| 71. |
- Ji, Xuemei, et al.
(författare)
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Protein-altering germline mutations implicate novel genes related to lung cancer development
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
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| 72. |
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| 73. |
- Jiang, X., et al.
(författare)
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Shared heritability and functional enrichment across six solid cancers
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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| 74. |
- Johansson, Mattias, et al.
(författare)
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Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer
- 2007
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Ingår i: International Journal of Cancer. - German Canc Res Ctr, Div Canc Epidemiol, DKFZ, D-69121 Heidelberg, Germany. Umea Univ Hosp, Dept Surg & Perioperat Sci Urol & Androl, S-90185 Umea, Sweden. Int Agcy Res Canc, F-69372 Lyon, France. Menzies Res Inst, Hobart, Tas, Australia. German Canc Inst, Genom Epidemiol Grp, DKFZ, Heidelberg, Germany. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Harvard Univ, Dept Epidemiol, Boston, MA 02115 USA. : Wiley. - 0020-7136 .- 1097-0215. ; 120:3, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor-I (IGF1) stimulates cell proliferation, decreases apoptosis, and has been implicated in cancer development. Epidemiological studies have shown elevated levels of circulating IGF1 to be associated with increased risk of prostate cancer. To what extent genetic variation in the IGF1 gene is related to prostate cancer risk is largely unknown. We performed a comprehensive haplotype tagging (HT) assessment of single nucleotide polymorphisms (SNPs) representing the common haplotype variation in the IGF1 gene. We genotyped 10 SNPs (9 haplotype tagging SNPs (htSNPs)) within Cancer Prostate in Sweden (CAPS), a case–control study of 2,863 cases and 1,737 controls, in order to investigate if genetic variation in the IGF1 gene is associated with prostate cancer risk. Three haplotype blocks were identified across the IGF1 gene and 9 SNPs were selected as haplotype tagging SNPs. Common haplotypes in the block covering the 3′ region of the IGF1 gene showed significant global association with prostate cancer risk (p = 0.004), with one particular haplotype giving an odds ratio of 1.46 (95% CI = 1.15–1.84, p = 0.002). This haplotype had a prevalence of 5% in the study population. Our results indicate that common variation in the IGF1 gene, particularly in the 3′ region, may affect prostate cancer risk. Further studies on genetic variations in the IGF1 gene in relation to prostate cancer risk as well as to circulating levels of IGF1 are needed to confirm this novel finding.
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| 75. |
- Johansson, Mattias, et al.
(författare)
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Genetic and plasma variation of insulin-like growth factor binding proteins in relation to prostate cancer incidence and survival
- 2009
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 69:12, s. 1281-1291
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Binding proteins regulate bioavailability of insulin-like growth factor-I (IGF-I) in the circulation and affect apoptosis of tumor cells in the prostate. We analyzed genetic variation within genes coding for IGF binding proteins in relation to prostate cancer incidence and survival. We also investigated if circulating IGFBP3 affects prostate cancer-specific survival. MATERIALS AND METHODS: Eleven haplotype tagging SNPs and two single SNPs in the IGFBP1, IGFBP3, and IGFALS genes were genotyped within the CAncer Prostate in Sweden (CAPS) study including 2,774 cases and 1,736 controls. Plasma samples for analyses of total- and intact IGFBP3 levels were available for 1,521 cases and 909 controls. Complete follow-up of vital status was achieved by linkage to the Swedish Cause of Death Register. RESULTS: We found no clear association between the genetic variants and prostate cancer incidence or survival. The rare allele of the IGFBP3 SNP rs2854744 was associated with elevated plasma levels of total IGFBP3 (P(trend) = 9 x 10(-8)), but not intact IGFBP3 (P(trend) = 0.16). Elevated levels of total- (P(trend) = 0.03) and intact IGFBP3 (P(trend) = 6 x 10(-14)) were associated with increased risk of prostate cancer specific death. Treatment and tumor characteristics accounted for the association with total IGFBP3, whereas the association with intact IGFBP3 was attenuated, but still statistically significant in adjusted analysis (P(trend-adjusted) = 0.0004). Elevated intact IGFBP3 was also significantly associated with increased risk of prostate cancer-specific death among patients who were chemically or surgically castrated (P(trend-adjusted) = 0.0003), and among patients who had not been treated (P(trend-adjusted) = 0.02). CONCLUSIONS: Circulating levels of intact IGFBP3 measured after diagnosis is associated with increased risk of prostate cancer-specific death.
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| 76. |
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| 77. |
- Johansson, Mattias, et al.
