Genetic Risk Score Offers Insight Into CLL Predisposition

Susan L. Slager, PhD

According to Susan L. Slager, PhD, over 42 genetic variants that may increase the risk of developing chronic lymphocytic leukemia (CLL) have been identified. By combining these variants into a polygenic risk score, a predictive model that offers a 3-and-a-half-fold increased risk estimate for CLL has been created.

For individuals with a family history of lymphoma, the risk score elevates further to a 7.5 times greater likelihood of developing CLL.

This polygenic risk score highlights both increased and decreased risks based on the number of inherited variants. Individuals with a lower score, containing fewer high-risk variants, appear to have a protective effect against CLL, suggesting a potential balance of risk across genetic backgrounds.

“We are finding that there is evidence that the score also helps us identify which individuals will progress to CLL, but more research is needed,” Slager, endowed professor of lymphoma research at Mayo Clinic, told Targeted Oncology^TM during an interview at the 2024 Society of Hematologic Oncology Annual Meeting (SOHO).

In the interview, Slager discussed the etiology and inherited genetic factors that are associated with the risk of CLL.

Microscopic image of CLL cells - Generated with Google Gemini AI

Targeted Oncology: Can you provide an overview of this research you are interested in and discussed at SOHO?

Slager: I am looking at the inherited germline genetics for risk of chronic lymphocytic leukemia. We and others have identified over 42 inherited variants that are associated with risk of getting CLL, and these inherited variants are distributed across the genome. They are not located in any particular region, but each of these inherited variants have a small effect on your risk of disease of getting CLL. We looked at combining these inherited variants into a score, a polygenic risk score, to see if that score is a better predictor of risk of getting chronic lymphocytic leukemia.

What we found is that score is a robust predictor, and we have been able to validate it so that individuals who have a large number of inherited variants have a 3-and-a-half-fold increased risk of getting CLL, and if you have a family history of CLL or lymphoma in general, we are finding that this this score is increases your risk of about 7-and-a-half-fold for risk of getting CLL. If you are on a low end, so if you have a low inherited number of these variants, your score is protective for risk of getting CLL.

We also screened individuals for monoclonal B-cell lymphocytosis, or which is the precursor to CLL. We wanted to see if this score would also help predict individuals with this precursor condition if they progress to having chronic lymphocytic leukemia. This precursor condition is very common in the population, especially over the age of 40, but not everybody progresses to CLL. So, can this genetic risk score predict who will progress to getting CLL? We are finding that there is evidence that the score also helps us identify which individuals will progress to CLL, but more research is needed.

What went into creating that score?

It is the 42 inherited variants and each inherited variance, you get 0, 1, or 2 copies, depending on if you get it from both parents or neither parent. Then, the score is weighted by the effect size from the genome wide association studies. For each variant, we determine 0, 1, or 2, and then we weigh it, and then we add it up across the variants, and then that is your score. Everybody has a score, and you can get a clear distribution of the score. Among individuals without CLL, that score is much lower. But among patients with chronic lymphocytic leukemia, the score is much higher.

Could you discuss some of the genetic risk factors for developing CLL and how these contribute to disease pathogenesis?

The inherited variants are located across the genome. They tend to be not in any particular genes per se, but they are located in regions that regulate downstream gene expression. They are in epigenomic regions and super enhancers. The actual biology of how these individual variants increase your risk of CLL is still under a lot of research, but we just know that they happen to be regulators of gene expression.

What are the recommendations for genetic testing in individuals with the family history of CLL?

You can get genetic testing, but there is nothing you can do about it yet. There are no preventive strategies. You can find that you have this genetic score, and you are on the high end, and you have a family history of CLL or lymphoma, but there is nothing you can do about it right at the moment. When I talk to the general population and ask the question, “Would you want to know?” it varies by individual. Some people say they do want to know and just be more informed and other people say they are not interested. I think it is still an individualized process. But as far as clinically, I do not recommend getting it tested, or at least having a conversation [before testing].

What are the most promising areas in the field of CLL genetics?

I am more interested in etiology, mostly about the precursors and conditions for monoclonal B-cell lymphocytosis, understanding why people get this precursor condition, and understanding why individuals progress and why a lot of people do not progress. I think that is the active area that excites me.

REFERENCE:

Slager S. Genetic predisposition to CLL. Presented at the 2024 Society of Hematologic Oncology Annual Meeting (SOHO); September 4-7, 2024; Houston, Texas. Session VII: Chronic Lymphocytic Leukemia.