Fetal Exposure to Cigarette Smoke Causes Genetic Changes, Raises Risk of Pediatric ALL

Exposure to tobacco smoke as a fetus or during early childhood can cause genetic changes that can increase a child’s risk of developing acute lymphoblastic leukemia (ALL), the most common type of pediatric cancer.

ALL is diagnosed in about 3100 children and teens in the United States. Despite a 75% and 90% 5-year survival rate among children under 15 years and those between 15 and 19 years, respectively, it’s the long-term risk of secondary cancers that can be life threatening.

Research conducted at the University of California San Francisco has identified key changes in the genetic make-up of pretreatment tumor samples of 559 children who were enrolled in the California Childhood Leukemia Study. The researchers analyzed the tumor samples for somatic copy numbers of 8 genes that are most commonly deleted in ALL: CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1.

A questionnaire was developed, directed at both the parents and the children, to assess passive tobacco exposure. Additionally, the samples were analyzed for DNA methylation in the aryl-hydrocarbon receptor repressor (AHRR) gene—an epigenetic biomarker that measures fetal exposure to maternal smoking.

The study found a positive association between the number of deletions per case and tobacco smoke exposure, especially when the mother smoked all the time (ratio of means, RM, 1.31; 95% CI, 1.08-1.59), mother smoked during pregnancy (RM, 1.48; 95% CI, 1.12-1.94), and when she smoked during breastfeeding (RM, 2.11; 95% CI, 1.48-3.02). The authors noted a stronger association between a mother who remained a smoker and her male child with ALL. Also, the total number of deletions were associated with DNA methylation of AHRR.

Adam de Smith, PhD, assistant researcher in the Department of Epidemiology and Biostatistics at the UCSF Helen Diller Family Comprehensive Cancer Center, said that while the link between ALL and parental smoking has already been established, their study is the first study to identify specific genetic changes in the tumor cells of children with ALL.

The study also noted a link between pre-conception smoking by the father and the child’s age at diagnosis. “Our results suggest that paternal pre-conception smoking, which is known to cause oxidative damage to sperm DNA, may lead to a higher propensity of deletions in children with earlier-onset ALL,” de Smith explained.

He acknowledged, however, that smoking is just one of the risk factors for ALL, in addition to the child’s internal genetic makeup, infections, pesticides and other environmental factors, adding, “If there was no smoking in the environment, then there would likely be fewer children with the disease.”

Reference

de Smith AJ, Kaur M, Gonseth S, et al. Correlates of prenatal and early-life tobacco smoke exposure and frequency of common gene deletions in childhood acute lymphoblastic leukemia. Cancer Res. 2017;77(7):1674-1683. doi: 10.1158/0008-5472.CAN-16-2571.