part 2. mechanisms of carcinogenesis

chapter 20 Age and susceptibility Jerry M. Rice and Zdenko Herceg PART 2 CHAPTER 20

Introduction with chemical agents. Experimental fetus or infant than that experienced evidence for susceptibility in utero by the mother. There is abundant experimental evi­ and during infancy to chemical car­ However, in some cases the tu­ dence from studies in animals, espe­ cinogens and, to a lesser extent, to mours that result from prenatal or cially rats and mice, that susceptibili­ various sources of ionizing radiation perinatal exposures are different ty to certain chemical carcinogens is has been summarized in reviews and from those that occur in exposed higher, and sometimes much higher, symposium proceedings (Tomatis adults. Tumours induced prenatally during prenatal and early postnatal and Mohr, 1973; Rice, 1979; Napal­ become manifest only during adult life than in adulthood. There is also an kov et al., 1989; Rice, 2004). life in rats and mice, except in certain extensive epidemiological literature At least in experimental animals, genetically modified strains, because on the differential effects of a wide greater susceptibility to chemical in these species the interval between variety of carcinogens in humans at carcinogens in utero and during birth and sexual maturity is only a different stages of life, including var­ early postnatal life is usually man­ few weeks. Therefore, the types of ious forms of radiation, carcinogen­ ifested as a higher incidence of the tumours that occur during childhood ic infectious agents, and chemicals same kinds of tumours that occur in in humans, including various embry­ and chemical mixtures. This chapter exposed adults, with a shorter laten­ onal solid tumours, are observed as summarizes the literature that docu­ cy period from the time of exposure tumours of adult life in conventional ments this high susceptibility of the to the carcinogen until the appear­ rodents. An example is the develop­ fetus, infant, and child to many po­ ance of the tumour. In bioassays for ment of nephroblastomas – embryo­ tentially carcinogenic exposures. carcinogenicity in adult rodents, the nal kidney tumours that correspond Studies in experimental incidence and multiplicity of tumours to Wilms tumour in humans – in the animals increase and the latency period de­ adult rat after perinatal exposure to a creases with increasing dose. Thus, chemical carcinogen. Such tumours Most experimental studies of the predominant results of early-life do not develop in rats exposed to the carcinogenesis during prenatal life exposure are what would be expect­ same carcinogen during adult life and infancy have been conducted ed from a higher effective dose to the (Diwan and Rice, 1995).

Part 2 • Chapter 20. Age and susceptibility 201 Chemical carcinogens that reach contribute to carcinogenic effects in when organogenesis starts. Tumour the fetus via the maternal circulation utero, but when the reactive metab­ multiplicity rises to a maximum in must have crossed the placenta, and olites formed in maternal tissues are offspring exposed at approximate­ consequently are generally referred too unstable to circulate in the mater­ ly 21 days of gestation, a few days to as transplacental carcinogens. All nal bloodstream, cross the placenta, before birth. The susceptibility of but a few known transplacental car­ and reach the fetus, a carcinogenic the fetus relative to that of adult rats cinogens are organic compounds chemical may have no transplacen­ is measured as the incidence and that act principally or entirely by a ge­ tal carcinogenic activity or may only multiplicity of tumours that develop notoxic mode of action. Factors that cause a low incidence of tumours in offspring after birth, compared contribute to fetal susceptibility to near the end of gestation, in offspring with the incidence and multiplicity of these agents include maternal, pla­ that were exposed trans­placentally. the same types of tumours in their cental, and fetal metabolism, the im­ This pattern can be seen in the directly exposed mothers. By that mature state of fetal DNA repair ca­ transplacental carcinogenicity of sin­ measure, the susceptibility of the rat pability, the high rate of cell division gle doses of N-nitrosodimethylamine fetus to induction of brain tumours by during prenatal development, and (NDMA) in rats (Alexandrov, 1968). ENU during the final week