lymphoma.6 Anticipation typically is interpreted as evidence for a genetic cause of familial hematologic malignancy, although some studies suggest that environment together with genetic susceptibility may better explain these malignancies.7 Anticipation in many familial neurologic disorders results from expansion of unstable trinucleotide repeats through successive generations.8 However, trinucleotide repeat expansion is not the cause of anticipation in leukemias,9-11 and the molecular basis for anticipation in leukemias and other hematologic malignancies remains unknown.
Previous studies have revealed a 2- to 4-fold increased risk of CLL in first-degree relatives of patients with MM12 or monoclonal gammopathy of unknown significance.13 Other observations support a link between MM and CLL as well14; for example, in both MM and CLL, healthy family members of patients may have subclinical evidence of the neoplasms (ie, paraproteinemia and a clonal population of B lymphocytes, respectively).15,16
The familial risk for HL in first-degree relatives of patients with HL is well recognized17 and, as stated above, the presence of anticipation in most families with multiple cases of HL supports a genetic basis for familial clustering. The genetic hypothesis is further strengthened by the observation that most sibling pairs with HL are of the same sex.18 This observation led to the postulate that a genetic locus in the pseudoautosomal region of the sex chromosomes might be at play in HL.19 That hypothesis was strengthened by the report of a family with Leri-Weill dyschondrosteosis (LWD) and HL.20 This family had a mother with LWD and her 2 daughters had LWD and HL. Because the LWD gene has been identified in the pseudoautosomal region of the X chromosome, an adjacent locus related to HL susceptibility seems possible. Interestingly, 4 of the 5 sibling pairs in our study were sex concordant.
There have also been studies on genetic susceptibility in HL. Salipante and colleagues21 discovered a gene located on 3p21.31 (KLHDC8B) and found a polymorphism in HL patients that decreases its translational expression. Decreased expression of the gene leads to the formation of binucleate cells (such as Reed-Sternberg cells) and twin births. Interestingly, HL is known to be more frequent in twins.22 More recently, Cozen and colleagues23 identified a novel locus at 19p13.3 located in intron 2 of the TCF3 gene (also known as E2A) that is associated with HL. The TCF3 gene is a regulator of B- and T-cell lineage commitment and is involved in the pathogenesis of HL.
Jain and colleagues24 reported on 8 families with familial MM and monoclonal gammopathy. In 2 families, there was a first-degree relative of the propositus with HL. Curiously, as in our study, the HL patients were older than the typical median age (34 and 37 years). Kulcsar and colleagues25 reported on an MM patient who developed HL after autologous stem cell transplantation, and Jønsson and colleagues26 reported on 1 family with HL and MM cases. These papers, taken together with our data, support the notion that there is a fundamental link between these 2 B-cell disorders that has not been previously recognized. However, not all studies have found an association between MM and HL.27,28
Also in our database are 16 families with MM and non-Hodgkin lymphoma; 7 families with MM, non-Hodgkin lymphoma, and CLL; and 3 families with MM, non-Hodgkin lymphoma, and HL. None of these families have been included in the above analyses. Analysis is still ongoing for these families, but it is evident that anticipation is present in most of the pedigrees. Taken together with the MM-HL families, they suggest a common genetic basis for several familial B-cell disorders. This hypothesis is further strengthened by the 78 families in our database with only HL and non-Hodgkin lymphoma in their pedigrees. In the future, we also will study these families at a molecular level.
