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A few months ago, someone in the DC-area support group asked whether or not CLL ran in families. This person had noticed that several family members had CLL or another lymphoproliferative disorder (LPD). Another person in the group then indicated that he had noticed the same thing in his family. I realized that I had never looked into this. But most CLL patients have children and some have more than one sibling, so it could be important to many people and seemed worth investigating.
Is chronic lymphocytic leukemia (CLL) a familial cancer?
Yes: CLL is a familial cancer. Registry studies, twin studies, and genome wide association studies confirm this. The most comprehensive population-based study to date, based on cancer registry data from Sweden and Denmark, found that first–degree relatives (parents, children, and siblings) of CLL patients had an 8.5-fold increased risk of developing CLL. The risk of developing CLL was also increased 1.9 times for those with a first-degree relative with non-Hodgkin’s lymphoma and 1.5 times for those with a relative with Hodgkin’s lymphoma.1
A twin study of 44,788 pairs of Scandinavian twins found an excess of concordant monozygotic (identical) twins compared with dizygotic (nonidentical) twins for leukemia, and heritability for CLL was estimated to be 21%, which is relatively high, although not as high as some of the more common cancers — for example, the heritable risk for colorectal cancer was estimated to be 35% and the heritable risk for breast cancer (for women only) was estimated to be 27%.2
A genome-wide association study is an approach that involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease. To carry out a genome-wide association study, researchers use two groups of participants: people with the disease being studied and similar people without the disease. If certain genetic variations are found to be significantly more frequent in people with the disease compared to people without disease, the variations are said to be “associated” with the disease. The associated genetic variations can serve as pointers to the region of the human genome where the disease-causing problem resides.
Genome-wide association studies have identified single nucleotide polymorphisms (SNPs), the most common type of genetic variation among people, in nearly 30 locations that are associated with familial CLL.3
Do we know yet what genes are responsible for familial CLL?
Recently, Law, et al. (2017) performed a meta-analysis of six genome-wide association studies from populations of European ancestry from Europe, North America and Australia. They identified nine risk loci at:
1p36.11 (rs34676223, P=5.04 × 10−13),
1q42.13 (rs41271473, P=1.06 × 10−10),
4q24 (rs71597109, P=1.37 × 10−10),
4q35.1 (rs57214277, P=3.69 × 10−8),
6p21.31 (rs3800461, P=1.97 × 10−8),
11q23.2 (rs61904987, P=2.64 × 10−11),
18q21.1 (rs1036935, P=3.27 × 10−8),
19p13.3 (rs7254272, P=4.67 × 10−8) and
22q13.33 (rs140522, P=2.70 × 10−9).
In the discussion section of their paper, the authors state:
“Besides providing additional evidence for genetic susceptibility to CLL, the new and established risk loci identified further insights into the biological basis of CLL development. These loci annotate genes that participate in interconnecting cellular pathways, which are central to B-cell development. In particular, we note the involvement of BCR-mediated signalling with immune responses and apoptosis. Importantly, gene discovery initiatives can have an impact on the successful development of new therapeutic agents26. In this respect it is notable that Ibrutinib27 (a BTK inhibitor) and Idelalisib28 (a PI3KCD inhibitor) mediate their effects through interference of BCR signalling, and Venetoclax29 targets the anti-apoptotic behaviour of BCL-2.”4 This, identifying the risk loci for CLL has had a beneficial effect on the development of new CLL drugs.
What does familial CLL mean for CLL patients and their families?
Susan Slager and Neil Kay’s article, “Familial CLL: What does it mean to me?” offers a reassuring summary for those in CLL families. They make the point that relatives of a CLL patient are at a relatively low risk of developing CLL or another lymphoproliferative disorder, with a lifetime risk of 1 in 48 (2.1%) in the U.S.5
James Cerhan and Susan Slager echo this, writing in 2015. They note that the absolute risk for CLL is low. The familial risk is relatively moderate. There is no screening test to determine whether or not a particular family member will develop CLL, and, even if there were, there is no effective intervention as yet.6
Nonetheless, to be on the safe side, you and your close family members may want to inform your primary medical care providers of your family history of CLL so it can be included your medical histories. If your close family members have any unexplained symptoms or concerns, a complete blood count (CBC) could be performed to rule out CLL.
Is further research being done and, if so, how could I get involved?