of gestat­ the rapidly changing patterns of gene In both the fetus and the pregnant ion is approximately 50 times that of expression in fetal target tissues, female rat, the target organ for single the mother. which may render the genetic mate­ doses of NDMA is the kidney, but a Transplacental carcinogenesis rial of fetal cells highly accessible to much lower incidence of tumours is stu­dies with ENU in non-human pri­ carcinogens. observed in the offspring. For many mates, although far less extensive Different organs and tissues are other compounds whose reactive than studies in rats, also indicate that not equally susceptible to transpla­ metabolites are longer-lived in vivo, the susceptibility of the fetus is great­ cental carcinogens: in experimental the maternal contribution of reactive er than that of the mother. Tumours animals, some fetal organs, nota­ metabolites to fetal tissue burden have been induced in the offspring of bly the developing nervous system, may be substantial, and the result­ rhesus and patas monkeys exposed are exceptionally susceptible to a ing susceptibility of the fetus may be to ENU during the first trimester of wide range of agents. Although dif­ greater than that of the mother. pregnancy (Rice et al., 1989). ferences between mother and fetus Short-chain alkylnitrosourea com­ Ionizing radiation, both from exter­ in absorption and distribution of a pounds are chemically highly reactive nal sources and from internalized ra­ carcinogen may well exist and may and are extremely potent, direct-act­ dionuclides, is capable of producing contribute to greater apparent ef­ ing transplacental carcinogens. In mutations, mainly by large-scale fects of an administered dose in the rats, a single exposure to one of gene deletions, as well as gross offspring, these differences are likely these short-lived agents can cause chromosomal damage, and thus is to be less important than certain oth­ a high incidence and multiplicity similar in its effects to direct-acting er physiological differences between of tumours of the nervous system genotoxic chemical carcinogens, mother and fetus, including differ­ in the offspring of females treated because there is no metabolic bio­ ences in metabolic competence and during the second half of gestat­ transformation of the agent (IARC, in DNA repair capacity. ion (Ivankovic and Druckrey, 1968). 2012e). There are many examples Most chemicals that have a geno­ These substances are direct-acting, of carcinogenesis by different forms toxic mode of action must be bio­ and the simplest members of this of ionizing radiation, in experimen­ transformed to chemically reactive chemical class, especially N-ethyl- tal animals and in humans and at metabolites to initiate carcinogeni­ N-nitrosourea (ENU), have been all ages, from prenatal life to adult­ city. The requisite enzymes are often used to probe changing susceptibility hood. Solar and ultraviolet radiation expressed in fetal tissues only late to carcinogenesis during prenatal life also are carcinogens that directly in gestation, and then at low levels due to factors other than carcinogen damage DNA, but they are less pen­ of activity; thus, only small amounts metabolism. Tumours are induced in etrating than the more highly ener­ of reactive metabolites are gener­ offspring exposed once transplacen­ getic forms of ionizing radiation (e.g. ated in fetal tissues. Metabolites of tally to ENU, beginning at approxi­ X-rays), and thus exert their carcino­ maternal or placental origin may mately 12 days of gestation in the rat, genic effects primarily on the skin,

202 causing distinctive mutations in DNA mice exposed to transplacental car­ increasingly effective and in many (Agar et al., 2004; IARC, 2012e). cinogens, presumably because the cases is curative, but it imposes a Results from experiments with ge­ probability of such a combination of long-term risk of second cancers in netically engineered transgenic and events without concomitant lethal survivors. The most intense expo­ knockout mice, especially double genetic damage is immeasurably sure of children to ionizing radiation knockouts, provide information about low. and to genotoxic chemicals most the significance of individual genes Although the importance of spe­ commonly occurs in the context of and gene combinations in suscepti­ cific genetic events, including muta­ anticancer therapy. Carcinogenic bility to and