As part of World Cancer Day (4th Feb), the journal of Molecular Oncology invited researchers to take part in a writing competition aimed at highlighting the impact of the exposome on cancer risk. This entry, by Roya Dolatkhah (IARC/WHO, France), received an Honourable Mention.

Leukemia is the most common cancer among children, yet it remains a rare and heterogeneous disease with unclear risk factors[1, 2]. The chromosomal translocation t(12;21)(p13;q22), resulting in the ETV6/RUNX1 (also known as TEL/AML1) fusion gene, is the most common structural chromosomal alteration in childhood leukemia, occurring in 17-25% of pediatric B-cell acute lymphoblastic leukemia (B-ALL) cases[3]. This makes it one of the most common, recurrent, and non-random translocations associated with childhood leukemia. Several studies have been conducted on the clinical significance and prognostic implications of the ETV6/RUNX1 fusion gene. Findings suggest that the TEL/AML1 gene is an independent factor associated with a favorable prognosis, higher overall survival rates, and a lower relapse rate[4, 5],indicating that these cases should be treated less aggressively[6].

Analysis of the genomic sequence of TEL/AML1 suggests that the predominant mechanism for this chromosomal translocation is the breakage of double-stranded DNA followed by error-prone repair through nonhomologous recombination. Although the specific mechanisms governing chromosomal changes in utero remain elusive, this translocation primarily affects pediatric patients aged one to 12, peaking between two to five years[7, 8]. This suggests that postnatal exposures or ‘promotional’ events are critical in precipitating secondary genetic transformations. However, the association between prenatal environmental, occupational, and domestic exposures and the risk of developing the TEL/AML1 fusion gene remains unclear[7, 8].

Epidemiological studies investigating the causes of childhood leukemia often lack sufficient statistical power. To overcome this limitation, the Childhood Leukemia International Consortium (CLIC) was established to pool data from various studies[9]. Some CLIC studies have found an association between exposure to home paint during pregnancy and after birth and an increased risk of ETV6/RUNX1 translocations, with odds ratios (OR) of 1.51 (95% CI: 1.08, 2.11) and 1.60 (95% CI: 1.16, 2.21) respectively[10]. Exposure to household pesticides during pregnancy was also associated with an increased risk of the TEL/AML1 fusion gene in offspring (OR = 1.67; 95% CI: 1.23, 2.26). Furthermore, there appeared to be minimal evidence suggesting that associations with coffee or tea consumption differed among childhood leukemia cases, regardless of the presence of this translocation[11]. However, an analysis of cancer risk for children living near vineyards in France found no significant association between childhood acute lymphoblastic leukemia and proximity to vineyards, based on the presence of the ETV6/RUNX1 transcript[12, 13].

Although no consensus has yet emerged, evidence increasingly suggests that infections may impact the risk of childhood acute lymphoblastic leukemia (ALL)[8]. The association between proxies of exposure to infections and the risk of childhood leukemia has been evaluated in several studies. These studies generally support the hypothesis that conditions leading to immune system maturation during infancy may protect against ALL. Moreover, factors such as daycare attendance and early common infections were negatively associated with childhood leukemia risk[14-17]. No definitive association has been identified between vaccination or immunization and the risk of childhood cancers. Additionally, research conducted by Metayer et al., which included a large cohort of childhood leukemia cases, suggested that the association with ALL varied according to parental educational levels, reflecting differences in lifestyle and socio-demographic characteristics[18]. To date, no direct link has been established between the TEL/AML1 fusion gene and infections, vaccinations, or immunizations. Environmental exposures may be associated with the ETV6/RUNX1 fusion gene risk. However, the outstanding challenge is identifying relevant exposures and deciphering how and when each contributes to the multistage development of this translocation, as this knowledge could lead to preventive interventions[1, 2].

