CLL INTRODUCTION: Familial CLL

Approximately 8–10% of patients with CLL have an inherited genetic predisposition, according to evidence from case control and cohort studies. Several international groups are actively conducting research on the genetic predisposition of CLL in order to identify the gene(s) responsible for the development of CLL in familial cases. Such genes may also be relevant to the pathogenesis of CLL in non-familial (sporadic) cases. The clinical characteristics of familial CLL do not appear to differ from those of sporadic CLL, even by examining some of the new prognostic factors like VH mutation status, ZAP-70, and cytogenetics by FISH analysis.

Investigators in the 1940's (Videbaek in Denmark) and 1970's (Gunz in Australia) noticed and reported the inherited patterns of familial CLL; however, research tools to identify the responsible genes have only recently become available.

Studies of first-degree relatives of CLL patients also show a slightly higher incidence of lymphoid malignancies (other than CLL) such as Hodgkin's disease and Non-Hodgkin's lymphoma, suggesting that the CLL predisposition gene(s) has a pleitropic effect; that is, the gene may also predispose to other lymphoid diseases.

Various research groups have performed studies to look for obvious candidate genes. However, these studies have all been, thus far, negative. The main issues are: 1) a large number of informative samples are required (e.g. at least from two affected individuals, preferably siblings or cousins) and 2) Leukemic DNA CLL cells as well as germ line DNA samples (as controls from normal DNA) are also required. The latter is usually obtained from buccal mucosa cells in the form of a swab or a mouth wash.

A linkage analysis carried out at the Institute of Cancer Research in the UK using high density, single nucleotide polymorphisms (or SNPs) identified two possible areas of linkage in chromosomes 6p and 11p (Sellick, et. al. ASH 2004) but further studies are needed to pinpoint the gene and to confirm and validate these findings. In order to progress further in this field, there is a paramount need for international collaboration. Both USA-based and UK/European-based consortiums are actively collecting data and suitable samples. Once, and if, the studies identify candidate genes (as has been the case in families with breast cancer), the genes will need to be examined for mutations and only then can family members be screened to evaluate the possible risk. At the present stage, the key function is to collect suitable samples which will allow the field to move forward more rapidly.

Pedigree showing the incidence of CLL in multiple generations. Studies suggests that between 5-10% of CLL patients have a first or second-degree relative with CLL. No test has yet been developed that can identify relatives likely to develop CLL.