Abstract

Abstract: It is becoming increasingly clear that the association between mutations and disease phenotypes in many instances are likely to be more complex than originally thought. For example, in a number of cases of classic single locus specific diseases, individuals lacking mutations in putative disease-associated genes have the disease phenotype, while individuals with specific mutations proven to be associated with the disease phenotype are perfectly normal. Further, we now know that many factors besides specific alterations to the genome can determine the product produced by a gene. At the present time our efforts have been limited to identifying a few of these possible genome-modifying factors, such as epigenetic processes, while other factors such protein-protein interactions, and the effect of tissue microenvironment have as received limited attention.

In the case of multifactorial diseases, such as cancer, the situation has become further confused as hundreds of genes have been identified as disease-associated, even though they may make very small contributions as individual genes to the cancer phenotype. An additional complication is that somatic genetic changes have been identified in putative cancer-associated genes not just in tumors but in normal tissues as well. Recently, the discovery within tumors of genetic heterogeneity has further added to the complexity of the genotype-phenotype relationship.

Traditionally, in our attempts to determine pathogenicity, we have assumed that our basic understanding of the relationship between genotype and phenotype is one of cause and effect, and that causes of pathogenicity need to be found within our understanding that specific mutations in particular genes will produce a specific disease phenotype. However, this talk will challenge some of these assumptions in order to explore some of the fundamental genetic issues raised by the above observations and how they might be incorporated into methodologies to determine not just pathogenicity in the age of precision medicine, but in the case of cancer a better understanding of the relationship between genetics, treatment and cure.