Tobacco Smoke and Ras Mutations Among Latino and Non-Latino Children with Acute Lymphoblastic Leukemia

Abstract

Background and Aims Childhood acute lymphoblastic leukemia (ALL) is a biologically heterogeneous disease, and mutations in the KRAS and NRAS oncogenes are present at diagnosis in about one-fifth of cases. Ras mutations were previously associated with environmental exposures in leukemias as well as in many other cancer types. This study examined whether Ras mutation could define a unique etiologic group of childhood ALL associated with tobacco smoke, a well-established mutagen and carcinogen. Methods We included 670 children with ALL enrolled in a case-control study in California (1995–2013), including 50.6% Latinos. Parental and child exposure to tobacco smoke was obtained from interviews. Sanger sequencing was used to detect the common KRAS and NRAS hotspot mutations in diagnostic bone marrow DNA. ALL cases were also characterized for common chromosome abnormalities. In case-case analyses, logistic regression analyses were used to estimate odds ratios to describe the association between tobacco smoke exposure and childhood ALL with Ras mutations. Results KRAS or NRAS mutations were detected in ~18% of children diagnosed with ALL. Ras mutations were more common among Latino cases compared with non-Latino whites and in high-hyperdiploid ALL. No associations were observed between parental smoking or child’s passive exposure to smoke and Ras positive ALL. Conclusions The apparent lack of association between tobacco smoke and Ras mutation in childhood ALL suggests that Ras mutations do not specifically define a tobacco-related etiologic pathway. Reasons for racial and ethnic differences in ALL are not well understood and could reflect differences in etiology that warrant further examination.

Is There Etiologic Heterogeneity between Subtypes of Childhood Acute Lymphoblastic Leukemia? A Review of Variation in Risk by Subtype

“…Deletions are more common among B-ALL (13%) than T-ALL (5%) cases and variation by cytogenomic subtype has been reported with over 80% BCR-ABL1-positive (58-60) and 70%-80% of BCR-ABL1-like ALL (53) cases harboring an IKZF1 deletions. Mutations in Ras family members are also found in 20%-30% of childhood ALL cases (61). Mutations are found more frequently in Latino children and among children diagnosed with high hyperdiploid ALL (61).…”

“…Mutations in Ras family members are also found in 20%-30% of childhood ALL cases (61). Mutations are found more frequently in Latino children and among children diagnosed with high hyperdiploid ALL (61). While characterizing deletion and mutation frequencies of the aforementioned genes in conjunction with cytogenomic abnormalities has begun, data on variation in deletion status by age, race, and sex are lacking.…”

Childhood Leukemia and Primary Prevention

“…Metabolites that adduct to DNA can directly cause miscoding mutations if unrepaired, or can result in repair-induced strand breaks. There is little current evidence that point mutations such as those found in RAS are caused by environmental chemicals 26 ; however, the most common translocation in ALL, ETV6-RUNX1 , appears to be strongly and specifically associated with parental smoking 27 and home paint use 28,29 , which provides some credence to viability of this pathway.…”