Stability of Cancer Pathways

Cancer is a genetic disease and genes operate through pathways. Variations in the gene regulation patterns in a pathway, as reflected by the change of cohesiveness in the pathway, may be indicative of pathway instability, which itself may be a result (or cause) of genetic abnormalities. Approximately half of the 962 analyzed pathways contain at least one of the 346 known "cancer genes" according to a recent census of human cancer genes (60).

A change in cohesiveness has been found in 25% of all the pathways analyzed, including both "down" and "up" pathways. The question is then whether the pathways that have shown a cohesiveness change in tumor compared to normal tissues can be considered to be cancer pathways based on the likelihood of them containing cancer genes, or whether cancer pathways in general are more likely to change their cohesiveness.

The answer to the first questions is "yes," because cancer genes are found in 57% of the pathways that have shown a change in their cohesiveness, which is significantly higher than the average probability (45%) of a pathway to contain cancer genes. (All comparative statements have been qualified using Fisher's exact test and have p-values of less than 10-3.) Moreover, a "down" pathway is found to be much more likely to contain cancer genes than an average pathway. Conversely, we have also found that cancer pathways are more likely to change their cohesiveness, that is, a significantly higher percentage of cancer pathways shows a cohesiveness change than the pathways that do not contain cancer genes (32% vs. 20%). Moreover, the cancer pathways are especially enriched in "down" pathways (22% vs. 11%), indicating that these pathways tend to become deregulated or dysfunctional in cancer.

The fact that cancer pathways tend to become less cohesive in tumor-bearing tissues may be exploited to find more cancer pathways or cancer genes; that is, other pathways that are shown to lose their cohesiveness in cancer, but are not known to contain cancer genes, may be additionally interesting pathways to be considered as therapeutic targets, for example, pathways involving fatty acid metabolism, basal transcription factors, and glycolysis/gluconeogenesis.

The instability of cancer pathways is also reflected by the number of tissue types in which they have shown a coherence change. Cancer pathways containing genes with germline or somatic mutations (66) exhibit a coherence change in significantly more tissue types than an average pathway (t-test: germline: p = 1.86 x 10-7; somatic:

p = 4.96 x 10-5), indicating that cancer pathways are generically less stable than other pathways.

Interestingly, regardless of the fact that individuals with a germline mutation carry that mutation in every cell of their body—whereas somatic mutations are found only in an individual's cancer cells (61,62) the tissue promiscuity/specificity of pathway instability is found to be not significantly different between pathways containing germline cancer genes and those containing somatic cancer genes This offers an explanation of the tissue specificity of gene defects, that is, even though the vast majority of inherited cancer genes appear to be expressed in most adult tissues, a germline mutation in these genes is manifested in only a limited spectrum of cancers.

We have found that most pathways, including the ones containing cancer genes, only show a coherence change in a small fraction of tissue types (15%-20%), indicating that probably not all mutations will be translated into pathway instability, and only in the tissue types where the stability of pathways is compromised by a mutation will cancer arise. Just as mutated proteins may render a pathway unstable or deregulated, it is equally probable that pathway instability itself may be the contributing factor to certain gene mutations. Unstable pathways are probably more susceptible to environmental influences, which can trigger or facilitate mutations. The final result will be a malignant cycle that promotes uncontrolled growth. The implication that pathway instability may be the cause of genetic instability makes pathways as a system of interactions, rather than individual genes, an interesting, albeit diffuse, target in itself for therapy considerations.

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