pathogenesis of specific tions and chromosomal alterations, effects resulting from early-life expo­ tumours, including embryonal neu­ in the genesis of cancers is clear, sures are most clearly seen among rogenic tumours of childhood such evidence is accumulating that many the long-term survivors of childhood as medulloblastoma (reviewed in carcinogens also cause intracellu­ cancers who were successfully treat­ Rice, 2004), and offer some insight lar changes that may contribute to ed with high doses of radiation and/ into why embryonal tumours appear the carcinogenic process but do not or chemotherapy. The examples relatively later in life in mice than in involve carcinogen-induced alter­ given here and in the next section humans. ations in genetic sequences. These are representative rather than For example, the gene PTCH1, the changes, which may occur several comprehensive. human homologue of the Drosophila cell generations after exposure to the The risk of acute myeloid leu­ PART 2 segment polarity gene patched, is a carcinogen, are termed epigenetic kaemia, non-Hodgkin lymphoma, CHAPTER 20 tumour suppressor gene associated and can be caused by ionizing radi­ and solid cancers of the breast, thy­ with nevoid basal cell carcinoma syn­ ation, chemicals, and ultraviolet light. roid, bone, central nervous system, drome. Patients with this syndrome They include genomic instability, a colorectum, and stomach increased are predisposed to develop primi­ reduced ability to replicate the geno­ significantly in survivors of Hodgkin tive neuroectodermal tumours of the type faithfully (Barcellos-Hoff, 2005), lymphoma diagnosed before age central nervous system, including and various other effects (IARC, 16 years and successfully treated medulloblastomas, and mutations 2012e). It is not yet clear how epige­ with radiation, chemotherapy with in PTCH1 have been identified in netic events in carcinogenesis may alkylating agents, or both. Breast a subset of sporadic primitive neu­ vary with age at time of exposure to cancer occurred only in women roectodermal tumours. Genetically the carcinogen. who had received X-radiation alone engineered knockout mice with only or chemotherapy and X-radiation a single normal allele of Ptc1, the Epidemiological findings in combined to treat Hodgkin lympho­ mouse homologue of PTCH1, devel­ humans ma. Breast cancers developed usu­ op medulloblastoma-like cerebellar ally within the radiation field, and the tumours (7–14% incidence). Neo- The consequences of environmen­ risk of breast cancer was 75 times natal exposure of these Ptc1+/− mice tal exposures to chemicals and ra­ as great as that in the general pop­ to 3 Gy X-radiation increased this diation during childhood for the risk ulation. Second cancers occurred incidence to 50%, but irradiation in of cancer later in life have been at increased rates in patients orig­ adulthood had no effect on medullo­ reviewed (Carpenter and Bushkin- inally treated with chemotherapy blastoma incidence (Pazzaglia et al., Bedient, 2013). In patients who re­ alone, X-radiation alone, or chemo­ 2002). ceive anticancer therapies, the ex­ therapy and X-radiation combined, Dramatically, 95% of Ptc1+/− mice posures are much more intense, and but at different sites; breast cancers that had also been genetically engi­ consequently the risk of cancer is occurred only in patients who had neered to remove both alleles of the higher. received X-radiation with or with­ tumour suppressor gene p53 devel­ Anticancer therapy out chemotherapy, and leukaemia oped medulloblastomas, and did so was observed only in patients who very early in life, at younger than Non-surgical therapy for cancer in had received chemotherapy (Bhatia 12 weeks (Wetmore et al., 2001). childhood and adolescence – by ion­ et al., 1996). In survivors of childhood This combination of inactivating gene izing radiation, combination chemo­ cancers overall, the risk of gastroin­ mutations is not seen in conventional therapy, or both – has become testinal second cancers increased

