Early-life tobacco exposure is causally implicated in aberrant RAG-mediated recombination in childhood acute lymphoblastic leukemia.

Autor:	de Smith A; University of Southern California., Liu T; University of Southern California., Xu K; University of Southern California., Pardeshi A; University of Southern California., Myint SS; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore., Kang A; University of California Berkeley., Morimoto L; UC Berkelely., Lieber M; Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine., Wiemels J; USC Keck School of Medicine., Kogan S; University of California San Francisco., Metayer C; University of California.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 Jun 20. Date of Electronic Publication: 2024 Jun 20.
DOI:	10.21203/rs.3.rs-4510345/v1
Abstrakt:	Acute lymphoblastic leukemia (ALL) is the most common cancer in children, yet few environmental risk factors have been identified. We previously found an association between early-life tobacco smoke exposure and frequency of somatic deletions of 8 leukemia driver genes among childhood ALL patients in the California Childhood Leukemia Study. To expand analysis genome-wide and examine potential mechanisms, we conducted tumor whole-genome sequencing in 35 ALL patients, including 18 with high prenatal tobacco exposure and 17 with low exposure as determined by established epigenetic biomarkers. High tobacco exposure patients had significantly more structural variants (P < .001) and deletions (P = .001) genome-wide than low exposure patients. Investigation of off-target RAG recombination revealed that 41% of deletions in the high tobacco exposure patients were putatively RAG-mediated (full RAG motif identified at one or both breakpoints) compared with only 21% in the low exposure group (P = .001). In a multilevel model, deletions in high tobacco exposure patients were 2.44-fold (95% CI:1.13-5.38) more likely to be putatively RAG-mediated than deletions in low exposure patients. No point mutational signatures were associated with prenatal tobacco exposure. Our findings suggest that early-life tobacco smoke exposure may promote leukemogenesis by driving development of somatic deletions in pre-leukemic lymphocytes via off-target RAG recombination. Competing Interests: Competing interests: The authors declare no competing interests in relation to the work described.
Databáze:	MEDLINE
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