Cross-cancer pleiotropic associations with lung cancer risk in African Americans

Jones, Corey; Bradford, Yuki; Amos, Christopher I.; Blot, William J.; Chanock, Stephen J.; Harris, Curtis C.; Schwartz, Ann G.; Spitz, Margaret R.; Wiencke, John K.; Wrensch, Margaret; Wu, Xifeng; Aldrich, Melinda C.

doi:10.1101/405035

Cited by 4 publications

(4 citation statements)

References 94 publications

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“…For example, DHODH G202A, R346W causes deficient protein stability and R135C impairs the enzymatic activity, which are linked to Miller syndrome 10 , 11 . DHODH polymorphism was reported to be linked with rheumatoid arthritis and lung cancer as well 12 – 14 . Additionally, enhanced activity of DHODH has been implicated as a biomarker of malignant tumor including gastric cancer and skin cancer 15 , 16 .…”

Section: Introductionmentioning

confidence: 99%

Elevated DHODH expression promotes cell proliferation via stabilizing β-catenin in esophageal squamous cell carcinoma

et al. 2020

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As a key enzyme in de novo pyrimidine biosynthesis, the expression level of dihydroorotate dehydrogenase (DHODH) has been reported to be elevated in various types of malignant tumors and its tumor-promoting effect was considered to relate to its pyrimidine synthesis function. Here, we revealed one intriguing potential mechanism that DHODH modulated β-catenin signaling in esophageal squamous cell carcinoma (ESCC). We demonstrated that DHODH directly bound to the NH2 terminal of β-catenin, thereby, interrupting the interaction of GSK3β with β-catenin and leading to the abrogation of β-catenin degradation and accumulation of β-catenin in the nucleus, which in turn, resulted in the activation of β-catenin downstream genes, including CCND1, E2F3, Nanog, and OCT4. We further demonstrated that the regulation of β-catenin by DHODH was independent of DHODH catalyzing activity. Univariate and multivariate analyses suggested that DHODH expression might be an independent prognostic factor for ESCC patients. Collectively, our study highlights the pivotal role of DHODH mediated β-catenin signaling and indicates that DHODH may act as a multi-functional switcher from catalyzing pyrimidine metabolism to regulating tumor-related signaling pathways in ESCC.

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Section: Introductionmentioning

confidence: 99%

Elevated DHODH expression promotes cell proliferation via stabilizing β-catenin in esophageal squamous cell carcinoma

et al. 2020

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“…Genome-wide association studies (GWAS) of individual cancers have identified loci associated with multiple cancer types, including 1q32 (MDM4) 7,8 ; 2q33 (CASP8-ALS2CR12) 9,10 ; 3q28 (TP63) 11,12 ; 4q24 (TET2) 13,14 ; 5p15 (TERT-CLPTM1L) 9,12 ; 6p21 (HLA complex) 15,16 ; 7p15 17 ; 8q24 12,18 ; 11q13 18,19 ; 17q12 (HNF1B) 18,20 ; and 19q13 (MERIT40) 21 . In addition, recent studies have tested single-nucleotide polymorphisms (SNPs) previously associated with one cancer to discover pleiotropic associations with other cancer types [22][23][24][25] . Consortia, such as the Genetic Associations and Mechanisms in Oncology, have looked for variants and pathways shared by breast, colorectal, lung, ovarian, and prostate cancers [26][27][28][29][30] .…”

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confidence: 99%

Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts

et al. 2020

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Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of crosscancer susceptibility.

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“…The present study was based on 35 SNPs that can potentially modify the risk of cancer. A literature research revealed that only 10 of these 35 SNPs were described in studies of African or Afro-American populations (Mechanic et al, 2007;Chornokur et al, 2013a;Nikolić et al, 2014;Oh et al, 2017a;Oussalah et al, 2017;Tong et al, 2018;Jones et al, 2019;Sagna et al, 2019;Song et al, 2019;Kamiza et al, 2020), suggesting that most association studies including these SNPs focused on European and Asian populations. The present results showed that a high number of individuals were homozygous for risk alleles with Native American and African ancestry that may modify the risk of cancer.…”

Section: Discussionmentioning

confidence: 99%

Haplotypes of single cancer driver genes and their local ancestry in a highly admixed long-lived population of Northeast Brazil

et al. 2022

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Admixed populations have not been examined in detail in cancer genetic studies. Here, we inferred the local ancestry of cancer-associated single nucleotide polymorphisms (SNPs) and haplotypes of a highly admixed Brazilian population. SNP array was used to genotype 73 unrelated individuals aged 80-102 years. Local ancestry inference was performed by merging genotyped regions with phase three data from the 1000 Genomes Project Consortium using RFmix. The average ancestry tract length was 9.12-81.71 megabases. Strong linkage disequilibrium was detected in 48 haplotypes containing 35 SNPs in 10 cancer driver genes. All together, 19 risk and eight protective alleles were identified in 23 out of 48 haplotypes. Homozygous individuals were mainly of European ancestry, whereas heterozygotes had at least one Native American and one African ancestry tract. Native-American ancestry for homozygous individuals with risk alleles for HNF1B, CDH1, and BRCA1 was inferred for the first time. Results indicated that analysis of SNP polymorphism in the present admixed population has a high potential to identify new ancestry-associated alleles and haplotypes that modify cancer susceptibility differentially in distinct human populations. Future case-control studies with populations with a complex history of admixture could help elucidate ancestry-associated biological differences in cancer incidence and therapeutic outcomes.

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Cross-cancer pleiotropic associations with lung cancer risk in African Americans

Cited by 4 publications

References 94 publications

Elevated DHODH expression promotes cell proliferation via stabilizing β-catenin in esophageal squamous cell carcinoma

Elevated DHODH expression promotes cell proliferation via stabilizing β-catenin in esophageal squamous cell carcinoma

Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts

Haplotypes of single cancer driver genes and their local ancestry in a highly admixed long-lived population of Northeast Brazil

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