Ontogeny of Gene Expression: a Changing Environment for Malignancy

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Editorial

Ontogeny of Gene Expression: A Changing Environment for Malignancy

Logan G. Spector, Anthony J. Hooten, and Julie A. Ross Division of Epidemiology/Clinical Research, Department of Pediatrics and Cancer Center, University of Minnesota, Minneapolis, Minnesota

More than 13,000 children are estimated to be newly Kleinjans (26) previously offered a paradigmatic example diagnosed with cancer each year in the United States (1). of the cytochrome P450 (CYP) phase I enzyme family. Despite substantial improvements in survival over the Whereas the fetal liver expresses primarily CYP3A7, last several decades, cancer is still the leading cause of CYP3A4 and CYP3A5 predominate postnatally (26-28) death due to disease in children ages 1 to 14 years (2). The The expression of other phase I and phase II enzymes overall incidence rate for childhood cancer has increased varies by developmental stage and tissue as well (29, 30). significantly since the 1970s, and our recent analysis of Consideration of developmental differences in expres- Surveillance, Epidemiology, and End Results program sion is thus critical to the successful identification of data for the period 1992 to 2004 points to a continuing genes conferring susceptibility to childhood cancer increase (3). As we investigate potential causes, it is (or any disease with in utero origins). Genes expressed important to consider what we know thus far. exclusively or predominantly during gestation by Gestation is a critical window of risk for most the placenta (an organ of partly fetal origin), zygote childhood cancers. In utero initiation is supported (first 2 weeks following conception), embryo (3-8 weeks), circumstantially by the young age at diagnosis (4) as well or fetus may be preferentially selected for inclusion in as the histologic and cytogenetic resemblance of embry- candidate gene studies (see Fig. 1, derived from data in ref. onal tumor (5) and leukemia (6, 7) cells, respectively, to 31). Developmental expression data may also provide a those found during fetal development. Moreover, child- basis for assigning prior probabilities of association to hood cancers have been associated with congenital single nucleotide polymorphisms assessed in genome- anomalies in several studies (8-10). Proof-of-principle wide association studies (32), which will be especially has been shown by case reports of prenatal diagnosis of important for childhood cancers because their rarity limits several cancer types (11-19) and the detection of leukemic achievable sample size and opportunities for replication. translocations in biospecimens taken at birth (20). The Defining the ‘‘Human Gestational Transcriptome’’. well-known association of vaginal clear-cell carcinoma Given the necessity of considering ontogeny in suscepti- with prenatal diethylstilbestrol exposure extends the bility gene studies, the Children’s Oncology Group observation of prenatal carcinogenesis to a diagnosis Epidemiology Committee1 has adopted, as part of its made primarily during young adulthood (21). research agenda, the creation of a database of genes that are Accumulating evidence supports in utero initiation of mainly expressed during human prenatal development. common adult cancers as well. Birth weight, as a broad Several approaches to defining the ‘‘human gestational indicator of prenatal conditions, is an accessible, widely transcriptome,’’ and their limitations, are discussed below. examined datum and seems to be associated with cancer The compilation of existing studies through systematic at many sites (22). Animal experiments have shown that literature searches and extensive curation will be a maternal diet can modulate the risk of breast cancer in worthwhile start. The data to be recorded should include the offspring (23). Lastly, mathematical modeling of the organ or cell population that provided tissue, the carcinogenesis confirms that gestational mutations can stage of gestation, and the relative level of expression. In increase cancer risk by expanding the pool of cells an initial set of searches, we used the following terms: susceptible to complete transformation (24, 25). Human + Not Mice + Not Mouse + Ontogeny + Fet* + Developmental Differences in Gene Expression. Gene* Gene expression has been observed to vary widely bet- Human + Not Mice + Not Mouse + Ontogeny + Gest* + ween fetal and postnatal life, with much research seeming Gene* to concentrate on xenobiotic metabolism. Wild and Human + Not Mice + Not Mouse + Ontogeny + In Utero* + Gene* Human + Not Mice + Not Mouse + Ontogeny +

(Cancer Epidemiol Biomarkers Prev 2008;17(5):1021 – 3) Express* + Gene* Received 3/20/08; accepted 3/28/08. Requests for reprints: Logan G. Spector, Division of Epidemiology/Clinical Research, where * means root searches. Department of Pediatrics, University of Minnesota, 420 Delaware Street, Southeast, MMC 715, Minneapolis, MN 55455. Phone: 612-624-3912; Fax: 612-624-7147. E-mail: [email protected] Copyright D 2008 American Association for Cancer Research. 1 J.A. Ross is the Chairman and L.G. Spector is a member of the Steering doi:10.1158/1055-9965.EPI-08-0275 Committee.

