Genome-wide association studies of cancer: current insights and future perspectives

Sud, Amit; Kinnersley, Ben; Houlston, Richard S.

doi:10.1038/nrc.2017.82

Cited by 316 publications

(322 citation statements)

References 194 publications

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“…In oncology, almost all common malignancies have been studied by GWAS and several genetic variants associated with increased risks have been identified 1 . These discoveries have suggested that much of the genetic architecture of cancer susceptibility is explained by polygenic inheritance.…”

Section: Introductionmentioning

confidence: 99%

“…These discoveries have suggested that much of the genetic architecture of cancer susceptibility is explained by polygenic inheritance. One of the most relevant deliverables from GWAS is also that the identification of causative variants of genes in specific pathways would provide new insights into cancer biology as previously demonstrated 1, 2 . However, variants identified within the above mentioned studies are usually markers and not represent the causative variants themselves.…”

Section: Introductionmentioning

confidence: 99%

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Fine mapping of 2q35 high‐risk neuroblastoma locus reveals independent functional risk variants and suggests full‐length BARD1 as tumor‐suppressor

Cimmino

Avitabile

Diskin

et al. 2018

Intl Journal of Cancer

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A previous genome-wide association study (GWAS) identified common variation at the BARD1 locus as being highly associated with susceptibility to high-risk neuroblastoma, but the mechanisms underlying this association have been not extensively investigated. Here, we performed a fine mapping analysis of BARD1 locus (2q35) using GWAS data from 556 high-risk neuroblastoma patients and 2,575 controls of European-American ancestry, and identified two independent genome-wide neuroblastoma-associated loci. Functional single-nucleotide polymorphism (SNP) prioritization identified two causative variants that independently contributed to neuroblastoma risk, and each replicated robustly in multiple independent cohorts comprising 445 high-risk cases and 3,170 controls (rs17489363: combined p = 1.07 × 10 , OR:1.79, 95% CI:1.62-1.98 and rs1048108: combined p = 7.27 × 10 , OR:0.65, 95% CI:0.58-0.73). Particularly, the T risk allele of rs17489363 in the canonical promoter region of full-length BARD1 altered binding site of the transcription factor HSF1 and correlated with low expression of full-length BARD1 mRNA and protein. Low-level expression of full-length BARD1 associated with advanced neuroblastoma. In human neuroblastoma cells, attenuating full-length BARD1 increased proliferation and invasion capacity. In conclusion, we have identified two potentially causative SNPs at the BARD1 locus associated with predisposition to high-risk neuroblastoma, and have shown that full-length BARD1 may act as tumor suppressor.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fine mapping of 2q35 high‐risk neuroblastoma locus reveals independent functional risk variants and suggests full‐length BARD1 as tumor‐suppressor

Cimmino

Avitabile

Diskin

et al. 2018

Intl Journal of Cancer

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“…eQTL data further demonstrated that the substitution of rs17458086 T to C significantly enhanced the mRNA expression of SLC2A13 . In addition, we noticed that the frequency of the rare allele C of SLC2A13 rs17458086 was just above the level of the inclusive criteria (1.0%‐1.6%), which reinforces that the functions of this class of subpolymorphic risk alleles (ie, those with rare risk allele frequencies <1%) have not been thoroughly investigated . Both SLC2A6 and SLC2A13 belong to SLC family members and encode GLUT6 and GLUT13, respectively.…”

