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A novel TP53 variant (rs78378222 A > C) in the polyadenylation signal is associated with increased cancer susceptibility: evidence from a meta-analysis.

ABSTRACT: Polymorphisms in TP53 are involved in the progression of different types of cancer. A rare novel TP53 variant (rs78378222 A > C allele) was found via whole-genome sequencing in 2011. This variant was shown to significantly increase the risk of glioma, colorectal adenoma and prostate cancer. Functional analysis further revealed that this variant hindered TP53 expression and its downstream effect on apoptosis. Several studies have investigated the relationship between rs78378222 and cancer susceptibility. However, the results were not consistent. We conducted the first meta-analysis to give a more credible assessment on the association about this variant and cancer risk. Our meta-analysis included 34 studies consisting of 36599 cases and 91272 controls. These studies were mostly on the basis of high-grade data from Genome-wide association studies (GWASs). The results indicated that TP53 rs78378222 was significantly associated with an increased risk of overall cancer (AC vs. AA: OR = 1.511, 95% CI = 1.285-1.777). Furthermore, stratified analyses indicated that rs78378222 increased the risk of nervous system cancer, skin cancer and other cancer. To summarize, this meta-analysis suggested that rs78378222 C allele is a potent risk factor for overall cancer.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5078057 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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A novel TP53 variant (rs78378222 A > C) in the polyadenylation signal is associated with increased cancer susceptibility: evidence from a meta-analysis.

Wang Ying Y Wu Xue-Song XS He Jing J Ma Tianjiao T Lei Wei W Shen Zhen-Ya ZY

Oncotarget 20160501 22

Polymorphisms in TP53 are involved in the progression of different types of cancer. A rare novel TP53 variant (rs78378222 A > C allele) was found via whole-genome sequencing in 2011. This variant was shown to significantly increase the risk of glioma, colorectal adenoma and prostate cancer. Functional analysis further revealed that this variant hindered TP53 expression and its downstream effect on apoptosis. Several studies have investigated the relationship between rs78378222 and cancer suscept ...[more]

PMID: 27147571

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Project description:UnlabelledAfrican trypanosomes, except Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which cause human African trypanosomiasis, are lysed by the human serum protein apolipoprotein L1 (ApoL1). These two subspecies can resist human ApoL1 because they express the serum resistance proteins T. b. gambiense glycoprotein (TgsGP) and serum resistance-associated protein (SRA), respectively. Whereas in T. b. rhodesiense, SRA is necessary and sufficient to inhibit ApoL1, in T. b. gambiense, TgsGP cannot protect against high ApoL1 uptake, so different additional mechanisms contribute to limit this uptake. Here we report a complex interplay between trypanosomes and an ApoL1 variant, revealing important insights into innate human immunity against these parasites. Using whole-genome sequencing, we characterized an atypical T. b. gambiense infection in a patient in Ghana. We show that the infecting trypanosome has diverged from the classical T. b. gambiense strains and lacks the TgsGP defense mechanism against human serum. By sequencing the ApoL1 gene of the patient and subsequent in vitro mutagenesis experiments, we demonstrate that a homozygous missense substitution (N264K) in the membrane-addressing domain of this ApoL1 variant knocks down the trypanolytic activity, allowing the trypanosome to avoid ApoL1-mediated immunity.ImportanceMost African trypanosomes are lysed by the ApoL1 protein in human serum. Only the subspecies Trypanosoma b. gambiense and T. b. rhodesiense can resist lysis by ApoL1 because they express specific serum resistance proteins. We here report a complex interplay between trypanosomes and an ApoL1 variant characterized by a homozygous missense substitution (N264K) in the domain that we hypothesize interacts with the endolysosomal membranes of trypanosomes. The N264K substitution knocks down the lytic activity of ApoL1 against T. b. gambiense strains lacking the TgsGP defense mechanism and against T. b. rhodesiense if N264K is accompanied by additional substitutions in the SRA-interacting domain. Our data suggest that populations with high frequencies of the homozygous N264K ApoL1 variant may be at increased risk of contracting human African trypanosomiasis.

Dataset Information

A novel TP53 variant (rs78378222 A > C) in the polyadenylation signal is associated with increased cancer susceptibility: evidence from a meta-analysis.

Publications

A novel TP53 variant (rs78378222 A > C) in the polyadenylation signal is associated with increased cancer susceptibility: evidence from a meta-analysis.

Similar Datasets

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