Association of genetic variation in mitotic kinases with breast cancer risk

Abstract

An RNAi based functional screen of mitotic kinases in Drosophila recently identified a number of members of the kinome that are required for normal cell division. Depletion of these kinases resulted in a number of different mitotic abnormalities including spindle malformation, chromosome missegregation, centrosome amplification and failure of cytokinesis [1]. Since mitotic defects are commonly observed in cancer cells, these kinases may contribute to tumor development and/or progression. To investigate whether common genetic variation in the mitotic kinases are associated with breast cancer risk, we genotyped 386 single nucleotide polymorphisms (SNPs) from 44 mitotic kinase genes, in 798 breast cancer cases and 843 unaffected controls from a clinic-based study. A total of 22 SNPs from 13 kinase genes displayed significant associations with breast cancer risk (P trend ≤ 0.05), including two SNPs from FYN (rs6914091 and rs1465061) that remained of interest after accounting for multiple testing (q=0.06). These associations were stronger when evaluating cases with estrogen and progesterone receptor positive tumors. In addition, haplotype-based tests identified significant associations with risk for common haplotypes of the MAST2 (P = 0.04) and MAP2K4 (P = 0.006) genes. Although requiring replication, these findings suggest that genetic polymorphisms in mitotic kinases that have been implicated in chromosome instability and aneuploidy may contribute to the development of breast cancer.

Systematically identify key genes in inflammatory and non-inflammatory breast cancer

“…Other major related key genes identified in our study, including FYN, CAV1, HSPG2, and MMP2, have been reported to be dysregulated or involved in some important biological processes in breast cancer (Wang et al, 2010;Rao et al, 2012;Hu et al, 2013;Slattery et al, 2013), which were consistent with our results. For example, the loss of caveolin-1 (CAV1) in cancer associated fibroblasts (CAFs) is associated with the induction of the autophagic program by activating the HIF1α and NFkB, then causes the production of highly energetic nutrients to support cancer cell growth (Morandi and Chiarugi, 2014).…”

Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality

“…Here, we examined key candidate genes encoding angiogenesis factors (9, 10) mitotic kinases (11), growth stimulatory mediators and stromal factors (12, 13), as well as genes and regions suggested by expression studies (14) and genome-wide association studies (15–17). We first evaluated the association between mortality and inherited single nucleotide polymorphism (SNP) variation among invasive epithelial ovarian cancer patients seen at the Mayo Clinic, and we pursued key findings via analysis of data from The Cancer Genome Atlas (TCGA).…”

Association of Mitotic Regulation Pathway Polymorphisms with Pancreatic Cancer Risk and Outcome

“…To explore this hypothesis we evaluated associations between tagging SNPs (r 2 >0.8) from over 200 genes encoding proteins implicated in the mitotic process in breast cancer cases and unaffected controls from the Mayo Clinic Breast Cancer Study. We identified 34 SNPs from 33 genes that displayed significant associations with breast cancer risk (p<0.01) (18, 19). Here, we further evaluated the contribution of SNPs in mitotic regulators to cancer by assessing associations between these 34 SNPs and pancreatic cancer risk in a rapid ascertainment clinic-based study of 1,143 pancreatic cancer cases and 1,097 unaffected controls from the Mayo Clinic.…”