Section: Discussionmentioning

confidence: 88%

Three novel genetic variants in NRF2 signaling pathway genes are associated with pancreatic cancer risk

et al. 2019

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Pancreatic cancer (PanC) is one of the most lethal solid malignancies, and metastatic PanC is often present at the time of diagnosis. Although several high‐ and low‐penetrance genes have been implicated in PanC, their roles in carcinogenesis remain only partially elucidated. Because the nuclear factor erythroid2‐related factor2 (NRF2) signaling pathway is involved in human cancers, we hypothesize that genetic variants in NRF2 pathway genes are associated with PanC risk. To test this hypothesis, we assessed associations between 31 583 common single nucleotide polymorphisms (SNP) in 164 NRF2‐related genes and PanC risk using three published genome‐wide association study (GWAS) datasets, which included 8474 cases and 6944 controls of European descent. We also carried out expression quantitative trait loci (eQTL) analysis to assess the genotype‐phenotype correlation of the identified significant SNP using publicly available data in the 1000 Genomes Project. We found that three novel SNP (ie, rs3124761, rs17458086 and rs1630747) were significantly associated with PanC risk ( P = 5.17 × 10 −7 , 5.61 × 10 −4 and 5.52 × 10 −4 , respectively). Combined analysis using the number of unfavorable genotypes (NUG) of these three SNP suggested that carriers of two to three NUG had an increased risk of PanC ( P < 0.0001), compared with those carrying zero to one NUG. Furthermore, eQTL analysis showed that both rs3124761 T and rs17458086 C alleles were associated with increased mRNA expression levels of SLC2A6 and SLC2A13 , respectively ( P < 0.05). In conclusion, genetic variants in NRF2 pathway genes could play a role in susceptibility to PanC, and further functional exploration of the underlying molecular mechanisms is warranted.

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“…Genome‐wide association studies (GWAS) have identified thousands of risk‐associated SNPs for many common diseases including cancer . Individually, these SNPs have a moderate effect on disease risk, with odds ratios (OR) typically ranging from 1.1‐1.5.…”

Section: Introductionmentioning

confidence: 99%

Concept and benchmarks for assessing narrow‐sense validity of genetic risk score values

Shi

et al. 2019

The Prostate

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Background While higher genetic risk score (GRS) has been statistically associated with increased disease risk (broad‐sense validity), the concept and tools for assessing the validity of reported GRS values from tests (narrow‐sense validity) are underdeveloped. Methods We propose two benchmarks for assessing the narrow‐sense validity of GRS. The baseline benchmark requires that the mean GRS value in a general population approximates 1.0. The calibration benchmark assesses the agreement between observed risks and estimated risks (GRS values). We assessed benchmark performance for three prostate cancer (PCa) GRS tests, derived from three SNP panels with increasing stringency of selection criteria, in a PCa chemoprevention trial where 714 of 3225 men were diagnosed with PCa during the 4‐year follow‐up. Results GRS from Panels 1, 2, and 3 were all statistically associated with PCa risk; P = 5.58 × 10−3, P = 1 × 10−3, and P = 1.5 × 10−13, respectively (broad‐sense validity). For narrow‐sense validity, the mean GRS value among men without PCa was 1.33, 1.09, and 0.98 for Panels 1, 2, and 3, respectively (baseline benchmark). For assessing the calibration benchmark, observed risks were calculated for seven groups of men with GRS values <0.3, 0.3–0.79, 0.8–1.19, 1.2‐1.49, 1.5‐1.99, 2‐2.99, and ≥3. The calibration slope (higher is better) was 0.15, 0.12, and 0.60, and the bias score (lower is better) between the observed risks and GRS values was 0.08, 0.08, and 0.02 for Panels 1, 2, and 3, respectively. Conclusion Performance differed considerably among GRS tests. We recommend that all GRS tests be evaluated using the two benchmarks before clinical implementation for individual risk assessment.

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Genome-wide association studies of cancer: current insights and future perspectives

Cited by 316 publications

References 194 publications

Fine mapping of 2q35 high‐risk neuroblastoma locus reveals independent functional risk variants and suggests full‐length BARD1 as tumor‐suppressor

Fine mapping of 2q35 high‐risk neuroblastoma locus reveals independent functional risk variants and suggests full‐length BARD1 as tumor‐suppressor

Three novel genetic variants in NRF2 signaling pathway genes are associated with pancreatic cancer risk

Concept and benchmarks for assessing narrow‐sense validity of genetic risk score values

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