The diverse mutation combinations between cancer genomes [ 5] may reflect the much larger variation between their starting germline genomes.
The latter parameter is one-fourth of the corresponding v in the previous LK simulations such that the average selective advantages produced in the fitness landscape are not much larger than the mutation rate at the lower bound of 10−6; otherwise the coupling between haplotypes is too weak and no diversity will be present at equilibrium.
The breast and ovarian cancer incidences in BRCA1 and BRCA2 mutation carriers are now based on a much larger number of mutation-carrying families and are, therefore, more reliable; the variance of the polygenic component is now age dependent as opposed to constant; and the incidences vary gradually with age and are cohort and calendar period specific.
Therefore, not surprisingly, a much larger number of mutations were found in HR23 compared with LC33, with 9 indels and 67 base substitutions, the latter including 26 missense mutations, 6 premature terminations, and 21 synonymous mutations.
This variation is much larger than the variation in synonymous substitution rates, so an explanation involving variation in mutation rates seems unlikely.
Also similar to the Wood et al. mutational landscape, we found that the overall gene-based mutational landscape was dominated by a much larger number of lower mutation frequency gene hills.
In this study, we have made three assumptions about mutation effects: first, the mean effects of deleterious mutations are much larger than those of beneficial ones; second, beneficial mutation effects are exponentially distributed; and finally, deleterious mutations effects follow a gamma distribution.
Surprisingly, the Ghrhr lit / lit mutation had much larger effects on gene expression than the GHR-KO mutation, even though both mutations affect the same endocrine pathway.
The clinical and statistical evaluation of a much larger set of BRCA2 mutation carrier and non-carrier PrCa cases is underway (Castro et al, manuscript in preparation).
Although the present analysis has been performed in a much larger sample set of mutation carriers and therefore has a greater power to detect an association compared with any previously published studies it remains underpowered to identify weaker effects.
