Wednesday, April 09, 2008

Using Father's Age to Explore the Role of Germ Cell Mutation as a Cause of Human Cancer

Journal of Epidemiology and Community Health 2006;60:851-853; doi:10.1136/jech.2005.045179
Copyright © 2006 by the BMJ Publishing Group Ltd.

Related Article



Advanced paternal age: How old is too old?
Isabelle Bray, David Gunnell, George Davey Smith

Department of Social Medicine, University of Bristol, UK

Correspondence to:
Correspondence to:
Dr I Bray
Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK;

Average paternal age in the UK is increasing. The public health implications of this trend have not been widely anticipated or debated. This commentary aims to contribute to such a debate. Accumulated chromosomal aberrations and mutations occurring during the maturation of male germ cells are thought to be responsible for the increased risk of certain conditions with older fathers. Growing evidence shows that the offspring of older fathers have reduced fertility and an increased risk of birth defects, some cancers, and schizophrenia. Adverse health outcomes should be weighed up against advantages for children born to older parents, mindful that these societal advantages are likely to change over time.


Keywords: paternal age; DNA damage; fertility; abnormalities; schizophrenia

1988 Oxford University Press


Using Father's Age to Explore the Role of Germ Cell Mutation as a Cause of Human Cancer

Epidemiology Branch, Biometry and Risk Assessment Program, National Institute of Environmental Health Science Research Triangle Park, North Carolina 27709, USA

It has been conjectured that single-gene mutations in the human sperm or egg may increase the risk of cancer in subsequent offspring. We propose an epidemiological test of this hypothesis, using an observation from paediatric genetics. Children with autosomal dominant disease are occasionally born into previously unaffected families. This signals the probable mutation of a parent's germ cell. Risk of producing these offspring is found to be related to father's age but not to mother's age. This suggests that sex differences in germ cell production lead to a greater accumulation of germ cell mutations in men than women. If germ cell mutations increase with father's age, and if germ cell mutations are associated with subsequent increase in cancer risk, then some association should exist between age of the father (but not the mother) and risk of cancer. We discuss the few available data, and suggest ways that this hypothesis might easily be tested.


IJE Advance Access originally published online on September 28, 2006
International Journal of Epidemiology 2006 35(6):1495-1503; doi:10.1093/ije/dyl177
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Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2006; all rights reserved.



Parental age and risk of childhood cancers: a population-based cohort study from Sweden
Benjamin H Yip, Yudi Pawitan and Kamila Czene*
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 171 77 Stockholm, Sweden.

* Corresponding author. E-mail:

Materials and methods

Background Frequent germ line cells mutations were previously demonstrated to be associated with aging. This suggests a higher incidence of childhood cancer among children of older parents. A population-based cohort study of parental ages and other prenatal risk factors for five main childhood cancers was performed with the use of a linkage between several national-based registries.

Methods In total, about 4.3 million children with their parents, born between 1961 and 2000, were included in the study. Multivariate Poisson regression was used to obtain the incidence rate ratios (IRR) and 95% confidence interval (CI). Children <5 years of age and children 5–14 years of age were analysed independently.

Results There was no significant result for children 5–14 years of age. For children <5 years of age, maternal age were associated with elevated risk of retinoblastoma (oldest age group's IRR = 2.39, 95%CI = 1.17–4.85) and leukaemia (oldest age group's IRR = 1.44, 95%CI = 1.01–2.05). Paternal age was significantly associated with leukaemia (oldest age group's IRR = 1.31, 95%CI = 1.04–1.66). For central nervous system cancer, the effect of paternal age was found to be significant (oldest age group's IRR = 1.69, 95%CI = 1.21–2.35) when maternal age was included in the analysis.

Conclusion Our findings indicate that advanced parental age might be associated with an increased risk of early childhood cancers.


