We used a novel, sophisticated, and rigorous method that gives unbiased estimates to investigate whether CRC risks for carriers of mutations in MMR genes depend on the parent-of-origin of their mutations. We estimated that male carriers who inherit their mutations from their mothers have on average a threefold increased incidence of CRC compared with those who inherit their mutations from their fathers. The corresponding cumulative risk to age 80 years was 88% (95% CI, 54–100%) for male carriers with maternally inherited mutations, almost double that for male carriers with paternally inherited mutations. We did not observe a POE for female carriers but we had limited statistical power so we cannot exclude this possibility. If confirmed by other studies, our findings have clear implications for genetic counselling, screening protocols, and counseling about prophylactic surgery for unaffected MMR gene mutation carriers.
Our findings suggest a maternally transmitted mechanism modifying CRC risk for MMR gene mutation carriers. Potential mechanisms include epimutations or the expansion of dynamic mutations in CRC susceptibility genes during maternal meiosis. Alternatively, as MMR proteins have been found to play a role in meiotic chromosome pairing and recombination [Baker et al., 1996
; Martin et al., 2000
] and sperm have a 50% lower recombination rate than ova [Tease and Hulten, 2004
] and are exposed to strong selective pressures, potential MMR haploinsufficiency during gametogenesis could result in a higher prevalence of mutations in ova compared to sperm. This might result in higher cancer risks for the offspring of female carriers. If the mutations accumulate over subsequent generations, this might cause genetic anticipation.
To date, only one other study has been conducted into a POE for MMR gene mutation carriers. Green et al. 
used survival analysis to estimate a POE using 12 families who were recruited from a medical genetics clinic and segregated the same mutation in MSH2. Opposite to our findings, they did not observe a POE for male carriers and they estimated that female carriers who inherited their mutations from their fathers rather than their mothers were at higher risk of CRC (relative risk [RR] 2.5; P
=0.05, CIs not given), although their estimated cumulative risks for female carriers to age 80 years were 76% regardless of the parent-of-origin of the mutation. As an aside, we note that this finding is similar to the POE reported in the recent study of familial CRC by Lindor et al. 
, although that study is of low relevance here because it specifically excluded all known or likely Lynch syndrome cases.
Given the marginal significance of our findings and those of Green et al. 
, the different genes studied and the fact that failure to reject the null hypothesis can occur simply because of a lack of statistical power, the results of our study and theirs are not necessarily inconsistent. However, there is some doubt about the validity of their results due to errors in their analytical methods. Green et al. 
did not adjust for the clinic-based ascertainment of their families, they imputed values of the exposure variable (mutation status) using the outcome variable (CRC affected status) and they preferentially excluded sibships with few cancers from their analysis. Each of these would tend to upwardly bias their risk estimates [Carayol et al., 2002
] and indeed their cumulative risk estimates are much higher than recent, more statistically rigorous estimates [Jenkins et al., 2006
; Quehenberger et al., 2005
]. Biases might have been introduced into their POE estimates by the sibship exclusion criterion described above coupled with the fact that they observed more female carriers transmitting their mutations to their offspring than male carriers.
Having said that, a strength of Green et al. 
was the genetic homogeneity of their study sample and a corresponding weakness of our study is that we combined families with mutations in all four MMR genes in order to increase statistical power. The genetic heterogeneity of our study sample could cause a spurious POE if carriers who inherit their mutations from their mothers are more likely to carry mutations in higher risk MMR genes than carriers who inherit their mutations from their fathers. This would happen, for instance, if mutations in a high-risk MMR gene reduce male fertility while mutations in lower risk MMR genes do not. However, if genetic heterogeneity were acting as a confounder then the HRPOE
estimates for the individual MMR genes would all be close to 1. This is in striking contrast to the observed estimates that were all similar to or larger than the combined estimate. It therefore seems unlikely that the genetic heterogeneity of our families has caused the observed POE.
Strengths of our study include the population-based ascertainment of families, the large number and proportion of relatives typed for the family mutations, our attempts to verify cancer diagnoses, the consistency between our main results and descriptive analyses, and our rigorous and powerful statistical methods. Limitations include the genetic heterogeneity discussed above, the small number of carrier families, and the marginal statistical significance of our findings. Nevertheless, we have demonstrated the feasibility of our approach to investigate POEs.
Our method for estimating POEs is a novel application of modified segregation analysis so it inherits the following advantages from this established method: it is asymptotically unbiased and efficient, data from pedigrees of arbitrary size and structure can be combined, it maximizes power because all data are used (including data for relatives not typed for the family mutation), rigorous adjustment for ascertainment can be performed without difficulty, and it is readily implemented in the freely available pedigree analysis software MENDEL 3.2.
Our study provides the first rigorous estimate of a POE in this setting. We did not find evidence of a POE for female carriers but CRC incidences were higher for male carriers who had inherited their mutations from their mothers rather than their fathers. If confirmed, this finding will have important implications for the aetiology of CRC in Lynch syndrome and for the clinical management of MMR gene mutation carriers.