FaCD Online Syndrome Fact Sheet

Last updated: 30 May 2013

Name: Chronic Lymphocytic Leukemia, Familial Clustering of

Synonym: Familial CLL

Mode of Inheritance: AD/ AR?

OMIM number: 151400  

Genes

DAPK1, mapped to 9q34.1

Tumor features

Hodgkin disease (Hodgkin's lymphoma)
multiple myeloma (Kahler's disease)
non-Hodgkin lymphoma

Tumor features (possible)

breast cancer
gastric cancer
prostate cancer

Comment

Familial clustering of CLL has been observed and is seen more frequently in CLL than in other leukemias[1-9,27], two affected siblings are the most commonly seen clusters[23]. Familial CLL does not appear to differ from sporadic CLL in terms of prognostic markers and clinical outcome[19]. Yuille et al.[10] presented a review of the published cases, in addition to their own survey of the family history of 268 CLL patients. In this latter survey, the authors observed a family history of CLL in 6% of CLL patients and a family history of (any type of) lymphoproliferative disorder in 12%. Cuttner[11] studied the family history of 29 CLL patients. Of these, 34 % had a first-degree relative with a hematological malignancy (10 % had a first-degree relative with CLL). Monoclonal B cell lymphocytosis has been observed in four unaffected first-degree relatives in a familial CLL) kindred[21].

Radovanovic et al.[12] studied the cancer mortality in family members of 130 CLL patients and the same number of matched controls. Death from leukemia (relative risk (RR) 5.5) and all types of cancer combined (RR 1.9) was more frequent in relatives of CLL patients compared with controls. Pottern et al.[13] studied familial cancers associated with CLL. CLL was significantly increased among those reporting a sibling with leukemia (RR 3) or lymphoma (RR 4.3). A history of gastric cancer in parents was associated with an increased CLL risk (RR 2). Prostate cancer among fathers or breast cancer among sisters and mothers was also associated with an increased risk to develop CLL (RR 2). In a study using data from the Swedish Cancer family database, relatives of CLL patients had an RR to develop CLL of 7.5, of 1.5 for non-Hodgkin lymphoma and 2,4 for Hodgkin lymphoma. CLL risks appeared to be similar in parents, siblings, and offspring of cases, in male and female relatives, and were not modified by the age at diagnosis of CLL in the index case[24]. In general, the risk of CLL is higher in individuals with a positive family history of malignancy than in those with a negative family history[25]

Horwitz et al.[14] studied 7 families with CLL and observed a decrease in age at diagnosis with each successive generation, a phenomenon referred to as anticipation. The authors suggested that a dynamic mutation, as seen for example in fragile X syndrome and myotonic dystrophy, might be responsible for this phenomenon. Yuille et al.[15] and Goldin et al.[16] confirmed the findings by Horwitz et al. Studies to map the genes predispopsing to familial CLL are under way[20,22]. In a large family with 11 CLL patients, no single predisposing gene region could be identified, nor was there evidence for shared exposure to a single strong antigen as an external cause of the familial occurrence of CLL[17]. Currently, there are no data to suggest a completely envorinmental single cause of familial CLL clustering[18].

Raval et al[26] showed that reduced expression of DAPK1, associated with a germline missense DAPK1 mutation, underlied a large familial cluster of CLL[27,28], and also demonstrated that epigenetic silencing of DAPK1 is present in the majority of sporadic CLL. Follow-up studies data indicated that allele specific expression of DAPK1 potentially predisposes to CLL[29].

