Increased prevalence of malignant diseases in the close neighborhood of children with cancer. (Features).Abstract
Clustering of cancer in families may be due to chance, inherited genetic mutations, common exposure to environmental agents, or a combination of these factors. The authors, to address a clinical impression that cancer occurs more often in the environment of a child with cancer, investigated whether the prevalence of cancer among children and adults in the neighborhood of children with cancer was higher than the prevalence in the neighborhood of healthy children. One hundred thirty-seven children diagnosed with a malignant disease between 1981 and 1992 at the Department of Pediatrics, University Hospital of Linkoping, Sweden, were investigated and compared with 232 healthy control children. The control children were traced from the official Swedish population registry. It was found that 13 percent of the children with cancer and six percent of the control children were close neighbors of other children diagnosed with cancer (p < .05). Cancer also was more common in the circles of acquaintances around the children with cancer than in circles of acquaintances around control children (p < .03). The frequency of cancer in the neighborhood or in the circle of acquaintances was significantly greater in older children than in younger children. These results support the hypothesis that environmental factors can initiate or precipitate cancer in children as well as in adults.
At the level of the cell, cancer is nearly always a genetic disease with such features as the involvement of oncogenes oncogenes
1. genes carried by tumor viruses that are directly and solely responsible for the neoplastic transformation of host cells. Many oncogenes function after integration into the DNA of the host cell and some up-regulate normal downstream host cell genes to cause neoplasia. and loss of the normal function of tumor suppressor genes tumor suppressor gene
A gene that suppresses cellular proliferation. When inherited in a mutated state, it is associated with the development of various cancers, including most familial cancers. Also called antioncogene. (Pizzo & Poplack, 1999), DNA repair DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light can cause DNA damage, resulting in as many as 1 genes, and genes affecting cell survival (Hawn et al, 1995; Takano, Harmon, & Kerr, 1991). These genetic changes might be mediated both by exogenous and endogenous factors (Behrman, Kliegman, & Arvin, 1996; Chang, Syrjanen, & Tervahauta, 1993).
In adults, about 30 percent of all cancers are supposed to be caused by smoking and 30 percent by dietary factor (Berkel, 1996). Pediatric pediatric /pe·di·at·ric/ (pe?de-at´rik) pertaining to the health of children.
Of or relating to pediatrics. cancer, by contrast, has contributed much less to knowledge of the environmental aspects of carcinogenesis car·ci·no·gen·e·sis
The production of cancer.
production of cancer.
viruses and some parasites are capable of initiating neoplasia. than to knowledge of genetic aspects. The Chernobyl reactor accident of April 1986 caused fear that the risk of cancer in children would increase as a result of increased exposure to radioactivity Investigations so far have not found such increase (Auvinen et al., 1994; Hjalmars, Gustafsson, & Kulldorf, 1994; Prisyazhiuk, Beral Buzanov Pjataj, & Reeves, 1991). Some studies have found a relation between magnetic fields magnetic fields,
n.pl the spaces in which magnetic forces are detectable; created by magnetostrictive ultrasonic scalers to cause the tips of instruments such as ultrasonic scalers to vibrate. and the risk for childhood brain tumors (Savitz, Barnes, John, Wachtel, & Tvrdik, 1988) and childhood leukemia (Feychting & Ahibom, 1993). Studies of smoking during pregnancy have shown conflicting results, some finding increased risk of leukemia in the child (Stjernfeldt, Berglund, Ludvigsson, & Lindsten, 1986) and others finding almost the opposite (P ershagen, Ericsson, Otterblad-Olausson, 1992). There is some evidence for a viral or infectious etiology in childhood leukemia (Alexander, 1993; Alexander et al., 1997; Greaves greaves
cracklings, an edible raw fat from the meat trade. The skimmings from the preparation of this fat are also called greaves. They represent a low grade of meat meal. & Alexander, 1993; Kinlen, 1995; Sandler, 1995) as well as for Hodgkin's disease Hodgkin's disease, a type of cancer of the lymphatic system. First identified in 1832 in England by Thomas Hodgkin, it is a type of malignant lymphoma. Incidence peaks in young adults and the elderly. (Grufferman & Delzell, 1984). The virus hypothesis is based on the assumption of an abnormal response to some common infection (Greaves, 1999; Greaves & Alexander, 1993).
The associations between parental occupation or exposure of parents at the time of conception and cancer in their offspring are largely inconsistent. Some studies have found evidence for an association (Alexander, 1993; Brunetti, Cavallieri, Stanta, & Tamoro, 1997), and others have failed to do so (Gustafsson, Carstensen, & Ludvigsson, 1995; Kinlen, 1993; Olsen, Bautz, Boice, Fraumeni, & Seershoim, 1995; Olsen, Schulgen, de Nully Brown, & Jensen, 1991).