Cancer Epidemiol Biomarkers Prev 2008;17(5). May 2008

Figure 1. Gestational windows of risk for childhood cancers.

References to expression studies in nonhuman, adult, be limited by a lack of tissue specificity (beyond blood or diseased tissues were manually screened out. As and placenta) and the inability to observe periods before of February 2008, we have identified more than parturition except among pregnancies at risk for poor 400 citations that included 152 unique genes. outcomes. Bioinformatic inquiries may be a useful complement. Determining tissue- and stage-specific gene expression Unigene is a National Center for Biotechnology Infor- profiles of developing animals presents no ethical mation catalogue of user-submitted expressed sequence constraints. Although it may be informative to examine tags grouped into gene-oriented clusters (33). In addition human orthologues of genes identified from test animals, to breaking down the frequency of expressed sequence it must be kept in mind that differences in gene tags by body site and disease state, Unigene classifies regulation seem to explain many of the differences in seven developmental stages, including blastocyst, development between species (40). embryo, and fetus. Restricted expression is denoted Lastly, some classes of genes may be designated a when a stage contributes a majority of expressed priori to be expressed by the developing human; for sequence tags to the pool. For instance, Unigene instance, the homeobox genes that regulate morphogen- identifies CYP3A7 (Unigene ID Hs.111944) as having esis (41). Genes that, when mutated, are embryonic lethal expression restricted to the fetus. Comparing the results or produce congenital abnormalities may also be as- of our literature search with Unigene, we noted that sumed relevant. 28 genes had a transcript level of at least 50 transcripts Conclusions. We have identified a clear need for the per million during the embryonic stage, whereas generation of more knowledge about gene expression 44 genes had this transcript level during the fetal stage. during human development. Having proposed several These data will be analyzed further to determine gene approaches to doing so, we are confident that a sustained, function and substrates, with consideration of single collaborative effort can produce this valuable informa- nucleotide polymorphisms that may affect expression. tion. The proposed endeavor can be expected to greatly A common limitation to the above approaches is the inform our understanding of childhood and adult cancer. inaccessibility of the developing human under normal circumstances. Many studies examining gene expression in the developing human are reticent about the source of Disclosure of Potential Conflicts of Interest tissue, making the extent to which reported results reflect disease states unclear. However, specimens obtained No potential conflicts of interest were disclosed. noninvasively or during frequently done intrauterine procedures hold the promise of providing information References on gene expression in a large number of healthy 1. Bleyer A, O’Leary M, Barr R, Ries LA, editors. Cancer epidemiology pregnancies. Cell-free mRNA has been isolated from in older adolescents and young adults 15-29 years of age, including amniotic fluid (34) and gene expression determined from SEER incidence and survival: 1975-2000. NIH Pub. No. 06-5767. Bethesda (MD): National Cancer Institute; 2006. chorionic villus samples (35). Fetal cells may also be 2. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J isolated from maternal blood(36); the small number of Clin 2008;58:71 – 96. circulating cells may not be an impediment because 3. Linabery AM, Ross JA. Trends in childhood cancer incidence in the quantifying gene expression even in a single cell is now U.S. (1992-2004). Cancer 2008;112:416 – 32. 4. Ries LAG, Eisner MP, Kosary CL, et al. SEER cancer statistics review, possible (37). Cord blood and placentas are, of course, 1975-2003. Bethesda (MD): National Cancer Institute; 2006. widely available and commonly scrutinized (38, 39). The 5. Pizzo PA, Poplack DG. Principles and practice of pediatric oncology. expression data obtained through these approaches will Philadelphia: Lippincott Williams & Wilkins; 2002.

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Cancer Epidemiol Biomarkers Prev 2008;17(5). May 2008

Logan G. Spector, Anthony J. Hooten and Julie A. Ross

Cancer Epidemiol Biomarkers Prev 2008;17:1021-1023.

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