International Journal of Epidemiology 2001;30:1428-1437
© International Epidemiological Association 2001



Case-control study of parental age, parity and socioeconomic level in relation to childhood cancers
John D Dockertya,b, Gerald Drapera, Tim Vincenta, Steve D Rowanc and Kathryn J Buncha
a Childhood Cancer Research Group, Department of Paediatrics, University of Oxford, 57 Woodstock Road, Oxford OX2 6HJ, UK.
b Department of Preventive and Social Medicine, University of Otago, PO Box 913, Dunedin, New Zealand.
c Office for National Statistics, 1 Drummond Gate, London SW1V 2QQ, UK.

Dr John Dockerty, Department of Preventive and Social Medicine, University of Otago, PO Box 913, Dunedin, New Zealand.


Background Parental ages, parity, and social class have been found in some studies to be associated with particular childhood cancers. Further investigation is warranted because of conflicting findings, biases, and the need to test specific hypotheses.

Methods A case-control study was conducted (England and Wales, ages 0–14 years). Cases were ascertained from the National Registry of Childhood Tumours, and were born and diagnosed during 1968–1986. Birth record controls were matched 1:1 to cases on date of birth, sex and area. Information on variables of interest for both groups came from birth records. In all, 10 162 pairs could contribute to matched analyses.

Results The odds ratio (OR) for retinoblastoma resulting from assumed new germ cell mutations among children of fathers aged 45 years was 3.0 (95% CI : 0.2–41.7). The risk of childhood acute lymphoblastic leukaemia (ALL) was significantly higher among children of older mothers and fathers, and significant trends with increasing mothers' (P < 0.001) and fathers' (P = 0.002) ages were found. There was a strong and significant protective effect of increasing parity on risk of childhood ALL. The adjusted OR for parity of 5 (versus 0) was 0.5 (95% CI : 0.3–0.8). Children in more deprived communities had a lower risk of ALL; but this was not significant after confounders were allowed for. There was no significant effect of social class based on parental occupation on ALL risk, but the numbers were small in those analyses.

Conclusions The associations between ALL and parental ages did not disappear when children with Down syndrome were excluded, suggesting an additional explanation beyond known links. The strong ALL association with parity may be because of an unknown environmental risk factor.

Keywords Child, cancer, leukaemia, retinoblastoma, parental age, parity, social class, case-control, risk

Accepted 21 May 2001

American Journal of Epidemiology Vol. 152, No. 12 : 1121-1128
Copyright © 2000 by The Johns Hopkins University School of Hygiene and Public Health



Birth Characteristics and Subsequent Risk for Breast Cancer in Very Young Women
Kim Innes1, Tim Byers1 and Maria Schymura2
1 Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, CO.
2 New York State Cancer Registry, New York State Department of Health, Albany, NY.

There is growing evidence that prenatal exposures may influence later breast cancer risk. This matched case-control study used linked New York State birth and tumor registry data to examine the association between birth characteristics and breast cancer risk among women aged 14–37 years. Cases were women diagnosed with breast cancer between 1978 and 1995 who were also born in New York after 1957 (n = 484). For each case, selected controls were the next six liveborn females with the same maternal county of residence. The authors found a J-shaped association between birth weight and breast cancer risk, and very high birth weight (4,500 g) was associated with the greatest elevation in risk (adjusted odds ratio (OR) = 3.10, 95% confidence interval (CI): 1.18, 7.97). The association of maternal age with breast cancer risk was also J-shaped, with maternal age of more than 24 years showing a positive, linear association (adjusted OR = 1.94, 95% CI: 1.18, 3.18 for maternal age 35 vs. 20–24 years; p for trend = 0.02). In contrast, women born very preterm had a lower risk (adjusted OR = 0.11, 95% CI: 0.02, 0.79 for gestational age <33 vs. 37 weeks). These findings support a role for early life factors in the development of breast cancer in very young women.

age factors; breast neoplasms; birth weight; infant, premature; prenatal exposure delayed effects; risk factors; women's health

Abbreviations: CI, confidence interval; IGF-1, insulin-like growth factor-1; OR, odds ratio



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