Research on familial CLL is ongoing at the National Cancer Institute’s Division of Cancer Epidemiology and Genetics. The purpose of this study is to:
- Find the gene or genes that cause familial CLL;
- Describe the clinical features of familial CLL;
- Explore whether or not families prone to familial CLL are also at greater risk of other types of cancer or leukemia; and
- Identify biomarkers that predict risk in family members.
The researchers are studying families who have at least two living family members who have a history of CLL. Parents, siblings, and adult children of affected family members may also join.
Participants are asked to:
- Provide a blood or buccal cell sample (cells rinsed from the inside of the cheek) for genetic studies
- Provide personal, medical, and family history information;
- Give consent to obtain medical records for cancer and related conditions.
If you are interested in more information about the National Cancer Institute’s Familial CLL study, contact Stephanie Steinbart, the Cancer Genetics Referral Nurse, at 1-800-518-8474 or 301-881-1460, or email her at firstname.lastname@example.org.
1 Cerhan, J. R., & Slager, S. L. (2018). Familial predisposition and familial risk factors for lymphoma. Blood, 126(20), 2265-2273. doi:10. 1182/blood-2015-04-53749
2 Lichtenstein, P., Holm, N. V., Verkasalo, P. K., Iliadou, A., Kaprio, J., Koskenvuo, M., Pukkala, E., Skytthe, A., & Hemminki, K. (2000). Environmental and heritable factors in the causation of cancer – analyses of cohorts of twins from Sweden, Denmark, and Finland. New England Journal of Medicine, 343(2), 78-85. doi:10.1056/NEJM2000071334302013
3 Kipps, T. J., Stevenson, F. K., Wu, C. J., Croce, C. M., Packham, G. Wierda, W. G., O’Brien, S., Gribben, J. & Rai, K. (2017). Chronic lymphocytic leukaemia. Nature Reviews. Disease Primers, 3, 16096. doi:10.1038/nrdp.2016.96
4 Law, P. J., Berndt, S. I., Speedy, H. E., Camp, N. J., Sava, G. P., Skibola, C. F., Holroyd, A., Joseph, V., Sunter, N. J., Nieters, A., Bea, S., Monnereau, A., Martin-Garcia, D., Goldin, L. R., Clot, G., Teras, L. R., Quintela, I., Birmann, B. M., Jayne, S., Cozen, W., Majid, A., Smedby, K. E., Lan, Q., Dearden, C., Brooks-Wilson, A. R., Hall, A. G., Purdue, M. P., Mainou-Fowler, T., Vajdic, C. M., Jackson, G. H., Cocco, P., Marr, H., Zhang, Y., Zheng, T., Giles, G.G., Lawrence, C., Call, T. G., Liebow, M., Melbye, M., Glimelius, B., Mansouri, L., Glenn, M., Curtin, K., Diver, W. R., Link, B. K., Conde, L., Bracci, P. M., Holly, E. A., Jackson, R. D., Tinker, L. F., Benavente, Y., Boffetta, P., Brennan, P., Maynadie, M., McKay, J., Albanes, D., Weinstein, S., Wang, Z., Caporaso, N. E., Morton, L. M., Severson, R. K., Riboli, E., Vineis, P., Vermeulen, R. C., Southey, M. C., Milne, R. L., Clavel, J., Topka, S., Spinelli, J. J., Kraft, P., Ennas, M. G., Summerfield, G., Ferri, G. M., Harris, R. J., Miligi, L., Pettitt, A. R., North, K. E., Allsup, D. J., Fraumeni, J. F., Bailey, J. R., Offit, K., Pratt, G., Hjalgrim, H., Pepper, C., Chanock, S. J., Fegan, C., Rosenquist, R., de Sanjose, S., Carracedo, A., Dyer, M. J., Catovsky, D., Campo, E., Cerhan, J. R., Allan, J. M., Rothman, N., Houlston, R., & Slager, S. (2017). Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia. Nature Communications, 8, 14175. doi:10.1038/ncomms14175
5 Slager, S. L., & Kay, N. E. (2009). Familial CLL: What does It mean to me? Clinical Lymphoma & Myeloma, 9(Suppl 3), S194-S197. doi:10.3816/CLM.2009.s.011.
6 Cerhan & Slager, op. cit.
Linda Lannom holds an M.A. in Sociology and a law degree. For 20 years she supported the Biostatistics Branch of the National Cancer Institute, managing case-control studies, cohort studies, and intervention trials in the US. and abroad. Currently she does consulting for the Elder Justice Initiative of the U.S. Department of Justice.
Originally published in The CLL Tribune Q2 2018.