In this study of 2061 pairs, selected from the Colon Cancer Family Registry,8
we sought to look at age of onset in affected offspring of affected mothers versus affected fathers as a potential marker for parent of origin effect on development of CRC. These data showed a similar age at diagnosis of CRC among all offspring of affected mothers and this was indistinguishable from age of onset in the sons of affected fathers (study design prohibits looking for anticipation in this data set). Unexpectedly, the daughters of affected fathers were, on average three years younger at diagnosis than all other offspring. Parent-of-origin effects relate to the gender of the parent
, not the offspring. Here we have a parent of origin effect (father) affecting age of onset in a gender-specific manner (daughters younger at diagnosis). There is not an obvious explanation based on ascertainment biases that might explain this observation. The ages at diagnosis of the mothers and fathers of sons and daughters affected with CRC were comparable. Although we do not have the data to prove it, it seems improbable that daughters of affected fathers were simply screening earlier or more diligently than all other offspring of affected parents.
Curiously, this sort of finding has been reported previously, albeit in the context of extended Lynch Syndrome kindred in Newfoundland (Lynch Syndrome families were excluded to the best of our ability in this study). Among 12 families with a founder mutation in MSH2
, females who inherited the mutation from their fathers had an increased risk of developing colorectal cancers (relative risk 2.5, p=0.05) and of dying of cancer (relative risk 2.7. p=0.04), compared with females who inherited the founder mutation from their mother.12
These results, combined with our current study support the existence of a mechanism for modification of colorectal cancer risk in a parent of origin specific manner that is operative in Lynch syndrome as well as in non syndromic familial CRC.
What biological factors could explain this aggregation of findings? Several hypotheses could be formulated. One might involve non random X inactivation in colonic tissue. The primary genetic difference between sons and daughters of fathers is that daughters inherit an X chromosome from their fathers, while sons do not. In each cell, one of the two X chromosomes of females is lyonized (undergoes inactivation). As selection of which X chromosome undergoes inactivation is thought to be a random event, there is equal probability overall of having cells with a maternal X inactivated or a paternal X inactivated. We could not determine from medical literature if this was true in normal colonic tissue, as there has been no reason to investigate this phenomenon. It is conceivable that there could be preferential inactivation of a maternal X chromosome in colonic tissue, so if father carried an X-linked predisposition allele on the X chromosome, the daughters might be at increased risk, developing cancer at a younger age.
A second hypothesis might relate to genomic imprinting of certain genes on the X chromosome itself. In reality, not all of the inactive X chromosome is inactivated: there are two pseudoautosomal regions near the telomeres on each chromosomal arm, and the inactivation center is active, transcribing the XIST
gene, resulting in the spread of inactivation along most of the inactive X chromosome. Thus, the genes that are not
involved in that major inactivation process would be candidates for genomic imprinting just as occurs on the autosomes. To our knowledge, parent of origin expression differences in the pseudoautosomal genes have not been reported. There is, however, a small and intriguing body of literature suggesting that this idea is plausible. Stemkens et al. (2006) noted phenotypic differences in men with Klinefelter Syndrome (47,XXY) when the two Xs were both of maternal origin compared with men in which one of the X chromosomes was of paternal origin: among 54 cases, impaired speech and motor development and increased body size was more common in those with a paternally inherited X suggesting the possibility of X chromosomal imprinting.13
There are conflicting reports on whether or not there are phenotypic differences in women with Turner Syndrome (45,X karyotype) according to whether the retained X is of maternal or paternal origin.14–18
In another study it was noted that male-to-female transsexuals have a significant excess of maternal aunts vs. uncles. The authors hypothesized there may be genes on the X chromosome that escape inactivation but may be imprinted: the first generation would be characterized by a failure to erase the paternal imprints on the paternal X chromosome. Daughters in the next generation would produce sons that are XpY or XmY. Since XpY expresses Xist, due to failure to erase the paternal imprint from generation 1, the X chromosome is inappropriately silenced and half of the sons are lost at the earliest stages of pregnancy. The authors go on to speculate further about how this relates to gender identification. Several imprinted genes on the X-chromosome have been identified in animals (listed at www.otago.ac.nz/IGC
) including mouse, Drosophila
, and sheep, but relevance to humans is unknown. Imprinting of human X chromosomal genes still remains an unproven possibility.
A third possible explanation for our observation is that there may be imprinted genes on the autosomal chromosomes that differentially affect expression in males versus females. Certainly there are a number of gender-related genes that are autosomal (e.g., those that direct expression of estrogenic and androgenic steroids, or receptors for steroids) that could be affected by imprinting resulting in gender-specific differences in offspring. Peters and Robson (2008) have reported now that micro-RNAs are included in the growing number of genes that are imprinted and expressed differently if maternally versus paternally inherited providing yet another explanation for the observed data in this study.
In conclusion, a large study of parent-offspring pairs affected with CRC, in which efforts were made to exclude single gene disorders, found the affected daughters of affected fathers were, on average, younger than affected sons of affected fathers and affected daughters and sons of affected mothers. This pattern is not consistent with our current understanding of genomic imprinting effect unless it involved the X-inactivation process somehow or if there was imprinting of the pseudoautosomal region of the X or X-chromosomal effects upon expression of sex-related autosomal genes. Similar results have been noted among Lynch Syndrome kindreds, suggesting the presence of a mechanism that is not disease specific. These results need confirmation in an independent data set before being considered potentially clinically relevant.