RECQL4 encodes an essential helicase that repairs DNA damage and maintains genomic stability. Biallelic pathogenic germline mutations in RECQL4 cause the autosomal recessive (AR) Rothmund-Thomson, Baller-Gerold, and RAPADILINO syndromes. Predisposition to cancer has been observed in all three syndromes, with osteosarcoma (OS) representing the greatest risk.

Monoallelic pathogenic variants in DNA damage response genes (e.g., ATM, NBN) are associated with a moderate increase in cancer risk. Building upon this notion, we sought to determine whether monoallelic RECQL4 loss of function (LOF) variants contribute to childhood cancer, particularly OS. Here, LOF variants were defined as nonsense, frameshift, or canonical splice altering variants that are classified as pathogenic or likely pathogenic based on the 2015 ACMG Guidelines. Among 4,436 pediatric cancer patients at St. Jude and 1,127 in the National Cancer Institute TARGET database (total: 5,563 patients), we identified 20 individuals (0.36%; tumor types in Table) harboring germline monoallelic RECQL4 LOF variants. Compared to reference controls in the Genome Aggregation Database (gnomAD), we observed an enrichment of RECQL4 LOF variants in pediatric cancer patients (P = 0.046, prevalence ratio [PR] = 1.51). We next assessed for enrichment of RECQL4 LOF variants across tumor types (Table). This examination revealed a significant association between monoallelic RECQL4 mutations and leukemia (P = 0.032, PR = 1.91) and more notably, with OS (P = 0.0028, PR = 7.03) where 1.7% of pediatric OS patients carried monoallelic RECQL4 LOF variants. No evidence of association was observed for the other tumor types examined.

Our data provide the first evidence of an association linking germline monoallelic RECQL4 LOF variants to childhood cancer, especially OS. Examination of larger cohorts are warranted to elucidate the extent to which these mutations increase the risk for leukemia and OS and the mechanisms by which they promote tumor formation.

 Pediatric Cancer Patients gnomADControls Cancer Risk(Fisher’s Exact Test) 
 Average age at cancer diagnosis (range) Carriers,RECQL4mut/wt Total Patients,RECQL4wt/wt Carriers, RECQL4mut/wt Total Controls, RECQL4wt/wt Prevalence Ratio (95% CI) P Value 
All cancers 7 (0.3 - 18) 20 5563 281 120659 1.51 (0.99, 2.30) 0.046 
OS 10 (6 - 16) 243 281 120659 7.03 (2.65, 18.69) 0.0028 
CNS tumor 579 281 120659 0.74 (0.10, 5.26) 0.74 
GCT 0.3 75 281 120659 5.74 (0.81, 40.88) 0.16 
Leukemia 4 (3 - 11) 11 2431 281 120659 1.91 (1.07, 3.41) 0.032 
Lymphoma 10 (7 - 18) 586 281 120659 2.19 (0.71, 6.76) 0.16 
 Pediatric Cancer Patients gnomADControls Cancer Risk(Fisher’s Exact Test) 
 Average age at cancer diagnosis (range) Carriers,RECQL4mut/wt Total Patients,RECQL4wt/wt Carriers, RECQL4mut/wt Total Controls, RECQL4wt/wt Prevalence Ratio (95% CI) P Value 
All cancers 7 (0.3 - 18) 20 5563 281 120659 1.51 (0.99, 2.30) 0.046 
OS 10 (6 - 16) 243 281 120659 7.03 (2.65, 18.69) 0.0028 
CNS tumor 579 281 120659 0.74 (0.10, 5.26) 0.74 
GCT 0.3 75 281 120659 5.74 (0.81, 40.88) 0.16 
Leukemia 4 (3 - 11) 11 2431 281 120659 1.91 (1.07, 3.41) 0.032 
Lymphoma 10 (7 - 18) 586 281 120659 2.19 (0.71, 6.76) 0.16 

OS = osteosarcoma; CNS tumor = central nervous system tumor; GCT = germ cell tumor

Citation Format: Jamie L. Maciaszek, Gang Wu, Kayla Hamilton, Rose B. McGee, Zhaoming Wang, Regina Nuccio, Stacy Hines-Dowell, Lynn Harrison, Elsie L. Gerhardt, Annastasia Ouma, Scott Newman, Aman Patel, Joy Nakitandwe, Elizabeth Azzato, Alberto S. Pappo, Sheila A. Shurtleff, David W. Ellison, James R. Downing, Melissa M. Hudson, Leslie L. Robison, Victor Santana, Jinghui Zhang, Kim E. Nichols, Chimene A. Kesserwan. Increased prevalence of germline monoallelic RECQL4 mutations in children with cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3651.