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Mental Health Services
Cancer Registry, Ministry of Health, Jerusalem
Gertner Institute, Tel Hashomer Hospital, Tel Hashomer
Department of Information and Evaluation, Mental Health Services, Ministry of Health, Jerusalem, Israel
Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island, USA
Cancer Registry
Mental Health Services, Ministry of Health, Jerusalem
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Correspondence: Dr Itzhak Levav, Ministry of Health, 2 Ben Tabai Street, Jerusalem 91010, Israel. Tel: +972 2 568 1429; fax: +972 2 672 5822; email: Itzhak.Levav{at}moh.health.gov.il
Declaration of interest None. Funding detailed in Acknowledgements.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Aims To investigate the risk of cancer among the biological parents and full siblings of people receiving in-patient care for schizophrenia.
Method Linkage analysis was conducted between national population, psychiatric and cancer databases. Standardised incidence ratios for all cancer sites were calculated by comparing the incident rates among first-degree relatives with national incidence rates.
Results A reduced cancer risk was found across all groups examined. Among parents, whose numbers were adequately large, the findings reached statistical significance. For index cases and siblings – a markedly younger population – only a trend was elicited.
Conclusions The genetic hypothesis – namely, the presence of a gene with the dual effect of reducing the cancer risk and disrupting neurodevelopment – is a plausible explanation for these findings.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Confirmation of the genetic hypothesis would require that the first-degree relatives of patients with schizophrenia be found to have a similar reduced cancer risk, compared with suitable populations. The epidemiological evidence remains inconclusive: both a lower risk (Lichtermann et al, 2001) and no risk differential (Dalton et al, 2004) have been found. The Finnish study (Lichtermann et al, 2001) reported a lower risk among fathers, with a standardised incidence ratio (SIR) 0.93 (95% CI 0.90–0.96), and also among mothers (SIR=0.89, 95% CI 0.86–0.92), brothers (SIR=0.85, 95% CI 0.76–0.93) and sisters (SIR=0.92, 95% CI 0.84–0.99). Curiously, the cancer risk for patients with schizophrenia in that study was higher than the cancer risk for the general reference population (SIR=1.17, 95% CI 1.09–1.25). In contrast, when the Danish researchers compared the parents of patients with schizophrenia with the general population, they found not only no overall risk differential, but a 20% increased risk of lung cancer among the mothers (Dalton et al, 2004). These results were contested by Lichtermann (2005), who argued that the observation period in the Danish study did not cover the whole lifetime of the parents, and that there was insufficient empirical evidence in the published literature for the ‘healthy parent’ effect as an explanation for the reduced cancer risk found in the parents of patients with schizophrenia in his own study. In their reply, Dalton et al (2005) supported their thesis by reporting that they did find a reduced cancer risk in parents, but only when the comparison population included childless adults as in the Finnish study.
Like Denmark and Finland, Israel also has a continuously updated population register as well as registers for cancer cases and psychiatric hospital admissions. This has enabled us to replicate the attempt to confirm a reduced cancer risk among first-degree relatives, a project that continues our earlier study in which we found a lower risk of cancer in patients with schizophrenia (Grinshpoon et al, 2005).
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METHODS |
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This was confirmed in a community-based study of an Israel-born birth cohort, which found that all respondents identified with schizophrenia in the cohort were known to the in-patient psychiatric services (Levav et al, 1993).
We used the nation-wide psychiatric case register to identify patients with schizophrenia for our sample. This 50-year-old register is mandated by law to maintain a cumulative record of all psychiatric hospital admissions (Lichtenberg et al, 1999; Mental Health Services, Department of Information and Evaluation, 2004). The identity number used to record all patient movements is the same as that used by the national population register and the cancer register. The psychiatric case register also provided the patients’ diagnoses upon admission and discharge as well as socio-demographic information. Diagnoses follow the ICD–10 (World Health Organization, 1992); those made prior to the introduction of ICD–10 have been updated. A test of the agreement between research diagnoses and those recorded in the register found a satisfactory match (Rabinowitz et al, 1994; Weiser et al, 2005). Although the recording of cases is complete for Jewish Israelis, this is not so for the Arab Israeli minority, particularly women, who use psychiatric in-patient services considerably less than Jewish Israelis (Mental Health Services, Department of Information and Evaluation, 2004). To avoid biasing the sample, the Arab Israeli minority was excluded.
