Abstract 4267: Association of polygenic risk scores and family history with the risk of chronic lymphocytic leukemia (CLL)
Authors: Kleinstern Geffen , Sanjosé Silvia de , Camp Nicola , Vajdic Claire M. , Call Timothy G. , Liebow Mark , Robinson Dennis , Kay Neil E. , Cunningham Julie , Benavente Yolanda , Monnereau Alain , Spinelli John , Cerhan James R. , Slager Susan L. 
Published: July 2017

Abstract
Background
Thirty-four single nucleotide polymorphisms (SNPs) are associated with CLL risk to-date. Moreover, family history (FH) of hematological malignancy has been consistently found to be associated with CLL, with an 8.5-fold increased risk of CLL among first-degree relatives. However, there has not been an evaluation of the interactive effects among genetic factors and FH with CLL risk.
Methods
We pooled data from 8 CLL case-control studies within the InterLymph Consortium (1499 CLL cases and 2601 controls). We computed a polygenic risk score (PRS), a weighted average of the number of risk alleles across the 34 SNPs, with the weights being the log of the previously reported odds ratio (OR) for each SNP. We categorized the PRS by quintiles using the cutoff points based on the distribution of all InterLymph controls (N=8228). Self-reported FH data was available for 60% of cases and 73% of controls. FH was defined as any hematological malignancy in one or more first-degree relative. Logistic regression was used to estimate ORs and 95% confidence intervals (CIs) adjusted for age, sex, socioeconomic status and study.
Results
The median age at diagnosis of CLL was 63 years and median age of consent was 60 years in the controls. 67% were male in CLL cases and 57% in controls. As expected, FH was associated with CLL risk (OR= 2.14, CI= 1.60-2.86). The median PRS in the cases was 0.40 and in the controls was -0.36 with the frequency of CLL cases in the upper PRS quintile as 48% while in the lowest quintile only 6%. The PRS was strongly associated with CLL risk (OR= 2.90, CI= 2.35-3.56 for upper versus middle quintile). When jointly modeling FH with PRS, a significant interaction was observed (P=0.03).
When stratifying by FH, the upper quintile of the PRS had an 11.8-fold (CI= 3.97-34.8) increased risk relative to those in the middle quintile in the FH+ strata, while a 3.11-fold (CI= 2.35-4.10) increased risk was observed in the FH- strata.
Conclusions
Our data suggest that the PRS has a strong association with CLL risk and this association varies with FH status. Among those with FH-, the risk of CLL was 3-fold for those with many inherited variants while the CLL risk was much higher than that in those with a FH+. Studies are needed to see whether this PRS stratifies risk among those with monoclonal B-cell lymphocytosis, the CLL precursor condition that affects 5-7% of the general population.
Citation Format: Geffen Kleinstern, Silvia de Sanjosé, Nicola Camp, Claire M. Vajdic, Timothy G. Call, Mark Liebow, Dennis Robinson, Neil E. Kay, Julie Cunningham, Yolanda Benavente, Alain Monnereau, John Spinelli, James R. Cerhan, Susan L. Slager. Association of polygenic risk scores and family history with the risk of chronic lymphocytic leukemia (CLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4267. doi:10.1158/1538-7445.AM2017-4267