title: Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia.
abstract: Tobacco smoke exposure has been associated with risk of childhood acute lymphoblastic leukemia (ALL). Understanding the relationship between tobacco exposures and specific mutations may yield etiologic insights. We carried out a case-only analysis to explore whether prenatal and early-life tobacco smoke exposure influences the formation of leukemogenic genomic deletions. Somatic copy number of 8 genes frequently deleted in ALL (CDKN2A,ETV6,IKZF1,PAX5,RB1,BTG1, PAR1 region, andEBF1) was assessed in 559 pretreatment tumor samples from the California Childhood Leukemia Study. Parent and child's passive tobacco exposure was assessed using interview-assisted questionnaires as well as DNA methylation in aryl-hydrocarbon receptor repressor (AHRR), a sentinel epigenetic biomarker of exposure to maternal smoking during pregnancy. Multivariable Poisson regressions were used to test the association between the smoking exposures and total number of deletions. Deletion burden varied by subtype, with a lower frequency in high-hyperdiploid and higher frequency in ETV6-RUNX1 fusion ALL. The total number of deletions per case was positively associated with tobacco smoke exposure, in particular for maternal ever-smoking (ratio of means, RM, 1.31; 95% CI, 1.08-1.59), maternal smoking during pregnancy (RM, 1.48; 95% CI, 1.12-1.94), and during breastfeeding (RM, 2.11; 95% CI, 1.48-3.02). The magnitude of association with maternal ever-smoking was stronger in male children compared with females (Pinteraction= 0.04). The total number of deletions was also associated with DNA methylation at theAHRRepigenetic biomarker (RM, 1.32; 95% CI, 1.02-1.69). Our results suggest that prenatal and early-life tobacco smoke exposure increase the frequency of somatic deletions in children who develop ALL.Cancer Res; 77(7); 1674-83. ©2017 AACR.
authors.affiliation: Department of Epidemiology and Biostatistics, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California. adam.desmith@ucsf.edu.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: de Smith
authors.affiliation: School of Public Health, University of California Berkeley, Berkeley, California.
authors.forename: Maneet
authors.initials: M
authors.lastname: Kaur
authors.affiliation: School of Public Health, University of California Berkeley, Berkeley, California.
authors.forename: Semira
authors.initials: S
authors.lastname: Gonseth
authors.affiliation: Department of Epidemiology and Biostatistics, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: Alyson
authors.initials: A
authors.lastname: Endicott
authors.affiliation: School of Public Health, University of California Berkeley, Berkeley, California.
authors.forename: Steve
authors.initials: S
authors.lastname: Selvin
authors.affiliation: School of Public Health, University of California Berkeley, Berkeley, California.
authors.forename: Luoping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Computational Biology Core, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: Ritu
authors.initials: R
authors.lastname: Roy
authors.affiliation: School of Public Health, University of California Berkeley, Berkeley, California.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Shao
authors.affiliation: Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Hansen
authors.affiliation: School of Public Health, University of California Berkeley, Berkeley, California.
authors.forename: Alice Y
authors.initials: AY
authors.lastname: Kang
authors.affiliation: Department of Epidemiology and Biostatistics, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.|Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walsh
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Gary V
authors.initials: GV
authors.lastname: Dahl
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Roberta
authors.initials: R
authors.lastname: McKean-Cowdin
authors.affiliation: School of Public Health, University of California Berkeley, Berkeley, California.
authors.forename: Catherine
authors.initials: C
authors.lastname: Metayer
authors.affiliation: Department of Epidemiology and Biostatistics, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.|Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
mesh_terms: D000293:Adolescent; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005333:Fetus / Q000187:drug effects; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D008297:Male; D016012:Poisson Distribution; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000235:genetics; D011247:Pregnancy; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D014028:Tobacco Smoke Pollution; D000097764:ETS Translocation Variant 6 Protein; C492162:AHRR protein, human; C493728:RUNX1 protein, human