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

Peer reviewe

The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes

Li-Fraumeni syndrome (LFS) is an autosomal-dominant cancer predisposition syndrome of which the majority is caused by TP53 germline mutations and is characterised by different tumour types occurring at relatively young age. Recently, it was shown that a single-nucleotide polymorphism (SNP) in the MDM2 gene, SNP309 (T>G variation), was associated with accelerated tumour formation in LFS patients who carry a TP53 germline mutation. To confirm this finding in different populations, we screened 25 Dutch and 11 Finnish TP53 mutation carriers for the presence of the SNP309 G allele in the MDM2 gene. Additionally, we investigated whether the SNP309 G allele plays a role in 72 Dutch TP53-negative LFS and LFS-related patients. In the TP53 germline mutation carriers, a significant difference was seen in the mean age of tumour onset for the SNP309 G allele group, that is, 29.7 years as compared to the SNP309 homozygous T group 45.5 years (P=0.005). In patients of LFS and LFS-related TP53-negative families, no difference was seen in the mean age of tumour onset. However, this TP53-negative group did show a significantly higher percentage of SNP309 homozygotes (G/G) compared to the general population (P=0.02). In conclusion, TP53 germline mutation carriers who have an SNP309 G allele have an earlier onset of tumour formation. The higher prevalence of MDM2 SNP309 homozygous G/G carriers in the TP53-negative group suggests that this allele contributes to cancer susceptibility in LFS and LFS-related familie

Characteristics of three patient populations used to define MDM2 SNP309 as a modifier of tumorgenisis in p53-mutation carriers.

<p>Characteristics of three patient populations used to define MDM2 SNP309 as a modifier of tumorgenisis in p53-mutation carriers.</p

The effect of the MDM2 SNP309 locus and gender on the age of diagnosis in p53 mutation carriers.

<p>The effect of the MDM2 SNP309 locus and gender on the age of diagnosis in p53 mutation carriers.</p

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.

<p>(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.</p

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.

<p>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.</p