Identification of cancer cases
The Israel National Cancer Registry
(http://www.health.gov.il/icr
was established in 1960 (Freedman et
al, 2001). Reporting has been mandatory since 1982 for all
medical facilities, public and private. The registry also collects data on
cancer deaths from district health authorities and from the Ministry of the
Interior’s population register. As in the psychiatric case register, the
information is organised using a personal identity number. Information
completeness exceeds 95%. Continuous efforts are made to improve reporting and
accuracy (Fishler et al,
2002). Multiple tests, as prescribed by the International Agency
for Research on Cancer (Parkin et
al, 2002), for example the percentage of cases with
morphological verification, the mortality to incidence ratio and the
percentage of cases ascertained by death certificate only, are conducted
regularly to check data quality.
The number of residents with cancer who seek diagnosis and treatment abroad is probably small, since medical services in Israel are free and adequate. However, the exact number of those going abroad for care, as well as the number of Israelis living abroad who might have returned home to avail themselves of free medical care, is unknown. Neither figure is likely to be large.
Linkage procedure
The two case registers and the population register can be linked by means
of the personal identity number. This identity number is supplemented
automatically with the person’s full name, gender, date of birth and
place of origin and the father’s first name, to ensure a reliable
linkage. The process of identification and linkage comprised four steps.
First, through the psychiatric case register, we identified a cohort of
persons discharged from their last or only in-patient episode with a diagnosis
of schizophrenic disorder (ICD–10 codes F20–29). To do this we
made use of an existing database of family-linked files of individuals with
schizophrenia. In this database (n=6132) almost all patients with
schizophrenia (about 95%) were born in Israel in the years 1970–1988,
either to immigrant or to native-born parents. The few who were born abroad
were 5 years old or less on immigration. Second, we identified their
biological parents (mothers n=5756; fathers n=5741) and
their full siblings (brothers n=9445; sisters n=9846) using
the population register’s computerised family files. Third, we ran the
files of both parents and siblings through the psychiatric case register to
identify all patients discharged from their last or only in-patient episode
with a diagnosis of schizophrenic disorder (F20–29), as noted above
(fathers n=224; mothers n=393; brothers n=508;
sisters n=354). Fourth, the files of index cases, parents and
siblings were run through the cancer register to locate cancer cases. This
four-stage process generated three sub-populations
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The case registers (psychiatric and cancer) owned and maintained by the Ministry of Health are administered under strict legislatively defined procedures. To preserve confidentiality, linkages are made by methods that ensure researchers are not given files with the individual’s real identity number. Internal review board approval to build the study family database was obtained from Butler Hospital, Providence, Rhode Island, USA.
Statistical analysis
The cancer incidence rates in the above three sub-populations were compared
with the rates in the Jewish Israeli population using standardised incidence
ratios (and their 95% confidence intervals), defined as the ratio of the
observed to the expected number of cancer cases. The expected number of cases
during the observation period was calculated by gender, area of origin
(Africa–Asia, Europe–America or Israel) and age. Period-specific
cancer incidence rates were used.
The person-years of exposure to cancer risk were defined as follows: index cases, from date of birth or date of immigration; parents, from date of immigration or from 1960, whichever was the later; and siblings, from date of birth or immigration or from 1960, whichever was the later (Table 2). The observation ended on death, diagnosis of cancer, emigration, or at the end of 2003.
