Reader Responses: The genetic risk for familial CLL

Here’s how readers responded to a You Make the Call question about the genetic risk for familial chronic lymphocytic leukemia.

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Familial CLL is a well-defined clinical entity. To a certain degree, all of the common leukemias have some degree of familial inheritance.

However, based on data in the Utah Cancer Registry, the incidence approaches 6 to 8 percent. Of equal importance is that monoclonal B-cell lymphocytosis (MBL) can occur in unaffected first-degree relatives up to 13 to 17 percent of the time. See studies by the National Cancer Institute, Mayo Clinic, and from Leeds, England.

It is my impression that the diagnosis of CLL in the second generation occurs at an earlier age than in the first generation. Some investigators say that this is just due to early detection. However, I almost always elicit a history of familial CLL from patients with CLL in their 50s. Be aware that relatives with familial CLL also can have other lymphoproliferative disorders such as non-Hodgkin lymphoma or hairy cell leukemia. It is not uncommon to find a child with acute lymphocytic leukemia whose grandfather has CLL. There is an important Italian study of these patterns, and it has been confirmed in other clinics.

What else do we know about familial CLL? Second primary tumors definitely occur. The FISH cytogenetic lesions of hemizygous and homozygous del13q14 are found more commonly in familial CLL. The hemizygous del13q14 is found in MBL and many of the oncogene mutations found in CLL have been detected in MBL.

Through the combined works of many groups, the number of identified single nucleotide polymorphisms associated with CLL continues to increase. At last count, some 43 markers from genomewide association studies have been reported, many of which have been confirmed. MBL is still the easiest biomarker for early preclinical detection at approximately six years prior to the diagnosis of CLL. The prevalence of an abnormal free light chain ratio, M-protein, or hypogammaglobulinemia can be detected as early as nine years prior to the diagnosis of CLL. MBL and serum abnormalities can be found in unaffected first-degree relatives with familial CLL.

Gerald Marti, MD, PhD
Center for Devices and Radiological Health, U.S. Food and Drug Administration
Silver Spring, MD

Even though CLL is likely the most inheritable leukemia, I believe the work is still ongoing to find a gene to explain it.

Monica Verma, MD
Hamilton Health Care System
Dalton, GA

There have been reports of inherited CLL in the context of a POT1 germline mutation. Historically, POT1 germline mutations have been associated with an increased risk of glioblastomas, melanoma, and cardiac angiosarcomas. Families with POT1 germline mutations and CLL tend to have CLL only without a solid tumor family history.

Brittany DeGreef, MS, CGC
Northwestern Medical Group
Chicago, IL