Part 2 • Chapter 20. Age and susceptibility 203 significantly with abdominal radia­ Medical radiation in survivors of various childhood tion and after high-dose chemother­ cancers who had received radio­ People who were exposed to di­ apy with procarbazine and platinum therapy for their first malignancy in­ agnostic X-rays in utero and in drugs (Henderson et al., 2012a). creased linearly with radiation dose childhood during the 1950s are at to the thyroid up to 20 Gy; the relative Radiation from nuclear increased risk of cancer, as doc­ risk peaked at 14.6-fold (Bhatti et al., weapons and nuclear reactor umented in the Oxford Survey of accidents 2010). Childhood Cancers (Wakeford and Therapeutic anti-tumour X-radia­ Little, 2003). However, a more recent There is a statistically significant ex­ tion to the chest during childhood or meta-analysis (Schulze-Rath et al., cess risk of solid cancers in people adolescence for Hodgkin lymphoma, 2008) of studies published after 1990 who were exposed to ionizing radia­ and to a lesser extent for non-Hodg­ did not find any association between tion from the atomic bombs in Japan kin lymphoma, Wilms tumour, leu­ in utero exposure to medical radia­ either in utero or during early child­ kaemia, bone cancer, neuroblasto­ tion and the risk of childhood cancer, hood (age < 6 years). Cancers devel­ ma, and soft tissue sarcoma, greatly probably because in utero diagnos­ oped in both children and adults (age increased the risk of breast cancer 12–55 years at the time of diagnosis) tic doses for single-film X-rays are in female survivors, who tended to and included leukaemia and a vari­ now substantially lower than those develop the second malignancy at ety of solid tumours (Preston et al., that were used previously and that a comparatively early age, during 2008; IARC, 2012e). Cancers of the formed the database for earlier young adulthood (Henderson et al., thyroid are notable in this cohort in reports of increased cancer risk. 2010). Secondary sarcomas are as­ the context of an exceptional sus­ Computed tomography (CT) diag­ sociated in a dose-dependent fash­ ceptibility to develop cancer during nostic scans, for which much higher ion with radiation therapy for child­ early life, because they occurred doses of radiation are used than for hood tumours; radiation exposure almost exclusively in survivors who single-film X-rays, have come into was the most important factor for were younger than 14 years at the common use for diagnostic proce­ development of secondary sarco­ time of the bombings. dures in both adults and children. CT mas in survivors of childhood cancer Short-lived radionuclides of io­ scans have recently been reported (Henderson et al., 2012b). dine, especially iodine-131, were re­ to increase the risk of leukaemia and leased into the atmosphere in enor­ brain tumours in a dose-dependent Solar radiation mous quantities during the accident fashion in patients who received with the Chernobyl Nuclear Power their first scan when younger than Solar radiation and sunburn during Plant in Ukraine, in 1986. Children in 22 years (Pearce et al., 2012). childhood are significant risk factors Ukraine and in neighbouring coun­ Therapeutic X-radiation of the for malignant melanoma of the skin. tries who were exposed to this radia­ head and neck during childhood Duration of residence in Australia – tion at an early age developed papil­ for non-neoplastic conditions, most and the associated exposure to in­ lary adenocarcinoma of the thyroid commonly to treat fungal infections tense solar radiation – is associated later in childhood, beginning only a of the scalp, caused a statistically with the risk of developing malig­ few years after the event (Bennett significant increase in the incidence nant melanoma, and childhood is et al., 2006; IARC, 2012e). Thyroid of intracranial meningiomas and an especially vulnerable life stage cancer has also been observed in nerve sheath tumours and a small­ (Holman and Armstrong, 1984). A children from highly contaminated er increase in the incidence of brain history of sunburn, especially dur­ areas who were in utero at the time tumours (Ron et al., 1988; Sadetzki ing childhood, is also correlated with of the accident (Hatch et al., 2009). et al., 2005). Thyroid carcinoma the risk of cutaneous melanoma. A Children exposed to radioisotopes also occurred in irradiated children, study in England concluded that the of iodine from the Chernobyl ac­ who were much more sensitive to strongest association with elevated cident were at much higher risk of X-ray-induced thyroid cancer than melanoma risk was for sunburn that thyroid cancer than adults who were were adults (Ron et al., 1995; IARC, occurred in children aged 8–12 years similarly exposed. 2012e). The risk of thyroid cancer (Elwood et al., 1990).

