Abstract:The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. Dysfunction of the Hippo pathway components has been linked with breast cancer stem cell regulation, as well as breast tumor progression and metastasis. TAZ, a key component of the Hippo pathway, is highly expressed in triple negative breast cancer; however, the associations of genetic variations in this important pathway with breast cancer risk remain largely unexplo… Show more
“…We were not able to compare our association findings in WWC1 and LATS2 with the previous study in African Americans because these two genes were not included in their custom genotyping assay design . In that study, CDH1 was found to be nominally associated with ER− breast cancer risk, and approached the borderline of significance for association with ER+ breast cancer risk, while we obtained a marginal significance with ER+ breast cancer risk.…”
Section: Discussioncontrasting
confidence: 68%
“…A few studies have examined the risk of breast cancer associated with genetic variations in the Hippo pathway . Single nucleotide polymorphisms (SNPs) in YAP1 and STK4 have been reported to be associated with breast cancer risk in Chinese and European populations, respectively .…”
Section: Introductionmentioning
confidence: 99%
“…Single nucleotide polymorphisms (SNPs) in YAP1 and STK4 have been reported to be associated with breast cancer risk in Chinese and European populations, respectively . A study conducted in African Americans reported a significant association of the whole pathway with estrogen receptor negative (ER−) breast cancer, and it revealed that CDH1 was responsible for the pathway association . E‐cadherin, encoded by CDH1 , can function as an upstream regulatory element in the Hippo signaling pathway in mammalian cells .…”
Section: Introductionmentioning
confidence: 99%
“…Genetic polymorphisms in CDH1 have also been reported to be associated with breast cancer susceptibility among Chinese Han women, but no association with lobular cancer was found in a large dataset of European population with 6023 cases and 34 271 controls. A noticeable limitation of previous studies is that only polymorphisms in a single candidate gene or a small subset of genes in this pathway were assessed, while some core elements of this pathway, such as LATS1/2 , were omitted . Furthermore, in addition to single‐SNP association analysis, it has been suggested that examining a group of SNPs within a biological pathway can provide complementary and valuable insights for the genetic architecture of complex diseases …”
Gene expression changes within the Hippo pathway were found to be associated with large tumor size and metastasis in breast cancer. The combined effect of genetic variants in genes of this pathway may have a causal role in breast cancer development. We examined 7086 SNPs that were not highly correlated (r < 0.8) in 35 Hippo pathway genes using data from the genome-wide association study of breast cancer from the Root Consortium, which includes 3686 participants of African ancestry from Nigeria, United States of America, and Barbados: 1657 cases (403 estrogen receptor-positive [ER+], 374 ER-) and 2029 controls. Gene-level analyses were conducted using improved AdaJoint test for large-scale genetic association studies adjusting for age, study site and the first four eigenvectors from the principal component analysis. SNP-level analyses were conducted with logistic regression. The Hippo pathway was significantly associated with risk of ER+ breast cancer (pathway-level P = 0.019), with WWC1 (P = 0.04) being the leading gene. The pathway-level significance was lost without WWC1 (P = 0.12). rs147106204 in the WWC1 gene was the most statistically significant SNP after gene-level adjustment for multiple comparisons (OR = 0.53, 95%CI = 0.41-0.70, P = 0.025). We found evidence of an association between genetic variations in the Hippo pathway and ER+ breast cancer. Moreover, WWC1 was identified as the most important genetic susceptibility locus highlighting the importance of genetic epidemiology studies of breast cancer in understudied populations.
“…We were not able to compare our association findings in WWC1 and LATS2 with the previous study in African Americans because these two genes were not included in their custom genotyping assay design . In that study, CDH1 was found to be nominally associated with ER− breast cancer risk, and approached the borderline of significance for association with ER+ breast cancer risk, while we obtained a marginal significance with ER+ breast cancer risk.…”
Section: Discussioncontrasting
confidence: 68%
“…A few studies have examined the risk of breast cancer associated with genetic variations in the Hippo pathway . Single nucleotide polymorphisms (SNPs) in YAP1 and STK4 have been reported to be associated with breast cancer risk in Chinese and European populations, respectively .…”
Section: Introductionmentioning
confidence: 99%
“…Single nucleotide polymorphisms (SNPs) in YAP1 and STK4 have been reported to be associated with breast cancer risk in Chinese and European populations, respectively . A study conducted in African Americans reported a significant association of the whole pathway with estrogen receptor negative (ER−) breast cancer, and it revealed that CDH1 was responsible for the pathway association . E‐cadherin, encoded by CDH1 , can function as an upstream regulatory element in the Hippo signaling pathway in mammalian cells .…”
Section: Introductionmentioning
confidence: 99%
“…Genetic polymorphisms in CDH1 have also been reported to be associated with breast cancer susceptibility among Chinese Han women, but no association with lobular cancer was found in a large dataset of European population with 6023 cases and 34 271 controls. A noticeable limitation of previous studies is that only polymorphisms in a single candidate gene or a small subset of genes in this pathway were assessed, while some core elements of this pathway, such as LATS1/2 , were omitted . Furthermore, in addition to single‐SNP association analysis, it has been suggested that examining a group of SNPs within a biological pathway can provide complementary and valuable insights for the genetic architecture of complex diseases …”
Gene expression changes within the Hippo pathway were found to be associated with large tumor size and metastasis in breast cancer. The combined effect of genetic variants in genes of this pathway may have a causal role in breast cancer development. We examined 7086 SNPs that were not highly correlated (r < 0.8) in 35 Hippo pathway genes using data from the genome-wide association study of breast cancer from the Root Consortium, which includes 3686 participants of African ancestry from Nigeria, United States of America, and Barbados: 1657 cases (403 estrogen receptor-positive [ER+], 374 ER-) and 2029 controls. Gene-level analyses were conducted using improved AdaJoint test for large-scale genetic association studies adjusting for age, study site and the first four eigenvectors from the principal component analysis. SNP-level analyses were conducted with logistic regression. The Hippo pathway was significantly associated with risk of ER+ breast cancer (pathway-level P = 0.019), with WWC1 (P = 0.04) being the leading gene. The pathway-level significance was lost without WWC1 (P = 0.12). rs147106204 in the WWC1 gene was the most statistically significant SNP after gene-level adjustment for multiple comparisons (OR = 0.53, 95%CI = 0.41-0.70, P = 0.025). We found evidence of an association between genetic variations in the Hippo pathway and ER+ breast cancer. Moreover, WWC1 was identified as the most important genetic susceptibility locus highlighting the importance of genetic epidemiology studies of breast cancer in understudied populations.