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Analysis by cancer site, gender and area of origin was conducted when the number of cancer outcomes in the sub-population was 10 or more. The test was performed for all index cases with a schizophrenic disorder (F20–29), and separately for ‘restricted’ cases (F20, F22, F25) (e.g. paranoid schizophrenia) and ‘extended cases’ (F21, F23, F24, F28, F29) (e.g. acute schizophrenia-like psychotic disorder), assuming a differential weight for the imputed genetic component in the aetiology of each group of disorders.
Since we could not know who in the general population sample was a parent, in order to check the ‘healthy parent’ hypothesis (Dalton et al, 2004) we performed a sensitivity analysis restricted to women, taking into account that in the latest national census about 7.0% of all women aged 35 or over had no children. For all cancers, we assumed that childless women had increased relative risks of 1.0, 1.5 and 2.0 as compared with mothers. The corrected expected number of cases among mothers, Ec, was calculated as Ec= E/(0.93+k0.07) where E is calculated using the official age groupxgenderxarea of originxperiod-specific cancer incidence rates, Ec is the corrected expected number of cases and k=1.0, 1.5 and 2.0. The standardised incidence ratio (SIR) and the corrected ratio (SIRc) and their 95% confidence intervals were calculated using Poisson regression, with E and Ec as the respective offset. All calculations were performed using SAS version 9.1.3 for Unix software.
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RESULTS |
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Standardised incidence ratios among parents by restricted or extended type of schizophrenia showed no statistically significant difference. By all areas of origin, mothers and fathers showed a statistically significant risk reduction (Table 3). With regard to the four leading cancer sites among parents, two sites showed reduced risks: breast cancer, expected 239, observed 204, SIR=0.85 (95% CI 0.74–0.97); prostate cancer, expected 60, observed 46, SIR=0.77 (95% CI 0.55–0.99). For lung and colorectal cancers the ratios were lower than unity in both parents, but failed to reach statistical significance. Index cases and siblings had a non-significant risk reduction, probably because of their relatively younger age. Index cases: females, SIR=0.78 (95% CI 0.37–1.19), males, SIR=0.88 (95% CI 0.55–1.20). Siblings: brothers, SIR=0.92 (95% CI 0.72–1.13); sisters, SIR=0.83 (95% CI 0.66–1.00). The cancer risk among siblings, after excluding those with schizophrenia, remained almost unchanged: brothers, SIR=0.93 (95% CI 0.72–1.13); sisters, SIR=0.83 (95% CI 0.66–1.00) (Table 3).
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The sensitivity analysis performed on mothers to check for the ‘healthy parent’ (mother) effect did not alter the findings; mothers of people with schizophrenia retained a significantly reduced cancer risk (Table 4).
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DISCUSSION |
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With regard to specific cancer sites, the test in this study for breast cancer was the most adequate, since the relatively large sample size generated enough statistical power to demonstrate a statistically significant reduction. For other cancer sites, except for prostate cancer, the results were less definite.
This study has several methodological limitations and strengths. A first possible limitation was pointed out by Dalton et al (2004, 2005) – namely, that to control for the ‘healthy parent’ effect, parents of children without schizophrenia constitute a better reference group than the general population. We doubt, however, that their objection to the Finnish study (Lichtermann et al, 2001) for using the general population as a reference group is relevant in our case, because of our different demographic patterns. Whereas in Denmark the total fertility rate was 1.7 and only 24.0% of households had three or more members (Danmark Statistik, http://www.dst.dk), among Jewish Israelis, the respective figures reached 2.6 and 60% (Central Bureau of Statistics, http://www.cbs.gov.il). In 1997 the Israeli census found only 7.2% of women aged 35 and older to be childless, whereas in Denmark the proportion was nearly 18.0%. Moreover, our ad hoc and conservative sensitivity analysis (Lichtermann, 2005) generated no indication of the healthy parent (in our case, mother) effect.
