Infertility and infertility treatment: childhood cancer and epigenetic risks.

Abstract

Although childhood cancer is rare, it can have a devastating impact on the children who develop it and their families. Just as in adults, cancer in children is comprised of many disease types. Since the window for exposure is quite limited in childhood cancer, exposures encountered in utero are likely to contribute to carcinogenesis. Thus, etiologic studies have focused on exposures that occur during pregnancy for cancers that arise early in life. Parental infertility and infertility treatment have been hypothesized as possible risk factors for childhood cancer. The link is suspected since many infertile couples may have specific genetic or epigenetic anomalies that could be passed on to their children, which in turn could lead to carcinogenesis. Infertility treatment occurs at or near conception and may persist for several days after conception, making it plausible for treatment to affect early embryo development. In addition, infertility or infertility treatment may alter epigenetic patterns in the developing embryo resulting in an increase risk of childhood cancer. All of these reasons suggest a need to examine infertility and its treatment further. Three related studies are combined in this thesis to examine the potential influence of infertility and infertility treatment on childhood cancer. The first two studies examined the potential link between infertility and its treatment and two specific childhood cancer diagnoses: infant leukemia and germ cell tumors (GCT). As these two diagnoses are quite rare, few previous studies have been performed to examine infertility or its treatment as a possible risk factor. Overall, no significant associations between infertility or its treatment and infant leukemia or childhood GCT were found. However, some notable subgroup associations were found in both studies. In infant leukemia, there was an increased risk of the rare MLL- subtype in children born to women not trying to conceive compared to those trying to conceive for less than one year for all types combined and for acute lymphoblastic leukemia (ALL). In contrast, there was a decreased risk of acute myeloid leukemia (AML) for children born to women who reported use of medication to help them become pregnant. In GCT, there was an increased risk for non-gonadal tumors in females born to women with at least two fetal losses. The final study examined DNA methylation as a potential mechanism by which assisted reproductive technology (ART) might influence the risk of childhood cancer. The data were consistent with no difference in methylation between groups at all loci for lymphocyte samples. Possible differences were found in buccal cell samples for two loci; IGF2 DMR0 and IGF2R. Subgroup analysis indicated potential lower methylation in those whose parents used ART for unexplained infertility. Correlation between lymphocyte and buccal cell samples was low for all loci. The combined results of all three studies indicate no increased risk of infant leukemia, pediatric germ cell tumors, or epigenetic disruptions in specific loci associated with Beckwith-Wiedemann syndrome and certain types of childhood cancer. While an association may still exist for different types of childhood cancer or methylation levels in other loci or tissues, these studies should reassure parents of children conceived through infertility treatment at least somewhat.