Integration of somatic mutation, expression and functional data reveals potential driver genes predictive of breast cancer survival

Suo, Chen; Hrydziuszko, Olga; Lee, Donghwan; Pramana, Setia; Saputra, Dhany; Joshi, Himanshu; Calza, Stefano; Pawitan, Yudi

doi:10.1093/bioinformatics/btv164

Cited by 44 publications

(37 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…62 Finally, while these methods mainly exploit DNA alterations, it is important to take into account RNA expression levels (determined for example by gene-expression array) that have been successfully used to identify points of addictions of the tumour cells and that should be integrated with DNA alterations for better predictions of t argetable pathways in cancer. 63 The ER is the most validated target to date in breast cancer, where altered protein expression is the key feature, any new target should be defined by protein overexpression and/or pathway activation, rather than DNA alterations alone. Several arguments support the hypothesis that pathway and protein activation could be as important as DNA mutations in breast cancer.…”

Section: Driver Identificationmentioning

confidence: 99%

Precision medicine for metastatic breast cancer—limitations and solutions

et al. 2015

View full text Add to dashboard Cite

The development of precision medicine for the management of metastatic breast cancer is an appealing concept; however, major scientific and logistical challenges hinder its implementation in the clinic. The identification of driver mutational events remains the biggest challenge, because, with the few exceptions of ER, HER2, PIK3CA and AKT1, no validated oncogenic drivers of breast cancer exist. The development of bioinformatic tools to help identify driver mutations, together with assessment of pathway activation and dependency should help resolve this issue in the future. The occurrence of secondary resistance, such as ESR1 mutations, following endocrine therapy poses a further challenge. Ultra-deep sequencing and monitoring of circulating tumour DNA (ctDNA) could permit early detection of the genetic events underlying resistance and inform on combination therapy approaches. Beside these scientific challenges, logistical and operational issues are a major limitation to the development of precision medicine. For example, the low incidence of most candidate genomic alterations hinders randomized trials, as the number of patients to be screened would be too high. We discuss these limitations and the solutions, which include scaling-up the number of patients screened for identifying a genomic alteration, the clustering of genomic alterations into pathways, and the development of personalized medicine trials.

show abstract

Section: Driver Identificationmentioning

confidence: 99%

Precision medicine for metastatic breast cancer—limitations and solutions

et al. 2015

View full text Add to dashboard Cite

show abstract

“…145,289,290 However, transcriptional and epigenomic control of breast epithelial systems in human cells does not reveal a genome-wide significant role for the VDR, 291 and the major breast cancer papers from TCGA have not identified a genome-wide significant role for the VDR to act as a cancer driver. [292][293][294][295] Putting these findings together from leukemia and common cancers suggests that the VDR itself does not act as a direct cancer driver, either through loss or gain of function. This finding may limit the likelihood of therapeutic exploitation in the cancer context.…”

