PO.BCS01.01 · 生物信息与计算

鉴定种系AEN多态性作为宫颈癌的风险因素

Identification of germline AEN polymorphisms as risk factors in cervical cancer

编号 45 展板 7 时间 4/19 02:00–05:00 区域 Section 3 主讲 Golya Shahrokhi, BS;MS;PhD

分会场 Application of Bioinformatics to Cancer Biology 1

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作者与单位 Authors & Affiliations

Golya Shahrokhi¹, Mari Kyllesø Halle², Vinodh Srinivasasainagendra³, Jianqing Zhang⁴, Aishwarya Sundaresan⁵, Roshan Kumar¹, Shafiq Shaikh¹, Nichol He¹, Camilla Krakstad², Sadeep Shrestha⁶, Paul Auer⁷, Janet Rader¹, Hemant Tiwari³, Akinyemi I. Ojesina¹

¹Department of Obstetrics and Gynecology, Medical College of Wisconsin, Wauwatosa, WI,²Department of Obstetrics and Gynecology, University of Bergen, Bergen, Norway,³Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL,⁴Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL,⁵Department of Biostatistics, University of Alabama, Birmingham, AL,⁶University of Alabama at Birmingham, Birmingham, AL,⁷Division of Biostatistics, Medical College of Wisconsin, Wauwatosa, WI

摘要 Abstract

中文摘要

背景：遗传性基因变异占宫颈癌风险的27-36%。虽然全基因组关联研究（GWAS）和候选基因方法已鉴定出风险等位基因和保护性等位基因（大多与免疫和DNA修复通路相关），但关于罕见或低频种系变异在整个外显子组中的作用仍有许多未知之处。方法：我们对来自105名挪威宫颈癌患者血液源DNA的全外显子组测序以及263名无癌欧洲女性对照（1000基因组）进行了基于基因的关联检验。按照GATK变异检出最佳实践鉴定了高质量、高置信度的变异，并进行了基于基因的序列核关联检验（SKAT）以鉴定显著的基因水平关联。在一个由9,286名挪威新生儿基因型组成的队列中进一步检查了显著变异的存在和连锁情况。为了评估所鉴定变异的潜在功能影响及其对癌症风险的作用，将含有野生型和变异型的载体构建体导入C4I宫颈癌细胞，并测量了细胞增殖率。结果：凋亡增强核酸酶（AEN）是一个TP53相关基因，显示出与宫颈癌显著的种系关联（SKAT-RC p = 3.69×10⁻⁹）。该信号由两个低频变异rs61752779和rs118097475驱动，它们在病例中比在对照中常见约9倍。连锁分析显示，这两个变异在宫颈癌患者中强相关（r² = 0.996），在挪威新生儿中也有类似的连锁（r² = 0.948）。功能验证表明，在C4I宫颈癌细胞中过表达野生型AEN构建体导致细胞增殖减少。然而，与野生型AEN构建体相比，过表达同时含有这两个变异的AEN构建体导致细胞增殖增加。结论：本研究提供了统计学和实验证据，支持AEN作为一个肿瘤抑制基因的作用，并提示两个高度连锁的种系变异可能促进宫颈癌风险。

查看英文原文 English abstract

Background: Inherited genetic variation contributes 27-36% of cervical cancer risk. While genome-wide association studies (GWAS) and candidate gene approaches have identified both risk and protective alleles, mostly associated with immune and DNA repair pathways, much remains unknown about the role of rare or low-frequency germline variants across the exome. Methods: We performed gene-based association testing on whole-exome sequencing from blood-derived DNA of 105 Norwegian cervical cancer patients and 263 cancer-free European female controls (1000 Genomes). High-quality and high-confidence variants were identified following GATK best practices for variant calling, and a gene-based sequence kernel association test (SKAT) was performed to identify significant gene-level associations. The presence and linkage of significant variants were further examined in a cohort of 9,286 Norwegian newborn genotypes. To assess the potential functional impact and the effects on cancer risk of the identified variants, vector constructs containing wild-type and variants introduced into C4I cervical cancer cells and cell proliferation rates were measured. Results: The Apoptosis Enhancing Nuclease ( AEN ), a TP53 -related gene, showed significant germline association with cervical cancer (SKAT-RC p = 3.69×10⁻⁹). The signal was driven by two low-frequency variants, rs61752779 and rs118097475, which were about 9-fold more common in cases than controls. Linkage analysis showed that these two variants were strongly correlated (r 2 = 0.996) in cervical cancer patients and similarly linked in the Norwegian newborns (r 2 = 0.948). Functional validation revealed that overexpression of the wildtype AEN construct in the C4I cervical cancer cell resulted in reduced cellular proliferation. However, overexpression of an AEN construct with both variants resulted in increased cell proliferation compared with the wildtype AEN construct. Conclusions: This study provides both statistical and experimental evidence supporting the role of AEN as a tumor suppressor gene and suggests that two highly linked germline variants may contribute to cervical cancer risk.

利益披露 Disclosure

G. Shahrokhi, None.. M. K. Halle, None.. V. Srinivasasainagendra, None.. J. Zhang, None.. A. Sundaresan, None.. R. Kumar, None.. S. Shaikh, None.. N. He, None.. C. Krakstad, None.. S. Shrestha, None.. P. Auer, None.. J. Rader, None.. H. Tiwari, None.. A. I. Ojesina, None.

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