通过对TCGA数据的综合分析进一步确认TP53基因种系胶质瘤风险变异rs78378222及其在肿瘤组织中的意义
Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data.
作者信息
Wang Zhaoming, Rajaraman Preetha, Melin Beatrice S, Chung Charles C, Zhang Weijia, McKean-Cowdin Roberta, Michaud Dominique, Yeager Meredith, Ahlbom Anders, Albanes Demetrius, Andersson Ulrika, Freeman Laura E Beane, Buring Julie E, Butler Mary Ann, Carreón Tania, Feychting Maria, Gapstur Susan M, Gaziano J Michael, Giles Graham G, Hallmans Goran, Henriksson Roger, Hoffman-Bolton Judith, Inskip Peter D, Kitahara Cari M, Marchand Loic Le, Linet Martha S, Li Shengchao, Peters Ulrike, Purdue Mark P, Rothman Nathaniel, Ruder Avima M, Sesso Howard D, Severi Gianluca, Stampfer Meir, Stevens Victoria L, Visvanathan Kala, Wang Sophia S, White Emily, Zeleniuch-Jacquotte Anne, Hoover Robert, Fraumeni Joseph F, Chatterjee Nilanjan, Hartge Patricia, Chanock Stephen J
机构信息
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc, Gaithersburg, Maryland.
出版信息
Hum Mutat. 2015 Jul;36(7):684-8. doi: 10.1002/humu.22799. Epub 2015 May 18.
We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 × 10(-11) ), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with ∼3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma.
我们通过对胶质瘤全基因组关联研究（1856例病例和4955例对照）进行归因分析，证实了TP53基因中一种种系罕见单核苷酸多态性（SNP）rs78378222:A>C（每等位基因优势比[OR]=3.14；P=6.48×10⁻¹¹）之间存在强关联。随后，我们对癌症基因组图谱（TCGA）中多形性胶质母细胞瘤（GBM）和肺腺癌（LUAD）的数据进行了综合分析。基于SNP数据，我们对rs78378222的基因型进行了归因，并选择了携带罕见风险等位基因（C）的个体。利用RNA测序数据，我们观察到这些个体的异常转录本比正常转录本长约3 kb。利用外显子组测序数据，我们进一步表明，携带常见保护性等位基因（A）的单倍型缺失在GBM中发生于体细胞，但在LUAD中未发生。我们的生物信息学分析表明，罕见风险等位基因（C）会破坏mRNA的终止，并且在胶质瘤的肿瘤发生或进展过程中，携带常见保护性等位基因（A）的基因组区域会发生等位基因缺失。
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