DNA methylation profiles and cancer in children conceived after assisted reproductive technology

Epidemiological studies have shown a small but significantly increased risk of leukemia in children conceived by in vitro fertilization. Atypical DNA methylation patterns observed in pediatric cancers are suspected to occur in utero, and it is known that periconceptional conditions linked to assisted reproductive technologies (ART) are responsible for DNA methylation modifications.

Using databases and systematic literature screens, we derived a list of cancer/leukemia genes (n = 1246 and n = 532 genes, respectively, corresponding to 1466 individual genes) and of differentially methylated genes (DMG) in leukemia (n = 2642) and pre-leukemia (n = 381). These lists were cross-referenced with DMG (n = 93) curated from 18 ART Epigenome-Wide Association Studies (EWAS) (2369 samples). Among the ART DMG, more than one-third (n = 33) were leukemia, and six were pre-leukemia DMG, all representing a significant enrichment. Seven of the enriched genes (NTM, PRSS16, SCAND3, SYCP1, TP73, ZNF184, and ISL1-DT) showed concordant methylation between ART and leukemia/pre-leukemia. Moreover, five of the ART DMG are known targets for somatic/germline alterations in leukemia: ATP10A, CHD2, FBRSL1, FGFR2, and SORCS1. The ART DMG were not significantly enriched in cancer genes, supporting the hypothesis that ART may not link broadly to any cancer type but rather to leukemia.

This study indicates that relatively few genes that are known targets for somatic/germline mutation in cancer experience DNA methylation changes in individuals conceived through ART. By contrast, DNA methylation disturbances reported in leukemia represent more than one-third of those associated with ART conception, thus raising the question of their role in leukemia risk in ART-conceived individuals. Among them, a few critical genes such as TP73, a tumor suppressor, were shown to be targeted for hypermethylation, both in ART and leukemia, warranting further investigation.