(författare)
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Genetic variation in the SST gene and its receptors in relation to circulating levels of insulin-like growth factor-I, IGFBP3, and prostate cancer risk
- 2009
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : AMER ASSOC CANCER RESEARCH. - 1055-9965 .- 1538-7755. ; 18:5, s. 1644-1650
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Somatostatin (SST) and its receptors (SSTR1-5) may have a role in prostate cancer by influencing the IGFI hormone axis or through direct effects on prostate epithelia. We have investigated if genetic variation in the SST and SSTR1-5 genes influences prostate cancer risk and/or circulating IGFI and IGFBP3 hormone levels. MATERIALS AND METHODS: We analyzed 28 haplotype tagging single nucleotide polymorphisms in the SST and SSTR1-5 genes in a case-control/genetic association study to investigate the association between genetic variation and prostate cancer risk. The study included 2863 cases and 1737 controls from the Cancer Prostate in Sweden (CAPS) study. To investigate the genetic influence on circulating hormone levels, plasma concentrations of IGFI and IGFBP3 were analyzed in 874 controls of the CAPS study and 550 male subjects from the Northern Sweden Health and Disease Cohort (NSHDC). RESULTS: No clear association between prostate cancer risk and genetic variation of the SST and SSTR1-5 genes was identified. The SSTR5 missense single nucleotide polymorphism rs4988483 was associated with circulating IGFI (P = 0.002) and IGFBP3 (P = 0.0003) hormone levels in CAPS controls, with a per allele decrease of approximately 11%. This decrease was replicated in NSHDC for circulating IGFBP3 (P = 0.01) but not for IGFI (P = 0.09). Combining CAPS and NSHDC subjects indicated evidence of association between rs4988483 and both IGFBP3 (P = 2 x 10(-5)) and IGFI (P = 0.0004) hormone levels. CONCLUSIONS: Our results suggest that genetic variation in the SSTR5 gene and, particularly, the rs4988483 single nucleotide polymorphism influence circulating IGFI and IGFBP3 hormone levels with no measurable effect on prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1644-50).
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| 78. |
- Johansson, Mattias, et al.
(författare)
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Implications for prostate cancer of insulin-like growth factor-I (IGF-I) genetic variation and circulating IGF-I levels
- 2007
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - Umea Univ Hosp, Dept Surgical & Perioperative Sci, S-90185 Umea, Sweden. Umea Univ Hosp, Dept Urol Androl, S-90185 Umea, Sweden. Umea Univ Hosp, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden. Int Agcy Res Canc, F-69372 Lyon, France. Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-85500 Utrecht, Netherlands. Harvard Univ, Dept Epidemiol, Boston, MA 02215 USA. German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. : ENDOCRINE SOC. - 0021-972X .- 1945-7197. ; 92:12, s. 4820-4826
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Tidskriftsartikel (refereegranskat)abstract
- Background: Elevated levels of circulating IGF-I have consistently been associated with increased prostate cancer risk. We recently found a haplotype in the 3 ' region of the IGF-I gene associated with increased risk of prostate cancer, and we hypothesized that the observed association is mediated by circulating IGF-I. Materials and Methods: We analyzed haplotypes and three haplotype-tagging single nucleotide polymorphisms (htSNPs) in the 3 ' region of the IGF-I gene in relation to circulating levels IGF-I in 698 control subjects from the CAncer Prostate in Sweden ( CAPS) study and 575 cases and controls from the prospective Northern Sweden Health and Disease Cohort ( NSHDC) study. We also performed a meta-analysis of these two and four other association studies on genetic variation in the 3 ' region of the IGF-I gene in relation to circulating IGF-I levels. Results: The IGF-I haplotype previously associated with prostate cancer risk, labeled "TCC," was associated with elevated levels of IGF-I in the CAPS study (P = 0.02), but not in the NSHDC study. In contrast, two of the three IGF-I htSNPs tagging this haplotype, rs6220 and rs7136446, were associated with elevated levels of IGF-I in the NSHDC ( P = 0.03 and P = 0.04, respectively), but not in the CAPS study. In the meta-analysis, the TCC haplotype and the rs6220 SNP were associated with elevated levels of circulating IGF-I ( P = 0.001 and P < 0.0001, respectively). Conclusions: Genetic variation in the 3 ' region of the IGF-I gene seems to influence circulating levels of IGF-I. This observation is consistent with the hypothesis that variation in the IGF-I gene plays a role in prostate cancer susceptibility by influencing circulating levels of IGF-I.
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| 79. |
- Kachuri, Linda, et al.
(författare)
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Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci
- 2016
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 37:1, s. 96-105
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000x) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73x10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64x10(-6)), rs112290073 (OR = 1.85, P = 1.27x10(-5)), rs138895564 (OR = 2.16, P = 2.06x10(-5); among young cases, OR = 3.77, P = 8.41x10(-4)). In addition, we found that rs139852726 (P = 1.44x10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84x10(-7)) and lung cancer (P = 2.37x10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.
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| 80. |
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