The aim of this study was to investigate whether the prevalence of cancer among children in the neighborhood of children with cancer was higher than the prevalence among children in the neighborhood of healthy control children.
Subjects and Methods
All 179 children diagnosed with a malignant disease between 1981 and 1992 at the Department of Pediatrics, University Hospital of Linkoping, in Sweden, were invited to participate in the study The pediatric department in Linkoping is the oncology center for the southeast part of Sweden. This region includes five pediatric departments. Because of variations in referral routines, leukemias and brain tumors are over-represented; some other malignancies are underrepresented un·der·rep·re·sent·ed
Insufficiently or inadequately represented: the underrepresented minority groups, ignored by the government. , since they are referred to other pediatric oncology centers. For each child with cancer, the authors selected two children matched for age, sex, and birthplace. The control children were traced with the help of the official Swedish population registry.
A questionnaire was mailed to the families of the two groups (see sidebar at right). If the questionnaire was not returned within a month, the family was reminded with a letter and, one month later, with a second letter. Among families of children with cancer, 76.5 percent (137 of 179) answered the questionnaire; 64.8 percent of the families of control children (232 of 358) responded.
The study was approved by the Ethical Committee of the Faculty of Health Sciences, Linkoping] University
The statistical analysis was performed with a Chi-square test chi-square test: see statistics. and Student's t-test A t test is any statistical hypothesis test in which the test statistic has a Student's t distribution if the null hypothesis is true. History
The t and, when there was indication of skewed distribution Skewed distribution
Probability distribution in which an unequal number of observations lie below (negative skew) or above (positive skew) the mean. , the Mann-Whitney U-test. The results are expressed as mean +/- standard error (SE).
Of the children with a neoplasm neoplasm or tumor, tissue composed of cells that grow in an abnormal way. Normal tissue is growth-limited, i.e., cell reproduction is equal to cell death. , 55 percent were boys. The mean age at diagnosis was 7.88 +/- 0.39 years (range: 0 to 20 years of age). Children with leukemia had a mean age of 5.3 [+ or -] 0.5 years, compared with 9.2 [+ or -] 0.6 years for children with tumors in the central nervous system (p < .000) and 8.3 [+ or -] 0.8 for children with other tumors (p < .005). Tumors in the central nervous system (CNS See Continuous net settlement.
See continuous net settlement (CNS). ) and leukemias were, as explained above, the most common types of cancer among the patients studied (Table 1).
Cancer in the Neighborhood of the Children
Of the children with cancer, 13 percent lived in the same street as other children with cancer, compared with six percent of the control children (p < .05). At the time of diagnosis, cancer was also significantly more common in the circles of acquaintances around the children with cancer than in the circles of acquaintances around the control children (p < .03) (Table 2). No differences were seen when the prevalence of cancer in the circle of parents' acquaintances was compared for the two groups of children, nor when the frequency of cancer at the place of work was compared for the two groups of parents (Table 3).
Cancer in the Family or Among FirstDegree Relatives
Of the children with cancer, eight percent had a mother with cancer, compared with three percent of the control children (p < .03) (Table 4). No such difference was seen with respect to the fathers or siblings (Table 4). When prevalence among other relatives was compared, the authors found that cancer was more common in paternal grandmothers of the children with cancer than in paternal grandmothers of healthy children; the values were 20 percent and 10 percent, respectively (p < .009) (Table 4). When leukemic children were compared with children who had either CNS tumors or other tumors, the authors found no significant differences in the frequency of cancers within the family or among other relatives apart from paternal grandmothers. Of the children with CNS tumors, 30 percent had a grandmother with cancer, compared with 17 percent of the children with leukemia and 11 percent of the children with other tumors (p < .04). Of the children with cancer, 6.1 percent had families with cancer in more than two genera tions, compared with 3.1 percent of the control children (not significant). Of the children with leukemias, 4.7 percent had families with cancer in more than two generations, compared with 7.8 percent of the children with tumors in the CNS (p = .1 compared with controls) and 5.3 percent of children with other cancers.
Differences Between Age Groups and Between Boys and Girls boys and girls
No significant differences were found between the age groups when the frequency of cancer in the family or among other relatives was compared. The frequency of cancer in the neighborhood or in the close circle of acquaintances was significantly greater in the oldest age group (15 to 20 years of age) than in the youngest (zero to four years of age); the figures were 45 percent and 18 percent, respectively (p < .04). No differences were found between the sexes.
