Genome-wide haplotype association study identifies BLM as a risk gene for prostate cancer in Chinese population

Wang, Qun; Lv, Hongchao; Lv, Wenhua; Shi, Miao; Zhang, Mingming; Luan, Meiwei; Zhu, Hongjie; Zhang, Ruijie; Jiang, Yixiang

doi:10.1007/s13277-014-2893-x

Cited by 15 publications

(13 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We first estimated the haplotypes and their frequencies in the LD blocks using the maximum likelihood (ML) method and expectation-maximization (EM) algorithm. Then, we performed the chi-square test for haplotype-phenotype association 26 , and statistical significance was also determined. We considered raw P -values ( P raw ) <1 × 10 −7 as significant and P -values <0.05 after 100,000 permutations as genome-wide significant (i.e.…”

Section: Methodsmentioning

confidence: 99%

A genome-wide association study identifies a genomic region for the polycerate phenotype in sheep (Ovis aries)

Ren

Yang

Peng

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Horns are a cranial appendage found exclusively in Bovidae, and play important roles in accessing resources and mates. In sheep (Ovies aries), horns vary from polled to six-horned, and human have been selecting polled animals in farming and breeding. Here, we conducted a genome-wide association study on 24 two-horned versus 22 four-horned phenotypes in a native Chinese breed of Sishui Fur sheep. Together with linkage disequilibrium (LD) analyses and haplotype-based association tests, we identified a genomic region comprising 132.0–133.1 Mb on chromosome 2 that contained the top 10 SNPs (including 4 significant SNPs) and 5 most significant haplotypes associated with the polycerate phenotype. In humans and mice, this genomic region contains the HOXD gene cluster and adjacent functional genes EVX2 and KIAA1715, which have a close association with the formation of limbs and genital buds. Our results provide new insights into the genetic basis underlying variable numbers of horns and represent a new resource for use in sheep genetics and breeding.

show abstract

Section: Methodsmentioning

confidence: 99%

A genome-wide association study identifies a genomic region for the polycerate phenotype in sheep (Ovis aries)

Ren

Yang

Peng

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Studies have also shown that BLM is highly expressed in breast cancer tissue and represents a novel breast cancer biomarker [21, 22]. Nonsense mutations in the BLM gene increase the risk of PC [23], and BLM expression is associated with PC susceptibility in the Chinese population [24]. Previous work has shown that knockdown of BLM inhibits PC cell proliferation and promotes PC apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells

Chen

Zhao

2019

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Purpose. Prostate cancer (PC) is a common malignant tumor and a leading cause of cancer-related death in men worldwide. In order to design new therapeutic interventions for PC, an understanding of the molecular events underlying PC tumorigenesis is required. Bloom syndrome protein (BLM) is a RecQ-like helicase, which helps maintain genetic stability. BLM dysfunction has been implicated in tumor development, most recently during PC tumorigenesis. However, the molecular basis for BLM-induced PC progression remains poorly characterized. In this study, we investigated whether BLM modulates the phosphorylation of an array of prooncogenic signaling pathways to promote PC progression. Methods. We analyzed differentially expressed proteins (DEPs) using iTRAQ technology. Site-directed knockout of BLM in PC-3 prostate cancer cells was performed using CRISPR/Cas9-mediated homologous recombination gene editing to confirm the effects of BLM on DEPs. PathScan® Antibody Array Kits were used to analyze the phosphorylation of nodal proteins in PC tissue. Immunohistochemistry and automated western blot (WES) analyses were used to validate these findings. Results. We found that silencing BLM in PC-3 cells significantly reduced their proliferative capacity. In addition, BLM downregulation significantly reduced levels of phosphorylated protein kinase B (AKT (Ser473)) and proline-rich AKT substrate of 40 kDa (PRAS40 (Thr246)), and this was accompanied by enhanced ROS (reactive oxygen species) levels. In addition, we found that AKT and PRAS40 inhibition reduced BLM, increased ROS levels, and induced PC cell apoptosis. Conclusions. We demonstrated that BLM activates AKT and PRAS40 to promote PC cell proliferation and survival. We further propose that ROS act in concert with BLM to facilitate PC oncogenesis, potentially via further enhancing AKT signaling and downregulating PTEN expression. Importantly, inhibiting the BLM-AKT-PRAS40 axis induced PC cell apoptosis. Thus, we highlight new avenues for novel anti-PC treatments.

show abstract

“…Subsequent studies did not find a positive association between this mutation and prostate cancer nor with ovarian cancer [Antczak et al, 2013;Bogdanova et al, 2015]. An increased risk for prostate cancer was found in Chinese men with a BLM haplotype block [Wang et al, 2015]. Mono-allelic loss-of-function BLM mutations were also found at a higher frequency than expected in an Australian highrisk breast cancer cohort [Thompson et al, 2012] and in an early-onset colorectal cancer cohort from the Netherlands [de Voer et al, 2015].…”

Section: Structure and Function Of The Blm Genementioning

confidence: 94%

Bloom's Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition

2016

View full text Add to dashboard Cite

Bloom's syndrome is an autosomal recessive disorder characterized by prenatal and postnatal growth deficiency, photosensitive skin changes, immune deficiency, insulin resistance, and a greatly increased risk of early onset of cancer and for the development of multiple cancers. Loss-of-function mutations of BLM, which codes for a RecQ helicase, cause Bloom's syndrome. The absence of a functional BLM protein causes chromosome instability, excessive homologous recombination, and a greatly increased number of sister chromatid exchanges that are pathognomonic of the syndrome. A common founder mutation designated blm^Ash is present in about 1 in 100 persons of Eastern European Jewish ancestry, and there are additional recurrent founder mutations among other populations. Missense, nonsense, and frameshift mutations as well as multiexonic deletions have all been observed. Bloom's syndrome is a prototypical chromosomal instability syndrome, and the somatic mutations that occur as a result of that instability are responsible for the increased cancer risk. Although there is currently no treatment aimed at the underlying genetic abnormality, persons with Bloom's syndrome benefit from sun protection, aggressive treatment of infections, surveillance for insulin resistance, and early identification of cancer.

show abstract

Genome-wide haplotype association study identifies BLM as a risk gene for prostate cancer in Chinese population

Cited by 15 publications

References 23 publications

A genome-wide association study identifies a genomic region for the polycerate phenotype in sheep (Ovis aries)

A genome-wide association study identifies a genomic region for the polycerate phenotype in sheep (Ovis aries)

Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells

Bloom's Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition

Contact Info

Product

Resources

About