“…3, 9 out of 17 modules are significantly enriched in 26 KEGG pathways. Several enriched KEGG pathways are associated with breast cancer, such as Cell cycle [50], TGF-beta signaling pathway [51], Pathways in cancer, Hippo signaling pathway [52], Ras signalling pathway [53], ErbB signaling pathway [54], Chemokine signalling pathway [55], and Calcium signalling pathway [56]. Specifically, three modules (M2, M3, and M4) are significantly involved in the KEGG pathway: Breast cancer, suggesting that the three BRCA-related miRSCoPPI modules are closely associated with breast cancer.Fig.…”
BackgroundRecent studies have shown that the crosstalk between microRNA (miRNA) sponges plays an important role in human cancers. However, the co-regulation roles of miRNA sponges in protein-protein interactions (PPIs) are still unknown.ResultsIn this study, we propose a multi-step method called miRSCoPPI to infer miRNA sponge co-regulation of PPIs. We focus on investigating breast cancer (BRCA) related miRNA sponge co-regulation, by integrating heterogeneous data, including miRNA, long non-coding RNA (lncRNA) and messenger RNA (mRNA) expression data, experimentally validated miRNA-target interactions, PPIs and lncRNA-target interactions, and the list of breast cancer genes. We find that the inferred BRCA-related miRSCoPPI network is highly connected and scale free. The top 10% hub genes in the BRCA-related miRSCoPPI network have potential biological implications in breast cancer. By utilizing a graph clustering method, we discover 17 BRCA-related miRSCoPPI modules. Through pathway enrichment analysis of the modules, we find that several modules are significantly enriched in pathways associated with breast cancer. Moreover, 10 modules have good performance in classifying breast tumor and normal samples, and can act as module signatures for prognostication. By using putative computationally predicted miRNA-target interactions, we have consistent results with those obtained using experimentally validated miRNA-target interactions, indicating that miRSCoPPI is robust in inferring miRNA sponge co-regulation of PPIs in human breast cancer.ConclusionsTaken together, the results demonstrate that miRSCoPPI is a promising tool for inferring BRCA-related miRNA sponge co-regulation of PPIs and it can help with the understanding of the co-regulation roles of miRNA sponges on the PPIs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-017-1672-2) contains supplementary material, which is available to authorized users.
Motivation: Recent breakthroughs in cancer research have come via the up-and-coming field of pathway analysis. By applying statistical methods to prior known gene and protein regulatory information, pathway analysis provides a meaningful way to interpret genomic data. While many gene/protein regulatory relationships have been studied, never before has such a significant amount data been made available in organized forms of gene/protein regulatory networks and pathways. However, pathway analysis research is still in its infancy, especially when applying it to solve practical problems. Results: In this paper we propose a new method of studying biological pathways, one that cross analyzes mutation information, transcriptome and proteomics data. Using this outcome, we identify routes of aberrant pathways potentially responsible for the etiology of disease. Each pathway route is encoded as a bayesian network which is initialized with a sequence of conditional probabilities specifically designed to encode directionality of regulatory relationships encoded in the pathways. Far more complex interactions, such as phosphorylation and methylation, among others, in the pathways can be modeled using this approach. The effectiveness of our model is demonstrated through its ability to distinguish real pathways from decoys on TCGA mRNA-seq, mutation, Copy Number Variation and phosphorylation data for both Breast cancer and Ovarian cancer study. The majority of pathways distinguished can be confirmed by biological literature. Moreover, the proportion of correctly indentified pathways is % higher than previous work where only mRNA-seq mutation data is incorporated for breast cancer patients. Consequently, such an in-depth pathway analysis incorporating more diverse data can give rise to the accuracy of perturbed pathway detection.
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