References

1. Marcotte EL, Spector LG, Mendes-de-Almeida DP, Nelson HH. The Prenatal Origin of Childhood Leukemia: Potential Applications for Epidemiology and Newborn Screening. Front Pediatr. 2021;9:639479. Epub 2021/05/11. doi: 10.3389/fped.2021.639479. PubMed PMID: 33968846; PubMed Central PMCID: PMCPMC8102903.
2. Schraw JM, Bailey HD, Bonaventure A, Mora AM, Roman E, Mueller BA, et al. Infant feeding practices and childhood acute leukemia: Findings from the Childhood Cancer & Leukemia International Consortium. Int J Cancer. 2022;151(7):1013-23. Epub 2022/05/10. doi: 10.1002/ijc.34062. PubMed PMID: 35532209.
3. Brown P. TEL-AML1 in cord blood: 1% or 0.01%? Blood. 2011;117(1):2-4. Epub 2011/01/08. doi: 10.1182/blood-2010-09-304337. PubMed PMID: 21212287.
4. Al-Sweedan SA, Neglia JP, Steiner ME, Bostrom BC, Casey T, Hirsch BA. Characteristics of patients with TEL-AML1-positive acute lymphoblastic leukemia with single or multiple fusions. Pediatr Blood Cancer. 2007;48(5):510-4. Epub 2006/06/10. doi: 10.1002/pbc.20911. PubMed PMID: 16763978.
5. Ozbek U, Sirma S, Agaoglu L, Yuksel L, Anak S, Yildiz I, et al. Prognostic significance of the TEL-AML1 fusion gene in pediatric acute lymphoblastic leukemia in Turkey. J Pediatr Hematol Oncol. 2003;25(3):204-8. Epub 2003/03/07. doi: 10.1097/00043426-200303000-00005. PubMed PMID: 12621238.
6. Borkhardt A, Harbott J, Lampert F. Biology and clinical significance of the TEL/AML1 rearrangement. Curr Opin Pediatr. 1999;11(1):33-8. Epub 1999/03/20. doi: 10.1097/00008480-199902000-00008. PubMed PMID: 10084082.
7. Sun C, Chang L, Zhu X. Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse. Oncotarget. 2017;8(21):35445-59. Epub 2017/04/19. doi: 10.18632/oncotarget.16367. PubMed PMID: 28418909; PubMed Central PMCID: PMCPMC5471068.
8. Zelent A, Greaves M, Enver T. Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia. Oncogene. 2004;23(24):4275-83. Epub 2004/05/25. doi: 10.1038/sj.onc.1207672. PubMed PMID: 15156184.
9. Metayer C, Milne E, Clavel J, Infante-Rivard C, Petridou E, Taylor M, et al. The Childhood Leukemia International Consortium. Cancer Epidemiol. 2013;37(3):336-47. Epub 2013/02/14. doi: 10.1016/j.canep.2012.12.011. PubMed PMID: 23403126; PubMed Central PMCID: PMCPMC3652629.
10. Bailey HD, Metayer C, Milne E, Petridou ET, Infante-Rivard C, Spector LG, et al. Home paint exposures and risk of childhood acute lymphoblastic leukemia: findings from the Childhood Leukemia International Consortium. Cancer Causes Control. 2015;26(9):1257-70. Epub 2015/07/03. doi: 10.1007/s10552-015-0618-0. PubMed PMID: 26134047; PubMed Central PMCID: PMCPMC5257283.
11. Milne E, Greenop KR, Petridou E, Bailey HD, Orsi L, Kang AY, et al. Maternal consumption of coffee and tea during pregnancy and risk of childhood ALL: a pooled analysis from the childhood Leukemia International Consortium. Cancer Causes Control. 2018;29(6):539-50. Epub 2018/03/31. doi: 10.1007/s10552-018-1024-1. PubMed PMID: 29600472.
12. Mancini M, Hémon D, de Crouy-Chanel P, Guldner L, Faure L, Clavel J, et al. Association between Residential Proximity to Viticultural Areas and Childhood Acute Leukemia Risk in Mainland France: GEOCAP Case-Control Study, 2006-2013. Environ Health Perspect. 2023;131(10):107008. Epub 2023/10/18. doi: 10.1289/ehp12634. PubMed PMID: 37850750; PubMed Central PMCID: PMCPMC10583703.
13. Bailey HD, Infante-Rivard C, Metayer C, Clavel J, Lightfoot T, Kaatsch P, et al. Home pesticide exposures and risk of childhood leukemia: Findings from the childhood leukemia international consortium. Int J Cancer. 2015;137(11):2644-63. Epub 2015/06/11. doi: 10.1002/ijc.29631. PubMed PMID: 26061779; PubMed Central PMCID: PMCPMC4572913.
14. Ajrouche R, Rudant J, Orsi L, Petit A, Baruchel A, Lambilliotte A, et al. Childhood acute lymphoblastic leukaemia and indicators of early immune stimulation: the Estelle study (SFCE). Br J Cancer. 2015;112(6):1017-26. Epub 2015/02/13. doi: 10.1038/bjc.2015.53. PubMed PMID: 25675150; PubMed Central PMCID: PMCPMC4366894.
15. Perrillat F, Clavel J, Auclerc MF, Baruchel A, Leverger G, Nelken B, et al. Day-care, early common infections and childhood acute leukaemia: a multicentre French case-control study. Br J Cancer. 2002;86(7):1064-9. Epub 2002/04/16. doi: 10.1038/sj.bjc.6600091. PubMed PMID: 11953850; PubMed Central PMCID: PMCPMC2364194.
16. Rudant J, Lightfoot T, Urayama KY, Petridou E, Dockerty JD, Magnani C, et al. Childhood acute lymphoblastic leukemia and indicators of early immune stimulation: a Childhood Leukemia International Consortium study. Am J Epidemiol. 2015;181(8):549-62. Epub 2015/03/04. doi: 10.1093/aje/kwu298. PubMed PMID: 25731888; PubMed Central PMCID: PMCPMC4850899.
17. Rudant J, Orsi L, Menegaux F, Petit A, Baruchel A, Bertrand Y, et al. Childhood acute leukemia, early common infections, and allergy: The ESCALE Study. Am J Epidemiol. 2010;172(9):1015-27. Epub 2010/09/03. doi: 10.1093/aje/kwq233. PubMed PMID: 20807738.
18. Metayer C, Milne E, Dockerty JD, Clavel J, Pombo-de-Oliveira MS, Wesseling C, et al. Maternal supplementation with folic acid and other vitamins and risk of leukemia in offspring: a Childhood Leukemia International Consortium study. Epidemiology. 2014;25(6):811-22. Epub 2014/09/11. doi: 10.1097/EDE.0000000000000141. PubMed PMID: 25207954; PubMed Central PMCID: PMCPMC5903563.

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