References

[1] Reilly EB, Rapaport SI, Karr NW, Mills H, Carpenter GE. Familial chronic lymphatic leukemia. Arch Intern Med 1952; 90:87-89.
[2] Blattner WA, Dean JH, Fraumeni jr JF. Familial lymphoproliferative malignancy: clinical and laboratory follow-up. Ann Intern Med 1979; 90(6):943-944.
[3] Gunz F, Dameshek W. Chronic lymphocytic leukemia in a family, including twin brothers and a son. JAMA 1957; 164(12):1323-1325.
[4] McPhedran P, Heath CW, Lee J. Patterns of familial leukemia: ten cases of leukemia in two interrelated families. Cancer 1969; 24:403-407.
[5] Branda RF, Ackerman SK, Handwerger BS, Howe RB, Douglas SD. Lymphocytic studies in familial chronic lymphatic leukemia. Am J Med 1978; 64:508-514.
[6] Neuland CY, Blattner WA, Mann DL, Fraser MC, Tsai S, Strong DM. Familial chronic lymphocytic leukemia. JNCI 1983; 71(6):1143-1150.
[7] Catovsky D. The search for genetic clues in chronic lymphocytic leukemia. Hematol Cell Ther 1997; 39 Suppl 1: S5-11:S5-11.
[8] Shah AR, Maeda K, Deegan MJ, Roth MS, Schnitzer B. A clinicopathologic study of familial chronic lymphocytic leukemia. Am J Clin Pathol 1992; 97:184-188.
[9] Eriksson M, Bergstrom I. Familial malignant blood disease in the country of Jamtland, Sweden. Eur J Haematol 1987; 38(3):241-245.
[10] Yuille MR, Matutes E, Marossy A, Hilditch B, Catovsky D, Houlston RS. Familial chronic lymphocytic leukaemia: a survey and review of published studies. Br J Hematol 2000; 109(4):794-799.
[11] Cuttner J. Increased incidence of hematologic malignancies in first-degree relatives of patients with chronic lymphocytic leukemia. Cancer Invest 1992; 10(2):103-109.
[12] Radovanovic Z, Markovic-Denic L, Jankovic S. Cancer mortality of family members of patients with chronic lymphocytic leukemia. Eur J Epidemiol 1994; 10:211-213.
[13] Pottern LM, Linet M, Blair A, Dick F, Burmeister LF, Gibson R, Schuman LM, Fraumeni jr JF. Familial cancers associated with subtypes of leukemia and non- Hodgkin's lymphoma. Leuk Res 1991; 15(5):305-314.
[14] Horwitz M, Goode EL, Jarvik GP. Anticipation in familial leukemia [see comments]. Am J Hum Genet 1996; 59(5):990-998.
[15] Yuille MR, Houston RS, Catovsky D. Anticipation in familial chronic lymphocytic leukaemia. Leukemia 12, 1696-1698. 1998.
[16] Goldin LR, Sgambati M, Marti GE, Fontaine L, Ishibe N, Caporaso N. Anticipation in familial chronic lymphocytic leukemia [letter]. Am J Hum Genet 1999; 65(1):265-269.
[17] Fuller SJ, Papaemmanuil E, McKinnon L, Webb E, Sellick GS, Dao-Ung LP, Skarratt KK, Crowther D, Houlston RS, Wiley JS. Analysis of a large multi-generational family provides insight into the genetics of chronic lymphocytic leukemia. British journal of haematology 2008; .
[18] Goldin LR, Slager SL. Familial CLL: Genes and Environment. Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program 2007; 2007():339-45.
[19] Goldin LR, Caporaso NE. Family studies in chronic lymphocytic leukaemia and other lymphoproliferative tumours. British journal of haematology 2007; 139(5):774-9.
[20] Ng D, Toure O, Wei MH, Arthur DC, Abbasi F, Fontaine L, Marti GE, Fraumeni JF, Goldin LR, Caporaso N, Toro JR. Identification of a novel chromosome region, 13q21.33-q22.2, for susceptibility genes in familial chronic lymphocytic leukemia. Blood 2007; 109(3):916-25.
[21] Abbasi F, Longo NS, Lipsky PE, Raveche E, Schleinitz TA, Stetler-Stevenson M, Caporaso N, Marti G. B-cell repertoire and clonal analysis in unaffected first degree relatives in familial chronic lymphocytic leukaemia kindred. British journal of haematology 2007; 139(5):820-3.
[22] Sellick GS, Goldin LR, Wild RW, Slager SL, Ressenti L, Strom SS, Dyer MJ, Mauro FR, Marti GE, Fuller S, Lyttelton M, Kipps TJ, Keating MJ, Call TG, Catovsky D, Caporaso N, Houlston RS. A high-density SNP genome-wide linkage search of 206 families identifies susceptibility loci for chronic lymphocytic leukemia. Blood 2007; 110(9):3326-33.
[23] Capalbo S, Callea V, Musolino C, Guglielmo P, D'Arena G, Fragasso A, Battista C, Giustolisi R, Brugiatelli M, Liso V. Familial B-cell chronic lymphocytic leukemia in a population of patients from Southern Italy. International journal of hematology 2004; 79(4):354-7.
[24] Goldin LR, Pfeiffer RM, Li X, Hemminki K. Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database. Blood 2004; 104(6):1850-4.
[25] Nenova IS, Karnolski IN, Mateva NG, Sotirova KN. Familial study of chronic lymphocytic leukemia: aggregation of different malignant processes in families with individuals affected with chronic lymphocytic leukemia. Folia medica 2006; 48(1):11-6.
[26] Raval A et al. Downregulation of Death-Associated Protein Kinase 1 (DAPK1) in Chronic Lymphocytic Leukemia. Cell 2007;129:879-890
[27] H.T. Lynch, D.D. Weisenburger, B. Quinn-Laquer, P. Watson, J.F. Lynch and W.G. Sanger, Hereditary chronic lymphocytic leukemia: an extended family study and literature review, Am. J. Med. Genet. 2002:113–117
[28] Henry T. Lynch, Kelly M. Ferrara, Dennis D. Weisenburger, Warren G. Sanger, Jane F. Lynch and Stephan D. Thomé. Genetic counseling for DAPK1 mutation in a chronic lymphocytic leukemia family. Cancer Genetics and Cytogenetics 2008; 186(2):95-102
[29] Wei QX, Claus R, Hielscher T, Mertens D, Raval A, Oakes CC, Tanner SM, de la Chapelle A, Byrd JC, Stilgenbauer S, Plass C. Germline allele-specific expression of DAPK1 in chronic lymphocytic leukemia.PLoS One. 2013;8(1):e55261.