An information-theoretic analysis of genetics, gender and age in cancer patients

Abstract

Germline genetics, gender and hormonal-signaling pathways are all well described modifiers of cancer risk and progression. Although an improved understanding of how germline genetic variants interact with other cancer risk factors may allow better prevention and treatment of human cancer, measuring and quantifying these interactions is challenging. In other areas of research, Information Theory has been used to quantitatively describe similar multivariate interactions. We implemented a novel information-theoretic analysis to measure the joint effect of a high frequency germline genetic variant of the p53 tumor suppressor pathway (MDM2 SNP309 T/G) and gender on clinical cancer phenotypes. This analysis quantitatively describes synergistic interactions among gender, the MDM2 SNP309 locus, and the age of onset of tumorigenesis in p53 mutation carriers. These results offer a molecular and genetic basis for the observed sexual dimorphism of cancer risk in p53 mutation carriers and a model is proposed that suggests a novel cancer prevention strategy for p53 mutation carriers.

Figure 1. An information-theoretic analysis reveals a significant level of mutual information between the MDM2 SNP309 locus, but not gender, and the age of tumor onset.

In order to compare the age dependent incidence of cancer between males and females, individuals who developed primarily gender-specific cancers were excluded from this analysis, leaving STS, osteosarcomas and leukemmias as the major tumor types analyzed as depicted in the pie charts for both males (A) and females (B). (C) The bar graph depicts the bits of mutual information between the MDM2 SNP309 locus and the age of tumor onset, gender and the age of tumor onset and lastly between all three variables. The associated p-values are depicted below. (D) The cumulative incidence of tumor diagnosis for both the individuals T/T in genotype (black squares) and T/G or G/G (SNP309) in genotype (grey diamonds) is plotted as a function of age. A square or a diamond represents at least one individual. (E) The cumulative incidence of tumor diagnosis for both males (black squares) and females (grey diamonds) is plotted as a function of age.

Figure 2. The G-Allele of SNP309 Associates with an Accelerated Age of Diagnosis of Non-Gender Specific Tumors in Female but not in Male p53 Mutation Carriers.

(A) The bar graph depicts the bits of mutual information between the MDM2 SNP309 locus and the age of tumor onset in females and in males. The associated p-values are depicted below. The MDM2 SNP309 locus and the age of tumor diagnosis share significant mutual information only in females and not in males. Statistical significance is represented by the black labeling of the bar graph and the p-values depicted below. The cumulative incidence of all non-gender specific tumor types for both the individuals T/T in genotype (black squares) and T/G or G/G in genotype (grey diamonds) is plotted as a function of age for females (B) and males (C). A square or a diamond represents at least one individual.