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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, and EBF1) 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 the AHRR epigenetic 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.

SUBMITTER: de Smith AJ

PROVIDER: S-EPMC5380517 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia.

de Smith Adam J AJ Kaur Maneet M Gonseth Semira S Endicott Alyson A Selvin Steve S Zhang Luoping L Roy Ritu R Shao Xiaorong X Hansen Helen M HM Kang Alice Y AY Walsh Kyle M KM Dahl Gary V GV McKean-Cowdin Roberta R Metayer Catherine C Wiemels Joseph L JL

Cancer research 20170215 7

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, < ...[more]

PMID: 28202519

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Project description:Acute lymphoblastic leukemia (ALL) is the most frequent childhood cancer. For the last three decades, conventional cytogenetic and molecular approaches allowed the identification of genetic abnormalities having prognostic and therapeutic relevance. Although the current cure rate in pediatric B cell acute leukemia is approximately 90%, it remains one of the leading causes of mortality in childhood. Furthermore, in the contemporary protocols, chemotherapy intensity was raised to the maximal levels of tolerability, and further improvements in the outcome will depend on the characterization and reclassification of the disease, as well as on the development of new targeted drugs. The recent technological advances in genome-wide profiling techniques have allowed the exploration of the molecular heterogeneity of this disease, even though some potentially interesting biomarkers such as conjoined genes have not been deeply investigated yet. In the present study, we performed the transcriptome sequencing (RNA-seq) of 10 pediatric B cell precursor (BCP)-ALL cases with different risk (four standard- and six high-risk patients) enrolled in the Italian AIEOP-BFM ALL2000 protocol, in order to characterize the full spectrum of transcriptional events and to identify novel potential genetic mechanisms sustaining their different early response to therapy. Total RNA was extracted from primary leukemic blasts and RNA-seq was performed by Illumina technology. Bioinformatics analysis focused on fusion transcripts, originated from either inter- or intra-chromosomal structural rearrangements. Starting from a raw list of 9001 candidate events, by employing a custom-made bioinformatics pipeline, we obtained a short list of 245 candidate fusions. Among them, 10 events were compatible with chromosomal translocations. Strikingly, 235/245 events were intra-chromosomal fusions, 229 of which involved two contiguous or overlapping genes, resulting in the so-called conjoined genes (CGs). To explore the specificity of these events in leukemia, we performed an extensive bioinformatics meta-analysis and evaluated the presence of the fusions identified in our 10 BCP-ALL cohort in several other publicly available RNA-seq datasets, including leukemic, solid tumor and normal sample collections. Overall, 14/229 (6.1%) CGs were found to be exclusively expressed in leukemic cases, suggesting an association between CGs and leukemia. Moreover, CGs were found to be common events both in standard- and high-risk BCP-ALL patients and it might be suggestive of a novel potential transcriptional regulation mechanism active in leukemic cells.

Project description:Background: How prenatal smoke exposure affects DNA methylation leading to atopic disorders remains to be addressed. Epigenetic biomarkers informative of prenatal smoke exposure and atopic disorders are wanting. Since most children suffering from atopic dermatitis (AD) continue to develop asthma later in life, we explored whether prenatal smoke exposure e induces DNA methylation and searched for predictive epigenetic biomarkers for smoke related atopic disorders. Methods: Methylation differences associated with smoke exposure were screened by Illumina methylation panel for children from the Taiwan birth panel study cohort initially. Information about development of atopic dermatitis (AD) and risk factors were collected. Cord blood cotinine levels were measured to represent prenatal smoke exposure. CpG loci that demonstrated a statistically significant difference in methylation were validated by methylation-dependent fragment separation (MDFS). Differential methylation in three genes (TSLP, GSTT1, and CYB5R3) was identified through the screen and their functions were investigated. Results: Among these, only thymic stromal lymphopoietin (TSLP) gene displayed significant difference in promoter methylation percentage after being validated by MDFS (p=0.029). TSLP gene was further investigated in a larger sample of 92 children from the cohort. Methylation status of the TSLP 5′-CpG island (CGI) was found to be significantly associated with prenatal smoke exposure (OR=3.59, 95%CI=1.49-8.64; cotinine level 0.10 ng/ml, sensitivity= 77%; specificity = 61%) and with AD (OR=4.77, 95%CI=1.47-15.53). The degree of TSLP 5′CGI methylation inversely correlated with TSLP protein expression levels (per unit: β=－6.69 ng/ml; 95% CIs, －12.80~－0.59; p=0.032). Conclusions: The effect of prenatal tobacco smoke exposure on the risk for AD may be mediated through DNA methylation. Cord blood methylated TSLP 5′CGI may be a potential epigenetic biomarker for environmentally-related atopic disorders.

Dataset Information

Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia.

Publications

Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia.

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