204 Chemicals and chemical These changes were found in spe­ although the weight of evidence mixtures other than cytotoxic cific genes (Fos and Ltf [lactoferrin]) favours the greater importance of anti-tumour agents and persisted even after cessation prenatal exposures. Also, a posi­ of treatment. Interestingly, chang­ tive association has been observed Diethylstilbestrol (DES) is a synthet­ es in gene expression were asso­ between parental smoking and risk ic non-steroidal estrogen that was ciated with epigenetic alterations: of childhood leukaemia (particular­ administered to pregnant women specifically, the genes that were ly acute lymphoblastic leukaemia) during the 1950s and 1960s in an differentially expressed in animals (IARC, 2012c). effort to maintain high-risk pregnan­ treated with DES also exhibited ab­ A plethora of experimental studies cies. Although DES is rarely used normal DNA methylation (Newbold indicate that chemical components now, it has been estimated that et al., 2000, 2006). These findings, in tobacco smoke induce a wide 5–10 million women in the USA were although limited in genome cover­ range of genetic changes (Hainaut treated with DES during pregnancy age, strongly suggest that exposure and Pfeifer, 2001; Pfeifer et al., or were exposed to the drug in utero to DES may have a significant and 2002; Wistuba et al., 2002; Lea et al., (Giusti et al., 1995). long-term effect on gene expression 2007). More recent studies also im­ Female offspring of women treat­ through epigenetic mechanisms. plicate epigenetic events in human ed with DES developed an unusual More recent studies that used mi­ cancer associated with tobacco cancer of the vagina and cervix, clear croarray-based transcriptome anal­ exposure (Herceg, 2007; Lin et al.,

cell adenocarcinoma, which became PART 2 ysis in both rats and mice identified 2010; Huang et al., 2011). clinically evident during adolescence CHAPTER 20 In a study of the methylome in and early adulthood (Herbst et al., DES-induced changes in expression cord blood of newborns in connec­ 1971). DES caused breast cancer of a wide range of genes (Hsu et al., tion with maternal smoking during and is positively associated with the 2009; Warita et al., 2010; Lee et al., pregnancy, differential DNA methyl­ risk of endometrial cancer in women 2011). Whether these changes are ation changes in a specific set of who were exposed while pregnant. caused by epigenetic deregulation In addition, a positive association has not been tested. genes were associated with tobacco has been observed between prena­ Another interesting feature of exposure (Joubert et al., 2012). A ge­ tal exposure to DES and squamous exposure to DES is its potential im­ nome-wide methylomics approach cell carcinoma of the cervix in female pact on cancer incidence in subse­ and measurement of cotinine (a offspring and cancer of the testis in quent generations. In addition to validated and objective biomarker male offspring (IARC, 2012d). DES is an increased cancer susceptibility of smoking) were used to identify the only chemical carcinogen known associated with epigenetic chang­ methylation alterations in newborn to have caused cancer in humans by es in parents treated with DES, an cord blood samples from a mother– transplacental exposure. epigenetic mechanism may operate child cohort in relation to maternal The mechanism of action of DES in subsequent generations of mice smoking. Maternal smoking during as a carcinogen is complex. DES is a (the second generation) (Newbold pregnancy influenced methylation potent estrogen, and some of its ef­ et al., 2006). These findings further changes in specific genes. CYP1A1 fects are mediated, at least in large support the notion that DES-induced and AHRR, which encode proteins part, by estrogen receptor alpha. carcinogenesis may operate in part involved in the detoxification of DES can also undergo oxidative through an epigenetic mechanism, chemicals in tobacco smoke, were metabolism. In fetal mouse tissues, although studies extending to the among the differentially methylated it causes aneuploidy, chromosomal third generation are needed to es­ genes (Joubert et al., 2012), sug­ breaks, and other chromosomal tablish a true transgenerational gesting a potential epigenetic mech­ aberrations; it binds covalently to epigenetic inheritance. anism involved in adverse effects DNA and thus probably acts in part Parental cigarette smoking caus­ associated with in utero exposure to through a DNA-reactive genotoxic es hepatoblastoma, an embryonal tobacco smoke. mechanism. In mice, neonatal expo­ tumour of the liver, in children. The Various forms of inorganic arsenic sure to DES also causes persistent effects of prenatal and postnatal ex­ have been collectively classified as changes in gene expression in tar­ posures to parental cigarette smoke carcinogenic to humans (Group 1). get tissues (Newbold et al., 2006). cannot be evaluated separately, These compounds cause cancer of

