Abstract 4516: Rare high-penetrance and common low-penetrance variants associated with risk of pediatric acute lymphoblastic leukemia
Authors: Wang Zhaoming , Chen Cheng , Qin Na , Song Nan , Wang Hui , Armstrong Gregory T. , Ness Kirsten K. , Hudson Melissa M. , Zhang Jinghui , Robison Leslie L. , Im Cindy 
Published: April 2023

Abstract
Leveraging existing genetic data for survivors of pediatric acute lymphoblastic leukemia (ALL) from the St. Jude Lifetime Cohort Study (SJLIFE) and Childhood Cancer Survivor Study (CCSS; the CCSS original cohort data was downloaded from dbGaP, phs001327.v2), genetic variants across the full allelic spectrum were analyzed for their associations with ALL risk. A total of 2,695 ALL cases with whole-genome or whole-exome sequencing were available for rare variant analyses. Pathogenic/likely pathogenic (P/LP) variants in 60 genes associated with autosomal dominant cancer predisposition syndromes were characterized and classified with “PeCanPIE” - the Pediatric Cancer Variant Pathogenicity Information Exchange, a web- and cloud-based platform. We subsequently carried out an enrichment analysis of P/LP variants by comparing ALL survivors with a general population from the GnomAD database and found seven significant genes after adjustment for multiple testing (P&lt; 8.3 × 10-4, i.e., 0.05/60) including: BRCA1 (odds ratio [OR]=4.06; 95% CI, 2.00-7.59; P=1.21 × 10-4), BRCA2 (OR=3.48; 95% CI, 1.82-6.15; P=1.50 × 10-4), CDKN2A (OR=22.30; 95% CI, 5.13-96.68; P=3.07 × 10-5), PALB2 (OR=5.12; 95% CI, 2.39-10.00, P=3.77 × 10-5), PAX5 (OR=44.58; 95% CI, 6.49-490.68; P=4.77 × 10-5), PTPN1 (OR=66.85; 95% CI, 11.96-670.57, P=1.63 × 10-7), and TP53 (OR=17.86; 95% CI, 6.12-50.36; P=3.43 × 10-7). Two of these genes have also been previously linked with pediatric ALL (CDKN2A and TP53). Repeating these analyses with 309 newly diagnosed patients from the Pediatric Cancer Genome Project, we observed similar results for five of these genes (BRCA1, BRCA2, CDKN2A, PALB2, and TP53). To further investigate common germline variants associated with ALL risk, we performed a genome-wide association analysis using 2,777 ALL cases and 6,255 controls (5,881 other pediatric cancer cases and 374 non-cancer controls) with whole-genome sequencing or imputed SNP-array data. In addition to replicating known associations at ARID5B, IKZF1, CDKN2A, BMI1, PIP4K2A, CCDC26 and CEPBE, we identified a novel variant (rs112425636, chr17:82324152:G:A; OR=1.65; 95% CI, 1.42-1.93; P=2.48 × 10-10) mapped to the intronic region of SECTM1 gene. Based on RNA sequencing data for 164 pediatric hematological cancer samples, we found that the expression of SECTM1 gene was significantly higher among patients with GG genotype than patients with AA or AG genotypes for rs112425636 (FPKM=1.34 vs. 0.71, P&lt;0.01). Among the subset of 32 B-ALL samples, the magnitude of difference was larger (FPKM=1.90 vs. 0.70, P=0.017). In summary, we found statistical evidence for several cancer predisposition genes harboring rare high-penetrance variants and a novel common low-penetrance variant associated with risk of pediatric ALL. Our novel findings add new knowledge to the full allelic spectrum of genetic architecture of pediatric ALL susceptibility.
Citation Format: Zhaoming Wang, Cheng Chen, Na Qin, Nan Song, Hui Wang, Gregory T. Armstrong, Kirsten K. Ness, Melissa M. Hudson, Jinghui Zhang, Leslie L. Robison, Cindy Im. Rare high-penetrance and common low-penetrance variants associated with risk of pediatric acute lymphoblastic leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4516.