Figure 4.

rs34988193 is a prognostic variant predicted to be highly deleterious.

(A) A Manhattan plot with the p-values resulting from testing each germline variant by Cox regression, controlling for the eleven covariates in bolded in Table 1. rs34988193 is prognostic (FDR<0.10) in the TCGA when restricting the analysis to the top 0.1% most deleterious variants by combined annotation dependent depletion (CADD).

(B-C) Kaplan-Meier plots depicting the deleterious outcome associated with rs34988193 in the (C) TCGA and (D) CGGA datasets, adjusted for the eleven covariates.

(D) A schematic showing that this variant is located in the ninth ankyrin repeat of ANKDD1a. The predicted protein structure of ANKDD1a reveals that this variant leads to an amino acid change from lysine to glutamate on the loop of an ankyrin repeat.

(E) Multiple sequence alignment of ANKDD1a in 22 species showing that lysine is conserved at this position in all of the species with this protein.

(F) Receiver operator characteristic curves comparing the ability of two survival models to label patients as alive or dead after seven years of follow up. The inclusion of rs61757955 variant status, rs34988193 variant status, GRB2 expression and ANKDD1a expression significantly improves the survival prediction compared to the eleven covariates bolded in table 1 alone (p=0.0279).