Part 2 • Chapter 20. Age and susceptibility 205 the skin, bladder, and lung, and pos­ infections in young children, setting ages 5–9 years. As a result of this sibly of the liver and kidney, in ex­ in motion pathogenic processes that combined infection, they are at high posed humans. Arsenic compounds may lead to overt cancer develop­ risk of developing endemic Burkitt have been notoriously difficult to ment during childhood. Examples are lymphoma (eBL) during that period evaluate in conventional animal bio­ Epstein–Barr virus (EBV) and hepa­ (IARC, 2012b). eBL is a high-grade assays for carcinogenicity. However, titis B virus (HBV). Other oncogenic B-cell lymphoma characterized by during the past decade sodium ar­ pathogens, including Kaposi sarco­ the consistent presence of EBV senite has been shown in several ma-associated herpesvirus (KSHV), (zur Hausen et al., 1970) and is the studies to be a transplacental car­ the bacterium Helicobacter pylori, most common paediatric cancer in cinogen for the lung, liver, ovary, and the bladder fluke Schistosoma sub-Saharan Africa (Greenwood and adrenal cortex in mice (Waalkes haematobium, establish prima­ et al., 1970). The determining factors et al., 2007; IARC, 2012a; see also ry infection during childhood, but that bring about eBL are, as far as Chapter 3, by Waalkes). Sodium the resulting cancers appear after is now known, the malaria parasite the paediatric age (> 18 years) and P. falciparum and EBV. arsenite is unique in this respect may require cofactors, especially HBV readily infects young chil­ among inorganic carcinogens. immunosuppression. Suppression dren by percutaneous and permu­ Also, recent epidemiological of the immune response may result cosal exposure to infected blood and studies indicate that early-life expo­ either from co-infection with a sec­ other body fluids. The infection caus­ sure of humans to inorganic arsenic, ond agent, generally the malarial es chronic active hepatitis that leads most commonly in drinking-water parasite Plasmodium falciparum or to a high incidence of hepatocellular but also in contaminated food prod­ human immunodeficiency virus type carcinoma (HCC) in young children ucts (Yorifuji et al., 2011), can lead to 1 (HIV-1), or by iatrogenic immuno­ in Asian and African countries where liver cancer during childhood (Liaw suppression before and after organ the prevalence of HBV infection is et al., 2008), to lung cancer in young or tissue transplantation. high. Perinatal transmission from adulthood (Smith et al., 2006), and to EBV is a ubiquitous oncogenic HBV surface antigen-positive moth­ kidney cancer decades later (Yuan gamma herpesvirus that infects and ers to their newborn babies, or trans­ et al., 2010). persists for life in more than 90% mission from one child to another, The possible transplacental ef­ of the adult population worldwide. is a major source of HBV infection fects of other inorganic Group 1 Children in certain regions of Africa in many areas of the world (WHO, agents, such as nickel, cadmium, and become infected with EBV early in 2001). In utero transmission is rela­ chromium(VI), in animals or humans life, and nearly all have serocon­ tively rare. Most (80–90%) of infect­ have not been well established. verted by age 3 years, whereas in ed infants and 30–50% of children affluent countries primary infection infected at ages 1–4 years develop Infectious agents is often delayed until adolescence a chronic infection, and about 25% The factors that underlie the high (Biggar et al., 1978a, b). Primary of those who become chronically susceptibility to oncogenic infectious EBV infection in early childhood, un­ infected during childhood develop ei­ agents during early life are different like that in adolescence, is usually ther cirrhosis or HCC. HCC can be­ from those that govern susceptibility asymptomatic (Chan et al., 2001). come clinically evident in chronically to chemical carcinogens and radia­ EBV coexists for a lifetime in HBV-infected children during – or tion. Lack of immunity to the agents most human hosts without caus­ even before – adolescence (IARC, in infants and immature immune re­ ing overt disease, but viral replica­ 2012b). sponses to infection in infancy and tion can be reactivated in several KSHV is transmitted primarily by during childhood are major contribu­ ways, including malaria infection, saliva; in geographical areas where tors to susceptibility to these agents specifically P. falciparum malaria. the virus is highly prevalent, infec­ early in life, in common with the well- Children living in areas endemic for tion occurs during childhood, and known susceptibility of children to malaria, notably in tropical regions of the peak age of acquisition is gener­ other, non-oncogenic infections. sub-Saharan Africa, have an elevat­ ally 6–10 years (Whitby et al., 2000; Several oncogenic infectious ed EBV viral load and a diminished Dedicoat et al., 2004; Malope et al., agents readily establish persistent EBV-specific immunosurveillance at 2007). KSHV infection is necessary