The authors have sometimes had the impression that there are strange coincidences with cancer diseases. Parents of children with cancer remarkably often have or develop a cancer disease close in time to the diagnosis of the child. Even more remarkable is the fact that children from the same street or in the close neighborhood have or get a malignant disease close to the time when a child is newly diagnosed (see sidebar at left).
Thus, the authors decided to study the frequency of malignant diseases among first-degree relatives and in the neighborhood of children with cancer diagnosed from 1981 to 1992. The authors are, however, well aware of several methodological problems. The study had a rather low response rate, which could mean that only a selection of patients or individuals answered the questionnaire. It is reasonable to expect that among control families, those who had had some encounter with cancer (e.g., cancer in the family, among relatives, or among neighbors) would have a higher response rate. Thus, self-selection perhaps masked possible differences between children with cancer and control children. On the other hand, this effect may have been compensated for by the fact that the subjects probably are more motivated and may know more about cancer in relatives and neighbors, which could lead to differences. But this effect should be small as cancer is so dramatic that people tend to remember. Finally, difficulties in reme mbering should, if anything, make it even more difficult to show differences between the groups. Thus, the results have to he interpreted carefully, but as differences tend to be underestimated, they may still give some interesting suggestions.
As in some other studies (Brunetti et al., 1997), case children had a mother with cancer significantly more often than did control children, while no significant differences were seen between the fathers of the two groups. This result could be explained either by genetic factors (Gustalsson et al., 1995; Narod, Lenoir, & Stiller, 1991) or by environmental carcinogenic carcinogenic
having a capacity for carcinogenesis. exposure (Pizzo & Poplack, 1999). Interestingly, Alexander and co-workers found a positive association between maternal migration during the children's gestation and childhood leukemia, which could be attributed to factors related to population movement or infection (Alexander, Cartwright, & McKinney, 1993). In Li-Fraumeni syndrome Li-Fraumeni syndrome SBLA syndrome An AD condition with ↑ risk of multiple malignancies––eg, sarcomas, carcinomas of adrenal cortex, breast, larynx and lung, brain tumors, leukemia and lymphomas at any time from infancy to adulthood, due to a , there seems to be a family clustering of multiple malignancies, including pediatric sarcomas Sarcomas Definition
A sarcoma is a bone tumor that contains cancer (malignant) cells. A benign bone tumor is an abnormal growth of noncancerous cells.
A primary bone tumor originates in or near a bone. , breast cancer, leukemias, brain tumors, and adrenocortical carcinomas (Frebourg, Barbier, & Yan, 1995; Li & Fraumeni, 1969). Inheritance may therefore to some extent explain the finding that children with CNS-tumors relative ly often had a paternal grandmother with cancer, although this association was seen only on the female side.
The following causal environmental factors of childhood cancer have been established:
* stilbestrol stil·bes·trol
a synthetic estrogen used in the treatment of female animals for infertility and bitches for urinary incontinence. during pregnancy causing vaginal adenocarcinoma adenocarcinoma: see neoplasm. in young women (Herbst, Poskanzer, & Ulfelder, 1971),
* ionizing radiation i·on·i·zing radiation
High-energy radiation capable of producing ionization in substances through which it passes.
Ionizing radiation , and
* certain cytotoxic cy·to·tox·ic
Of, relating to, or producing a toxic effect on cells.
Many environmental risk factors have been discussed during the years, such as exposure to electric and magnetic fields (Feychting & Ahlbom, 1993; Gardner et al., 1990), viral infections (Alexander, 1993; Greaves & Alexander, 1993; Sandler, 1995), parental employment at the time of conception (Hemminki, Saloniemi, Salonen, Partanen, & Vainio, 1981; Olsen et al., 1991), and ionizing radiation (Feychting & Ahlbom, 1993; Savitz et al., 1988). There seems also to be a prenatal initiation of acute leukemia acute leukemia Hematology A rapidly progressive malignancy of sudden onset, characterized by an uncontrolled 'clonal' proliferation of immature WBCs which replace BM and spill into the peripheral circulation; untreated AL may be fatal in wks to months. in young patients (Gale et al., 1997).
With respect to leukemia, Kinlen and Petridou (1995), as well as Hjalmars and Gustafsson (1999), have shown that, at the community level, increased population mobility and mixing are associated with higher rates of leukemia. Some studies have found evidence of space-time clustering of childhood leukemia and lymphomas, both at birth (Gilman & Knox, 1995; Gustafsson & Carstensen, 1999; Knox & Gilman, 1996) and at diagnosis (Gilman & Knox; Kinlen & Petridou; Petridou et al., 1996). This clustering is not so obvious with respect to solid cancers (Gilman & Knox; Knox & Gilman). Such findings suggest that a common infection of high virulence but low pathogenicity may be involved in the etiology of leukemia and lymphomas in childhood. One hypothesis is that the suspected virus could affect the genome of B-lymphocytes at a very early stage of maturity in utero in utero (in u´ter-o) [L.] within the uterus.