Although some have argued for an environmental cause of familial hematologic malignancies, this seems less likely than a genetic cause alone or a genetic and environmental interaction. None of the affected members of the MM-HL families had lived together in the same environment for years, usually for decades. Furthermore, an environmental cause alone would not likely explain the predominance of male transmission in most of the families or the predominance of sex concordance among most sibling pairs. Our working hypothesis is that there is a heritable genetic factor in these families that enhances susceptibility to an etiologic agent in the environment (eg, a virus), and that the agent can cause B-cell malignancies of various phenotypes. Consistent with this hypothesis is our observation that mouse mammary tumor virus may play a role in the etiology of both non-Hodgkin lymphoma and breast cancer in some patients with both neoplasms,29 and the fact that the SV40 virus can cause lymphoma, osteogenic sarcoma, and other tumors in hamsters.30


We have begun molecular studies on our HL-MM families and will present our results as they are obtained. We encourage others to investigate a possible relationship between HL and MM, and to report on patients with familial hematologic malignancies. It also may be important to investigate other diseases that appear to segregate with hematological malignancies more commonly than expected, such as multiple sclerosis31,32 and systemic lupus erythematosus.33-35 We expect that modern molecular techniques for examining the genome will yield important information on the genetic bases for hematologic malignancies in the near future.

Presented in part at the American Federation for Medical Research Eastern Regional Meeting, April 9, 2014, in Washington, DC. Supported in part by the Cancer Research Foundation of New York.

The authors have declared no financial conflicts of interest.


1. Koura DT, Langston AA. Inherited predisposition to multiple myeloma. Ther Adv Hematol. 2013;4(4):291-297.
2. Deshpande HA, Hu XP, Marino P, Jan NA, Wiernik PH. Anticipation in familial plasma cell dyscrasias. Br J Haematol. 1998;103(3):696-703.
3. Lynch HT, Watson P, Tarantolo S, et al. Phenotypic heterogeneity in multiple myeloma families. J Clin Oncol. 2005;23(4):685-693.
4. Alexandrescu DT, Wiernik PH. The influence of parental age and gender on anticipation in familial B-cell malignancies. Med Oncol. 2007;24(1):55-62.
5. Wiernik PH, Ashwin M, Hu XP, Paietta E, Brown K. Anticipation in familial chronic lymphocytic leukaemia. Br J Haematol. 2001;113(2):407-414.
6. Wiernik PH, Wang SQ, Hu XP, Marino P, Paietta E. Age of onset evidence for anticipation in familial non-Hodgkin’s lymphoma. Br J Haematol. 2000;108(1):72-79.
7. McDuffie HH, Pahwa P, Karunanayake CP, Spinelli JJ, Dosman JA. Clustering of cancer among families of cases with Hodgkin lymphoma (HL), multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL), soft tissue sarcoma (STS) and control subjects. BMC Cancer. 2009;9(1):70.
8. Choi KD, Yook JW, Kim MJ, et al. Possible anticipation associated with a novel splice site mutation in episodic ataxia type 2. Neurol Sci. 2013;34(9):1629-1632.
9. Horwitz M. The genetics of familial leukemia. Leukemia. 1997;11(8):1347-1359.
10. Horwitz M, Benson KF, Li FQ, et al. Genetic heterogeneity in familial acute myelogenous leukemia: evidence for a second locus at chromosome 16q21-23.2. Am J Hum Genet. 1997;61(4):873-881.
11. Auer RL, Dighiero G, Goldin LR, et al. Trinucleotide repeat dynamic mutation identifying susceptibility in familial and sporadic chronic lymphocytic leukaemia. Br J Haematol. 2007;136(1):73-79.
12. Greenberg AJ, Rajkumar SV, Vachon CM. Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics. Blood. 2012;119(23):5359-5366.
13. Landgren O, Kristinsson SY, Goldin LR, et al. Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood. 2009;114(4):791-795.
14. Makower D, Venkatraj U, Dutcher JP, Wiernik PH. Occurrence of myeloma in a chronic lymphocytic leukemia patients after response to differentiation therapy with interleukin-4. Leuk Lymphoma. 1996;23(5-6):617-619.
15. Goldin LR, Lanasa MC, Slager SL, et al. Common occurrence of monoclonal B-cell lymphocytosis among members of high-risk CLL families. Br J Haematol. 2010;151(2):152-158.