206 but not sufficient to cause Kaposi Children whose mothers are in­ leukaemia, non-Hodgkin lymphoma, sarcoma or other cancers in the fected with HIV-1 can be infected dur­ and solid cancers of the breast, thy­ absence of severe immunosup­ ing gestation and at birth, and during roid, bone, central nervous system, pression, for example by co-infection infancy by nursing (IARC, 2012b). colorectum, and stomach. Certain with HIV-1 (IARC, 2012b). In the absence of any intervention, tissues are extremely radiosensitive The bacterium H. pylori typically transmission of HIV-1 in utero and during childhood and adolescence, establishes infection of the human during birth is estimated to occur in including the thyroid and the female stomach during childhood, and un­ approximately 25% of infants born breast. Cancers of these and other treated infections may persist for to HIV-1-positive women (Connor tissues occur at increased frequency life (Malaty and Graham, 1994; et al., 1994). The risk of mother-to- not only among survivors of child­ Goodman et al., 1996; Brown, 2000). child transmission increases steadily hood cancer but also in individuals The infection evolves to cause chron­ towards the late stages of pregnan­ exposed as children and adoles­ ic atrophic gastritis, a pre-neoplastic cy; almost 80% of new HIV-1 infec­ cents to diagnostic X-rays (including condition that leads to development tions occur during the period from CT scans) and to ionizing radiation of gastric adenocarcinoma and gas­ 36 weeks of pregnancy to delivery from nuclear weapons and nuclear tric mucosa-associated lymphoid (Kourtis et al., 2006). reactor accidents. tissue lymphoma later in life (IARC, In summary, infants and chil­ Other high-dosage circumstanc­ 2012b). dren are exceptionally susceptible es early in life that pose increased PART 2 Infestation with the bladder fluke to many carcinogenic infectious cancer risks include transplacental CHAPTER 20 S. haematobium causes squamous agents. Some infections can result cell carcinoma of the bladder as a in the onset of malignancy within the exposure to the non-steroidal estro­ result of chronic inflammation. The first decade of life. In children, HBV gen DES, which causes distinctive parasite has a complex life-cycle infection causes HCC, and EBV ac­ carcinomas of the reproductive tract that includes an infective cercar­ companied by P. falciparum malaria in female offspring of women treated ia form present in freshwater bod­ infection results in eBL. Infections with DES during pregnancy. Intense ies in sub-Saharan Africa, the Nile with KSHV, H. pylori, and S. haema- and repeated exposures to solar ra­ valley in Egypt and Sudan, and the tobium typically occur within the first diation during childhood, including Arabian Peninsula. Infections are few years of life but result in devel­ sunburn, predispose to development percutaneous and result from direct opment of cancer – Kaposi sarcoma, of cutaneous malignant melanoma. contact with contaminated water. gastric adenocarcinoma and gastric Evidence is beginning to accumu­ Maintenance of transmission of the mucosa-associated lymphoid tissue late that exposure to inorganic ar­ infection depends on contamination lymphoma, and bladder carcinoma, senic in utero and during childhood of fresh water with excreta contain­ respectively – decades later. On a can cause cancer of the liver during ing schistosome eggs, the presence global scale, in terms of the numbers childhood and of the lung or kidney of snails as intermediate hosts, and of children exposed and the numbers decades later. human contact with contaminated of cancer cases that result, oncogen­ The consequences of exposures water (Jordan and Webbe, 1993). ic infectious agents pose the greatest to lower doses or concentrations of Children start to accumulate worms cancer risks during childhood. other carcinogens during prenatal as soon as they are old enough to and early postnatal life have been have contact with water, and they Summary more difficult to establish (Carpenter may be continuously reinfected and remain infected throughout their Treatment of childhood cancers with and Bushkin-Bedient, 2013). Parental lives (IARC, 2012b). The incidence high doses of ionizing radiation and cigarette smoking can cause hepato­ of schistosome-related bladder combinations of cytotoxic drugs, blastoma in children, an extreme cancer in Africa peaks at ages 40– many of which are carcinogenic to case of the danger of second-hand 49 years, whereas infection with S. humans (Group 1), has been very tobacco smoke. Possible environ­ haematobium begins as early as age successful in recent years, but sur­ mental causes of other embryonal 6 months and usually peaks at ages vivors are at high risk of second tumours of childhood continue to be 5–15 years (Mostafa et al., 1999). cancers, including acute myeloid investigate.

Part 2 • Chapter 20. Age and susceptibility 207 References

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