Cooperation of DLC1 and CDK6 affects breast cancer clinical outcome

Abstract

Low DLC1 expression is found to frequently co-occur with aberrant expression of cell cycle genes including CDK6 in human lung and colon cancer. Here, we explore the influence of the synergistic effect of DLC1 and CDK6 on human breast cancer survival at the genetic, transcriptional, and translational levels. We found that high DLC1 and low CDK6 expression are associated with good prognosis. The DLC1 intronic SNP rs561681 is found to fit a recessive model, complying with the tumor suppressive role of DLC1. The heterozygote of the DLC1 SNP is found to increase the hazard when the CDK6 intronic SNP rs3731343 is rare homozygous, and it becomes protective when rs3731343 is common homozygous. We propose that DLC1 expression is the lowest in patients harboring the rare homozygote of rs561681 and functional DLC1 is the lowest when rs561681 is heterozygous and rs3731343 is rare homozygous. We are the first to report such synergistic effects of DLC1 and CDK6 on breast cancer survival at the transcriptional level, the overdominant model fitted by the SNP pair, and the dominant negative effect at the translational level. These findings link the germline genetic polymorphisms and synergistic effect of DLC1 and CDK6 with breast cancer progression, which provide the basis for experimentally elucidating the mechanisms driving differential tumor progression and avail in tailoring the clinical treatments for such patients based on their genetic susceptibility.

Keywords: CDK6; DLC1; breast cancer; cooperation; survival.

Figure 1

Kaplan Meier plots of patients’ survival showing interactions in the identified SNP pair between DLC1 and CDK6. The plots were drawn for the DLC1 SNP (rs561681) stratified by the genotypes of the CDK6 SNP (rs3731343). Results from HEBCS and POSH data were pooled. Plots showing (A–B) the interactive effect of AA:AC/CC (aa:bB/BB, the rare homozygote of the DLC1 SNP vs. the combination of the heterozygote and common homozygote of the CDK6 SNP), (C–D) the interactive effect of AG:AA (aA:bb, the heterozygote of the DLC1 SNP vs. the rare homozygote of the CDK6 SNP), and (E–F) the interactive effect of AG:CC (aA:BB, the heterozygote of the DLC1 SNP vs. the common homozygote of the CDK6 SNP).

Figure 2

Gene expression pattern and copy number variation of DLC1 categorized by the genotypes of the DLC1 SNP (rs561681). (A) Gene expression pattern categorized by the genotypes of rs561681. (B) Copy number variation categorized by the genotypes of rs561681. The vertical axis of (A) shows the gene expression value, which is lowess-normalized, followed by log2 transformation of the ratio between two channels, and that of (B) shows the log2 transformed copy number values from Affymetrix SNP6. Both datasets are retrieved from TCGA.

Figure 3

Kaplan Meier plots of patients’ survival showing interactions between DLC1 and CDK6 gene expression. (A) Kaplan Meier plots on patient survival for DLC1 gene expression when the expression level of CDK6 is less than the 74% percentile of all the samples. (B) Kaplan Meier plots of patient survival for DLC1 gene expression when the expression level of CDK6 is no less than 74% percentile of all the samples. (C) Kaplan Meier plots of patient survival for DLC1 gene expression when all samples are included. Median was used to split the gene expression of CDK6 into high and low expressions in both subplots.