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The expression of tumour suppressors and proto-oncogenes in tissues susceptible to their hereditary cancers.
BackgroundStudies of familial cancers have found that only a small subset of tissues are affected by inherited mutations in a given tumour suppressor gene (TSG) or proto-oncogene (POG), even though the mutation is present in all tissues. Previous tests have shown that tissue specificity is not due to the presence vs absence of gene expression, as TSGs and POGs are expressed in nearly every type of normal human tissue. Using published microarray expression data we tested the related hypothesis that tissue-specific expression of a TSG or POG is highest in tissue where it is of oncogenic importance.MethodsWe tested this hypothesis by examining whether individual TSGs and POGs had higher expression in the normal (noncancerous) tissues where they are implicated in familial cancers relative to those tissues where they are not. We examined data for 15 TSGs and 8 POGs implicated in familial cancer across 12 human tissue types.ResultsWe found a significant difference between expression levels in susceptible vs nonsusceptible tissues. It was found that 9 (60%, P<0.001) of the TSGs and 5 (63%, P<0.001) of the POGs had their highest expression level in the tissue type susceptible to their oncogenic effect.ConclusionsThis highly significant association supports the hypothesis that mutation of a specific TSG or POG is likely to be most oncogenic in the tissue where the gene has its highest level of expression. This suggests that high expression in normal tissues is a potential marker for linking cancer-related genes with their susceptible tissues
Forced gradings and the Humphreys-Verma conjecture
Let be a semisimple, simply connected algebraic group defined and split
over a prime field of positive characteristic. For a positive
integer , let be the th Frobenius kernel of . Let be a
projective indecomposable (rational) -module. The well-known
Humprheys-Verma conjecture (cf. \cite{Ballard}) asserts that the -action
on lifts to an rational action of on . For (where
is the Coxeter number of ), this conjecture was proved by Jantzen in 1980,
improving on early work of Ballard. However, it remains open for general
characteristics. In this paper, the authors establish several graded analogues
of the Humphreys-Verma conjecture, valid for all . The most general of our
results, proved in full here, was announced (without proof) in an earlier
paper. Another result relates the Humphreys-Verma conjecture to earlier work of
Alperin, Collins, and Sibley on finite group representation theory. A key idea
in all formulations involves the notion of a forced grading. The latter goes
back, in particular, to the recent work of the authors, relating graded
structures and -filtrations. The authors anticipate that the Humphreys-Verma
conjecture results here will lead to extensions to smaller characteristics of
these earlier papers
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