Although risk of several types of childhood cancers has been linked to parental age at an offspring's birth (5
), studies on the role of parental age at birth in the development of nonfamilial adult cancers have been predominantly limited to breast and prostate cancers (8
). For breast cancer, both older maternal (9
) and paternal (8
) ages have been associated with increased risk for female offspring. However, only older paternal age was associated with increased prostate cancer risk for male offspring (11
). Our study revealed a moderate, independent association of advanced paternal age, but not maternal age, with increased risk of sporadic NHL for women.
Advanced paternal age at conception appears to be associated with a wide range of effects on the health and development of the offspring, including germ cell mutations resulting from the continuous replication of stem cells in male spermatogenesis (12
). Specifically, spermatogonia undergo 30 divisions before puberty and thereafter continue at approximately 23 divisions per year throughout most of a male's life; oocytes undergo only 24 divisions in a female's life, with the last cell division occurring between puberty and fertilization (13
). A previous study of human sperm by Singh et al. (14
) found a gradual increase in DNA damage in human sperm (and decreased apoptosis) with increasing age, including a distinct change at age 35 years. Recent studies have shown that de novo point mutations are associated with older paternal age (15
) and several rare autosomal dominant disorders (16
). There is also increasing evidence linking advanced paternal age with moderately increased risks of common complex disorders (16
). Nonetheless, experimental data on advancing paternal age and mutations in these diseases, including hematologic malignancies, are limited, in part because of the low incidence rates in the population and the decades-long interval from birth to disease onset.
Aberrant epigenetic regulation is another possible mechanism linking advancing paternal age with risk of sporadic hematologic malignancies; the frequency of epigenetic errors appears to increase with age (19
). A specific epigenetic process of genomic imprinting has been linked to development of cancer, such as lung cancer, colorectal cancer, and acute myeloblastic leukemia (20
). Mechanistically, an imprinting error may contribute to tumor formation by silencing tumor-suppressing genes or by activating growth-stimulating genes, since the inactivation of only one suppressor allele is necessary to increase cancer susceptibility (22
Paternal but not maternal age at birth has been positively linked to offspring leukocyte telomere length (23
). Studies have also shown that telomere length increases in human sperm cells with increasing age of the donor (27
). On the basis of these observations, our results would suggest that long telomere length in individuals with older fathers (e.g., aged ≥35 years) may place these individuals at higher risk of hematologic malignancies through a telomere/telomerase–related pathway (e.g., a genetic and epigenetic process) (28
). This hypothesis is supported by a recent prospective study in which longer telomere length predicted increased NHL risk (29
Our hypothesis is also supported by observations in 2 independent TERT
(the gene that encodes the catalytic subunit of the telomerase holoenzyme) transgenic mouse models (30
). These studies showed that increased telomerase activity was associated with increased susceptibility to tumor formation. Interestingly, in spite of their increased mortality from cancer, these transgenic mice showed evidence of improved tissue regeneration as well as a slight increase in maximum life span (32
). This observation is in accordance with what had been observed in humans: that long telomere length is positively associated with longevity (26
) and decreased susceptibility to several age-related conditions such as insulin resistance (33
) and heart disease (35
). Such seemingly contradictory attributes suggest a trade-off phenomenon between competing diseases such as cancer and other age-related diseases (38
In addition to the several possible mechanisms discussed above, other factors that might play a role in increased NHL risk due to advanced paternal age include hormonal influences and decreased effectiveness of antioxidants, which could result in increased chromosomal abnormalities in spermatocytes (39
). It is thought that individuals of high socioeconomic status tend to have children at older ages and provide their children a better childhood social environment. If the increased risk of hematologic malignancies were attributable to this factor, however, we might expect to find increased risk associated with both advanced paternal age and advanced maternal age. Furthermore, in the restricted analyses among women who had no siblings, although sample size was limited, we observed a pronounced and statistically significant dose response for increased NHL risk with increasing paternal age. Nevertheless, paternal age may be a surrogate for some unmeasured confounders that confer risk of NHL.
Our study is the first known to explore the specific effect of parental age on the risk of sporadic adult-onset hematologic malignancies. Major study strengths include the prospective design, comprehensive follow-up for incident cancer diagnoses, the ability to exclude women with a family history of hematologic malignancies, and assessment of a broad range of potential confounders. Study limitations include the limited numbers of cases within NHL and leukemia subtypes for evaluation and the potential for error in participants’ reports of parental age at birth. However, self-reports of parental age have been found to be highly reliable (10
). Furthermore, given our cohort design, any such measurement error would be expected to be nondifferential with regard to risk of hematologic malignancies and attenuate any true underlying associations. Finally, 86% of cohort members were non-Hispanic white and all were women, limiting generalizability to NHL risk for other races and for men.
In conclusion, the results from this large female cohort suggest that advanced paternal age at birth may be a risk factor for NHL. Potential molecular mechanisms to explain these results, which require replication in other studies, are de novo gene mutation, aberrant paternal gene imprinting, or telomere/telomerase biology.