Enrichment of heterozygous germline RECQL4 loss-of-function variants in pediatric osteosarcoma

Abstract

Patients harboring germline pathogenic biallelic variants in genes involved in the recognition and repair of DNA damage are known to have a substantially increased cancer risk. Emerging evidence suggests that individuals harboring heterozygous variants in these same genes may also be at heightened, albeit lesser, risk for cancer. Herein, we sought to determine whether heterozygous variants in RECQL4, the gene encoding an essential DNA helicase that is defective in children with the autosomal recessive cancer-predisposing condition Rothmund–Thomson syndrome (RTS), are associated with increased risk for childhood cancer. To address this question, we interrogated germline sequence data from 4435 pediatric cancer patients at St. Jude Children's Research Hospital and 1127 from the National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and identified 24 (0.43%) who harbored loss-of-function (LOF) RECQL4 variants, including five of 249 (2.0%) with osteosarcoma (OS). These RECQL4 variants were significantly overrepresented in children with OS, the cancer most frequently observed in patients with RTS, as compared to 134,187 noncancer controls in the Genome Aggregation Database (gnomAD v2.1; P = 0.00087, odds ratio [OR] = 7.1, 95% CI, 2.9–17). Nine of the 24 (38%) individuals possessed the same c.1573delT (p.Cys525Alafs) variant located in the highly conserved DNA helicase domain, suggesting that disruption of this domain is central to oncogenesis. Altogether these data expand our understanding of the genetic factors predisposing to childhood cancer and reveal a novel association between heterozygous RECQL4 LOF variants and development of pediatric OS.

Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients

“…ABCB11 mutations also confer increased risk of developing HCC (72-77), but only in a recessive mode of inheritance, such as the FAH gene. Interestingly, emerging evidences suggest that individuals harboring germline variants in heterozygosity in autosomal recessive cancer predisposition genes may also be at increased cancer risk (78)(79)(80)(81)(82)(83).…”

“…These findings strongly suggest that pediatric/embryonal tumors and congenital anomalies share common etiologic factors underlying their development, and this is a relevant and ongoing discussion in the literature. Particularly, there is a relevant association between craniosynostosis and renal/genital anomalies with HB development (76)(77)(78)(79)(80), suggesting a yet unknown common molecular mechanism. In our cohort, five patients exhibited congenital renal anomalies, and the syndromic patient had craniosynostosis.…”

Compound Heterozygous Variants in Pediatric Cancers: A Systematic Review

“…The sequencing methods used were highly variable across the studies ( Table 3 and Supplementary Data 1:T1). Of the studies in this review, 10 indicated that they used one or more forms of NGS sequencing (whole-exome, whole-genome, RNA-seq) and thus were able to sample CH variants broadly (Valentine et al, 2014;Spinella et al, 2015;Zhang et al, 2015Zhang et al, , 2018Diets et al, 2018;Diness et al, 2018;Gröbner et al, 2018;Waszak et al, 2018;Maciaszek et al, 2019;Schieffer et al, 2019). Thirteen studies indicated that they used non-NGS methods (Sanger, Direct sequencing, SNP-array, Multiplex ligation-dependent probe amplification) and were therefore limited in the number of genes and CH variants analyzed (Quesnel et al, 1999;De Rosa et al, 2000;Østergaard et al, 2005;Okkels et al, 2006;Scott et al, 2007;Herkert et al, 2011;Leenen et al, 2011;Chmara et al, 2013;Bakry et al, 2014;Piane et al, 2016;Svojgr et al, 2016;Moriyama et al, 2017;Sharapova et al, 2018).…”

“…Across all studies, cancer types with more than 10 samples included AML, ALL, high-grade glioma, medulloblastoma (Valentine et al, 2014;Zhang et al, 2015;Diets et al, 2018;Gröbner et al, 2018). Thirteen studies evaluated a single patient (Quesnel et al, 1999;De Rosa et al, 2000;Okkels et al, 2006;Scott et al, 2007;Peters et al, 2009;Majumdar et al, 2010;Chmara et al, 2013;Piane et al, 2016;Diness et al, 2018;Salih et al, 2018;Sharapova et al, 2018;Maciaszek et al, 2019;Schieffer et al, 2019).…”

“…Germline cancer associations for RECQL4 include osteosarcoma, skin basal cell, and skin squamous cell ( Table 2). CH variants in RECQL4 have been associated with osteosarcoma in two studies (Salih et al, 2018;Maciaszek et al, 2019). TP53 is involved in many cancer pathways, and germline variation in this gene has been associated with a wide range of tumor types ( Table 2).…”