A second factor that might undermine our conclusions is that whereas patients with schizophrenia are more frequently found in the low socio-economic groups (Dohrenwend et al, 1992), cancer in Israel is more frequent in the higher socio-economic groups (Israel National Cancer Registry, 1990; Israel Center for Disease Control, 1998). Curiously, socio-economic status as a confounding variable has seldom been discussed in the research literature. In our study, however, it may not constitute a problem since parents of patients with schizophrenia are not found in the lower socio-economic groups at a higher proportion than in the general population (Goldberg & Morrison, 1963; Byrne et al, 2004). Nor may socio-economic status be problematic with regard to the healthy siblings. Nevertheless, we checked for the socio-economic status effect by grouping our parents by ethnic origin. In Israel this is a reasonable proxy measure for socio-economic status, since Israelis born in Asia or Africa generally have a lower socio-economic status than their counterparts born in Europe or America (Schwartz et al, 1991). We found that parents of patients with schizophrenia had a decreased cancer risk, regardless of their continent of origin.
Third, our index cases were diagnosed by clinicians who, in the nature of their work, do not attempt to achieve a research-standard diagnosis. To increase validity we extended the period of observation by using the discharge diagnosis from the last or only in-patient episode. However, if our final sample included people diagnosed as having schizophrenia but who in fact had other disorders, these false-positive cases would only buttress our results. Fourth, our finding that more mothers than fathers had schizophrenia might suggest a sampling bias, because in the psychiatric case register we found considerably more men than women hospitalised with schizophrenia, for both index cases and siblings. Conceivably, there is a greater likelihood that women marry and have children before they require hospital treatment, given that their mean age at disease onset is higher than that of men. Fifth, although we did not have access to lifestyle issues highly associated with cancer, such as smoking, we doubt that health-promoting behaviour is any more frequent among parents of offspring with schizophrenia than among parents in the reference population. Finally, early death among the parents of people with schizophrenia cannot be ruled out as a confounding factor. However, there is no evidence to suggest that early mortality is linked to cancer risk.
Our register-based study had two particular methodological strengths. Both databases provided us with fairly complete and accurate data; furthermore, we repeated the database linkage procedures to make sure that the matches were correct. Additionally, the differential cancer risk among ethnic groups in Israel and the closeness to the rates found in the USA for frequent cancer sites (Freedman et al, 2006) reduce the possible group-specificity of our results.
In sum, if the strengths of our study outweigh its limitations, we are confident that we detected a consistently lower risk of cancer among the parents of people with schizophrenia, and a trend among index cases and siblings. Several hypotheses have been proposed to explain these findings (Mortensen, 1994), among them, the dual role of a tumour suppressor gene such as p53 (Catts & Catts, 2000; Ni et al, 2005). Tumour suppressor p53 has been identified as the most frequently mutated gene in human cancer. The gene is usually activated following DNA damage or other types of cellular insult. Activated p53 may block progression through the cell cycle or, alternatively, may lead to apoptosis, and in this way prevent the accumulation and transmission of genetic damage to daughter cells. In the specific context of neural development, it has been shown that p53 fulfils an important role in the normal apoptosis-driven neurogenesis of various brain structures. In accordance with this notion, it has been postulated that increased p53 levels in schizophrenia patients may increase cell death in potentially critical areas of the central nervous system. This hypothesis is consistent with the multiple structural defects in cerebral anatomy reported in schizophrenia. On the other hand, mutations in the p53 gene (the most common cause for p53 accumulation) may be associated with genomic instability in particular tissues and a greater probability of organ-specific neoplastic transformation. Taken together, these features suggest that p53 might constitute a dual effector with important roles in the aetiology and development of schizophrenia and, concomitantly, in cancer protection or promotion (Catts & Catts, 2000; Park et al, 2004; Yang et al, 2004; Cui et al, 2005; Ni et al, 2005).
Although the genetic hypothesis has been challenged (Jablensky & Lawrence, 2001), based on our findings this hypothesis constitutes an attractive tentative explanation that deserves further research. An advantage of this line of research would be that by probing into the purported link between schizophrenia genes and cancer, we might learn something about schizophrenia by studying cancer (Kalkman, 2006).
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication April 2, 2006. Revision received August 17, 2006. Accepted for publication October 3, 2006.
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