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 $G$ be a semisimple, simply connected algebraic group defined and split over a prime field ${\mathbb F}_p$ of positive characteristic. For a positive integer $r$, let $G_r$ be the $r$th Frobenius kernel of $G$. Let $Q$ be a projective indecomposable (rational) $G_r$-module. The well-known Humprheys-Verma conjecture (cf. \cite{Ballard}) asserts that the $G_r$-action on $Q$ lifts to an rational action of $G$ on $Q$. For $p\geq 2h-2$ (where $h$ is the Coxeter number of $G$), 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 $p$. 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 $p$-filtrations. The authors anticipate that the Humphreys-Verma conjecture results here will lead to extensions to smaller characteristics of these earlier papers