A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

Guðmundsson, Jūlı́us; Sulem, Patrick; Guðbjartsson, Daníel F.; Másson, Gísli; Agnarsson, Bjarni A.; Benediktsdóttir, Kristrún R.; Sigurðsson, Ásgeir; Magnússon, Ólafur Þ.; Gudjonsson, Sigurjon A.; Magnúsdóttir, Droplaug N; Johannsdottir, Hrefna; Helgadottir, Hafdís T.; Stacey, Simon; Jónasdóttir, Aðalbjörg; Olafsdottir, Stefania B.; Þorleifsson, Guðmar; Jonasson, Jón G.; Tryggvadóttír, Laufey; Navarrete, Sebastián; Fuertes, Fernando; Helfand, Brian T.; Hu, Qiaoyan; Csiki, Irma Eva; Mateș, Ioan Nicolae; Jinga, Viorel; Aben, Katja K.H.; Oort, Inge M. van; Vermeulen, Sita H.; Donovan, Jenny; Hamdy, Freddie C.; Ng, Chi Fai; Chiu, Peter Ka‐Fung; Lau, Kin Mang; Ng, Maggie C. Y.; Gulcher, Jeffrey R.; Kong, Augustine; Catàlona, William J.; Mayordomo, J. I.; Einarsson, Guðmundur; Barkardóttir, Rósa B.; Jónsson, Eiríkur; Mateș, Dana; Neal, David E.; Kiemeney, Lambertus A.; Þorsteinsdóttir, Unnur; Rafnar, Thorunn; Stefánsson, Kāri

doi:10.1038/ng.2437

Cited by 166 publications

(135 citation statements)

References 27 publications

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…High-throughput whole-genome sequencing techniques have already identified one such SNP in 8q24, rs188140481, that confers relatively high risk (OR ¼ 2.90) for prostate cancer (17). Such SNPs are more important for disease prediction and prevention, and more relevant for cancer screening.…”

Section: Even Snps With Weak Effects Can Identify Central Mechanisms mentioning

confidence: 99%

Lessons from Functional Analysis of Genome-Wide Association Studies

Sur

Tuupanen²,

Whitington

et al. 2013

Cancer Research

View full text Add to dashboard Cite

Most cancer-associated single-nucleotide polymorphisms (SNP) identified using genome-wide association studies are located outside of protein-coding regions, and their significance and mode of action have been a source of continuing debate. One proposed mechanism of action of the SNPs is that they would affect the activity of enhancer elements regulating critical target genes. In this review, we summarize recent results that substantiate this model. These studies have identified a cancer-specific enhancer element at the 8q24 gene desert that controls the expression of the MYC oncogene. We further discuss implications of the observed difference between normal growth control and cancer for drug development, and the inherent features of genome-wide association studies that may specifically lead to identification of disease-specific regulatory elements.

show abstract

Section: Even Snps With Weak Effects Can Identify Central Mechanisms mentioning

confidence: 99%

Lessons from Functional Analysis of Genome-Wide Association Studies

Sur

Tuupanen²,

Whitington

et al. 2013

Cancer Research

View full text Add to dashboard Cite

show abstract

“…While a rare variant of HOXB13 G84E was observed in 0.1-0.2% of the control population, the patients of hereditary PC or early-onset PC had 1-3% with an OR of 2.7-5.1 (Ewing et al 2012). WGS in an Icelandic population that identified a rare variant in the PC critical region at chromosome 8q24, whose frequency was 0.5% in the control population, which is independent of the reported SNPs or loci at chromosome 8q24 (Gudmundsson et al 2012). Now next-generation GWAS are focusing on rare variants.…”

Section: Rare Variants Associated With Pc Susceptibilitymentioning

confidence: 99%

Prostate cancer genomics by high-throughput technologies: genome-wide association study and sequencing analysis

Nakagawa¹

2013

Endocrine-Related Cancer

View full text Add to dashboard Cite

Prostate cancer (PC) is the most common malignancy in males. It is evident that genetic factors at both germline and somatic levels play critical roles in prostate carcinogenesis. Recently, genome-wide association studies (GWAS) by high-throughput genotyping technology have identified more than 70 germline variants of various genes or chromosome loci that are significantly associated with PC susceptibility. They include multiple 8q24 loci, prostate-specific genes, and metabolism-related genes. Somatic alterations in PC genomes have been explored by high-throughput sequencing technologies such as whole-genome sequencing and RNA sequencing, which have identified a variety of androgen-responsive events and fusion transcripts represented by E26 transformation-specific (ETS) gene fusions. Recent innovations in high-throughput genomic technologies have enabled us to analyze PC genomics more comprehensively, more precisely, and on a larger scale in multiple ethnic groups to increase our understanding of PC genomics and biology in germline and somatic studies, which can ultimately lead to personalized medicine for PC diagnosis, prevention, and therapy. However, these data indicate that the PC genome is more complex and heterogeneous than we expected from GWAS and sequencing analyses.

show abstract

“…Multiple SNPs in this region are associated, with association being different in different populations and multiple variants in this region are associated with other cancers. 19,20,[25][26][27] Despite some effort to directly link these variants to MYC gene expression levels, no clear correlation could be found, but this region is known to interact at the chromatin level with the MYC locus. 26,27 One of the strongest SNP associations is to the rs10993994 SNP on chromosome 10, in front of the MSMB gene.…”

Section: Genome-wide Association Studies (Gwas)mentioning

confidence: 99%

Genetics and genomics of prostate cancer

Dean¹,

Li²

2013

Asian J Androl

View full text Add to dashboard Cite

Prostate cancer (PCa) is one of the most common malignancies in the world with over 890 000 cases and over 258 000 deaths worldwide each year. Nearly all mortalities from PCa are due to metastatic disease, typically through tumors that evolve to be hormone-refractory or castrate-resistant. Despite intensive epidemiological study, there are few known environmental risk factors, and age and family history are the major determinants. However, there is extreme heterogeneity in PCa incidence worldwide, suggesting that major determining factors have not been described. Genome-wide association studies have been performed and a considerable number of significant, but low-risk loci have been identified. In addition, several groups have analyzed PCa by determination of genomic copy number, fusion gene generation and targeted resequencing of candidate genes, as well as exome and whole genome sequencing. These initial studies have examined both primary and metastatic tumors as well as murine xenografts and identified somatic alterations in TP53 and other potential driver genes, and the disturbance of androgen response and cell cycle pathways. It is hoped that continued characterization of risk factors as well as gene mutation and misregulation in tumors will aid in understanding, diagnosing and better treating PCa.

show abstract

A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

Cited by 166 publications

References 27 publications

Lessons from Functional Analysis of Genome-Wide Association Studies

Lessons from Functional Analysis of Genome-Wide Association Studies

Prostate cancer genomics by high-throughput technologies: genome-wide association study and sequencing analysis

Genetics and genomics of prostate cancer

Contact Info

Product

Resources

About