Genetic screening for CLL premature, speaker says

Occupational exposures

Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.

Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.

Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.

Family history

One of the strongest risk factors for CLL is family history.

Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.

They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).

GWAS in CLL

Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.

Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.

Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.

Unrelated cases and controls are included in the studies.

The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.

In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.

They identified 9 more inherited variances with CLL, for a total of 43 identified to date.

The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.

“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”

Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.

However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.

She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.

Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.

For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.

Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.

Impact on clinical practice

Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.

Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.

MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.