Genetic Modifiers

Abstract

Cancer is caused by a complex interaction between an individual's intrinsic genetic composition and extrinsic environmental exposures. Cancer modifiers, a special class of cancer genes that accounts for the majority of the intrinsic genetic differences in cancer susceptibility among individuals, contribute to a significant proportion of all human cancers. Modifiers are often normal allelic variants of genes that do not produce abnormal phenotypes alone, but rather “modify” the action of other cancer genes. Frequently, these genes are also called low‐penetrance cancer genes since, individually, they typically have small effects on cancer phenotypes. However, cumulatively, they can have major influences on all stages of cancer development from initiation through response to therapy. Similar to the unique characteristics that distinguish cancer modifiers from high‐penetrance cancer‐causing genes, the methods used to identify these genes are distinct. Because of the low‐penetrance nature of their actions, this class of cancer gene is particularly difficult to detect using human populations. As such, the mouse has become the predominant model to identify cancer modifiers. The unique characteristics, methods for detection and identification of cancer modifiers, and their use in human studies are described in this chapter.

Differential susceptibility to chemically induced thymic lymphomas in SENCARB and SSIN inbred mice

“…Differences in tumor susceptibility are also found among inbred strains of mice. These observations support the concept that susceptibility to most cancers is strongly influenced by low‐penetrance genes, natural allelic variants which are present in individuals and are collectively known as cancer modifiers [27]. Strain differences to susceptibility to tumor induction by different protocols emphasize the potential of the mouse as a tool in the search of cancer modifier genes [28,29].…”