Section: Author Manuscriptmentioning

confidence: 99%

Vitamin D Receptor Signaling and Cancer

Campbell

Trump

2017

Endocrinology and Metabolism Clinics of North America

View full text Add to dashboard Cite

The primary biological action of the secosteroid hormone vitamin D (1,25(OH) 2 D 3 ) is to bind to the vitamin D receptor (NR1I1/VDR) and to regulate serum calcium levels. As a downstream consequence, the actions of the receptor control bone formation and maintenance. The first clinical manifestation of insufficient VDR endocrine signaling, rickets, was discovered by Daniel Whistler in the Netherlands in the 17th century; 300 years later, the VDR gene was cloned by Bert O'Malley and coworkers. 1 Between these dates, research into vitamin D was at the forefront of areas of public health, chemistry and biochemistry including the light catalyzed synthesis of vitamin D 3 by Adolf Windaus. For this work, he received the Nobel Prize in Chemistry (1928). Work in the 1960s and 1970s led to analyses of vitamin D endocrine metabolism and led to remarkable strides describing biochemical synthesis of 1,25(OH) 2 D 3 and the diverse biology in which VDR participates.The precursor of 1,25(OH) 2 D 3 , cholecalciferol or vitamin D 3 , is produced in the skin and converted in the liver to 25-hydroxyvitamin D 3 , (25(OH)D 3 ); circulating levels of 25(OH)D 3 serve as a useful index of vitamin D total body stores. A further hydroxylation occurs in the principally in the kidney at the carbon 1 position by 25-hydroxyvitamin D-1α-hydroxylase (encoded by CYP27B1) to produce the biologically active hormone, 1,25(OH) 2 D 3 . A second mitochondrial cytochrome P450 enzyme, the 24-hydroxylase (encoded by CYP24A1), can use both 25(OH)D and 1,25(OH) 2 D 3 as substrates, and is the first step in the inactivation pathway for these metabolites. Because of the direct role 1,25(OH) 2 D 3 plays in control of serum calcium levels, elevated levels of 1,25(OH) 2 D 3 block its synthesis and induce inactivation and accelerate catabolism 2 via induction of CYP24A1, in a classical negative feedback loop.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). The first report that VDR actions could control cancer cell growth were discovered partly through serendipity, and partly through logical extension of other studies. Reports in the 1970s identified purified cell fractions that bound 1,25(OH) 2 D 3 with high affinity, 14 and encouraged investigators to begin to consider what were the molecular actions of the VDR in the classic tissues involved in calcium homeostasis, for example, skin, bone, intestine, and kidney. 15 In 1981, Kay Colston and coworkers 16 were first to demonstrate that 1α,25(OH) 2 D 3 at nanomolar concentrations inhibited human melanoma cell proliferation in vitro. That the workers used a cancer cell model was serendipitous; cancer cell models are more readily available to study in cell culture experiments than nonmalignant counterparts, and in this case 16 the cells chosen were available in an adjacent laboratory. Campbell and Trump In parallel, it was also known that retinoids, which are also small lipophilic molecules that target NRs, could drive cell differentiation, for exa...

show abstract

“…With rapid advances in high-throughput sequencing technologies, some large-scale cancer genomics projects, such as The Cancer Genome Atlas (TCGA) [1] and International Cancer Genome Consortium (ICGC) [2], have produced different omics data including a rich dataset of whole-exome and RNA sequence data [3,4], which provides chances to allow us to accurately infer tumorspecific alterations [5] and help in precision medicine in cancers treatment [6,7]. However, many of genetic changes represent neutral variations that do not contribute to cancer development which are called passenger mutations [6,8].…”

Section: Introductionmentioning

confidence: 99%

DriverFinder: A Gene Length-Based Network Method to Identify Cancer Driver Genes

Wei

Zhang

et al. 2017

Complexity

View full text Add to dashboard Cite

Integration of multi-omics data of cancer can help people to explore cancers comprehensively. However, with a large volume of different omics and functional data being generated, there is a major challenge to distinguish functional driver genes from a sea of inconsequential passenger genes that accrue stochastically but do not contribute to cancer development. In this paper, we present a gene length-based network method, named DriverFinder, to identify driver genes by integrating somatic mutations, copy number variations, gene-gene interaction network, tumor expression, and normal expression data. To illustrate the performance of DriverFinder, it is applied to four cancer types from The Cancer Genome Atlas including breast cancer, head and neck squamous cell carcinoma, thyroid carcinoma, and kidney renal clear cell carcinoma. Compared with some conventional methods, the results demonstrate that the proposed method is effective. Moreover, it can decrease the influence of gene length in identifying driver genes and identify some rare mutated driver genes.

show abstract

Integration of somatic mutation, expression and functional data reveals potential driver genes predictive of breast cancer survival

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 44 publications

References 28 publications

Precision medicine for metastatic breast cancer—limitations and solutions

Precision medicine for metastatic breast cancer—limitations and solutions

Vitamin D Receptor Signaling and Cancer

DriverFinder: A Gene Length-Based Network Method to Identify Cancer Driver Genes

Contact Info

Product

Resources

About