In the uterus.
in utero adv. . A second event could then induce cancer. The viral hypothesis is also supported by the well-known "childhood peak" in leukemia (Greaves & Alexander, 1993).
This study found malignant diseases to be more common, not only in mothers and grandmothers of children with cancer than in those of control children, but also in the close neighborhood. The authors therefore conclude that environmental factors can be involved in the development of cancer during childhood.
Corresponding Author: Ulf Samuelsson Ulf Samuelsson (Born March 26, 1964, in Fagersta, Västmanlands län, Sweden) is a retired Swedish-American professional ice hockey player and currently an assistant coach with the Phoenix Coyotes. , Division of Pediatrics, Department of Health and Environment Mission Statement:
"To create, promote and enhance health and vitality through innovation, collaboration and celebration."
The 10 Essential Public Health Services
(excerpted from "The Essential Services of Public Health" by James A. , Linkoping University S-581 85 Linkoping, Sweden. E-mail: <Ulf.Samuelsson@lio.se>.
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TABLE 1 Frequency of the Different Types of Cancer Among Children Included in the Study Leukemia 29% Tumors of the central nervous system 43% Hodgkin's and non-Hodgkin's lymphomas 14% Ewing's sarcoma and osteosarcoma 4% Other 10% TABLE 2 Number and Frequency of Persons with Cancer in the Neighborhood of the Children Studied Childern in Children Living in Classmates Day Nursery the Same Street Children with cancer 3 (2%) 14 (13%) (*) 2 (2%) Control children 6 (3%) 14 (6%) 15 (7%) Schoolmates Friends Children with cancer 8 (5%) 24 (22%) (**) Control children 13 (6%) 27 (12%) (*)p < .05. (**)p < .03 TABLE 3 Number and Frequency of Cancer Case in the Neighborhood of Children's Parents Colleague Good Friend In the Circle Colleague of Mother of Mother of Mother's of Father Acquaintances Children with cancer 18 (14%) 9 (7%) 14 (11%) 13 (10%) Control children 36 (15%) 23 (10%) 27 (12%) 29 (13%) Good Friend In the Circle of Father of Father's Acquaintances Children with cancer 6 (5%) 14 (11%) Control children 13 (6%) 21 (9%) Note: A "good friend" is defined as a person the mother or father meets regularly. TABLE 4 Number and Frequency of Relatives with Cancer Father Mother Siblings Siblings of Mother Children with cancer 4 (3%) 11 (8%) (**) 2 (1%) 10 (8%) Control children 6 (3%) 7 (3%) 0 16 (7%) Siblings Mother Father Mother of Father of Mother of Mother of Father Children with cancer 8 (7%) 13 (10%) 21 (17%) 24 (20%) (***) Control children 18 (8%) 26 (12%) 48 (21%) 22 (10%) Father of Father Children with cancer 22 (18%) Control children 37 (17%) (**)p < .03. (***)p < .009
RELATED ARTICLE: Examples of Cluster Incidents of Cancer
1. Boy with osteosarcoma osteosarcoma /os·teo·sar·co·ma/ (os?te-o-sahr-ko´mah) a malignant primary neoplasm of bone composed of a malignant connective tissue stroma with evidence of malignant osteoid, bone, or cartilage formation; it is subclassified as . Two years later, another boy in the same street of a small town has osteosarcoma (yearly incidence 1/100,000).
2. Girl with ALL. Two years later, her best friend and neighbor, a girl of the same age, gets osteosarcoma.
3. Girl with AML AML - A Manufacturing Language . Three years later her best friend and classmate in a village of about 5,000 inhabitants
The game is based loosely on the concepts from SameGame. gets osteosarcoma.
4. Girl diagnosed, with ALL Boy at the same day-care center is diagnosed with retinoblastoma Retinoblastoma Definition
Retinoblastoma is a malignant tumor of the retina that occurs predominantly in young children.
The eye has three layers, the sclera, the choroid, and the retina. .
5. Man dies from brain tumor. The house is sold to a family whose daughter one year later gets a brain tumor.
6. Two children diagnosed with ALL. Their fathers are neighbors and were close friends as children.
7. Girl diagnosed with ALL. One month later, a classmate, a girl, is diagnosed with a brain tumor.
ALL = acute lymphoblastic leukemia.