16. Ögmundsdóttir HM, Valgeirsdóttir S, Schiffhauer HR, Óskarsdóttir LB, Steingrímsdóttir H, Haraldsdóttir V. Familial predisposition to monoclonal gammopathies: deviations in B-cell biology. Clin Lymphoma Myeloma Leuk. 2013;13(2):191-193.
17. Altieri A, Hemminki K. The familial risk of Hodgkin’s lymphoma ranks among the highest in the Swedish Family-Cancer Database. Leukemia. 2006;20(11):2062-2063.
18. Grufferman S, Cole P, Smith PG, Lukes RJ. Hodgkin’s disease in siblings. N Engl J Med. 1977;296(5):248-250.
19. Horwitz M, Wiernik PH. Pseudoautosomal linkage of Hodgkin disease. Am J Hum Genet. 1999;65(5):1413-1422.
20. Shears DJ, Endris V, Gokhale DA, et al. Pseudoautosomal linkage of familial Hodgkin’s lymphoma: molecular analysis of a unique family with Leri-Weill dyschondrosteosis and Hodgkins lymphoma. Br J Haematol. 2003;121(2):377-379.
21. Salipante SJ, Mealiffe ME, Wechsler J, et al. Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells. Proc Natl Acad Sci USA. 2009;106(35):14920-14925.
22. Timms AE, Horwitz MS. KLHDC8B in Hodgkin lymphoma and possibly twinning. Commun Integr Biol. 2010;3(2):154-158.
23. Cozen W, Timofeeva MN, Li D, et al. A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus. Nat Commun. 2014;5:3856.
24. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol. 2009;84(1):34-38.
25. Kulcsar I, Szanto A, Varoczy L, Mehes G, Zeher M. Hodgkin’s lymphoma developed after autologous stem cell transplantation for multiple myeloma: transformation or coincidental appearance? Pathol Oncol Res. 2012;18(3):733-736.
26. Jønsson V, Awan H, Nyquist E, et al. Familial Hodgkin’s lymphoma in Scandinavia. In Vivo. 2011;25(3):431-437.
27. Altieri A, Chen B, Bermejo JL, Castro F, Hemminki K. Familial risks and temporal incidence trends of multiple myeloma. Eur J Cancer. 2006;42(11):1661-1670.
28. Goldin LR, Pfeiffer RM, Gridley G, et al. Familial aggregation of Hodgkin lymphoma and related tumors. Cancer. 2004;100(9):1902-1908.
29. Etkind PR, Stewart AF, Dorai T, Purcell DJ, Wiernik PH. Clonal isolation of different strains of mouse mammary tumor virus-like DNA sequences from both the breast tumors and non-Hodgkin’s lymphomas of individual patients diagnosed with both malignancies. Clin Cancer Res. 2004;10(17):5656-5664.
30. Diamandopoulos GT. Induction of lymphocytic leukemia, lymphosarcoma, reticulum cell sarcoma, and osteogenic sarcoma in the Syrian golden hamster by oncogenic DNA simian virus 40. J Natl Cancer Inst. 1973;50(5):1347-1365.
31. Deftereos S, Farmakis D, Papadogianni A, et al. Waldenström’s macroglobulinemia developing in a patient with multiple sclerosis: coincidence or association? Mult Scler. 2004;10(5):598-600.
32. Hjalgrim H, Rasmussen S, Rostgaard K, et al. Familial clustering of Hodgkin lymphoma and multiple sclerosis. J Natl Cancer Inst. 2004;96(10):780-784.
33. Xu Y, Wiernik PH. Systemic lupus erythematosus and B-cell hematologic neoplasm. Lupus. 2001;10(12):841-850.
34. Lu M, Bernatsky S, Ramsey-Goldman R, et al. Non-lymphoma hematological malignancies in systemic lupus erythematosus. Oncology. 2013;85(4):235-240.
35. Apor E, O’Brien J, Stephen M, Castillo JJ. Systemic lupus erythematosus is associated with increased incidence of hematologic malignancies: a meta-analysis of prospective cohort studies. Leuk Res. 2014;38(9):1067-1071.