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