Assessment of DNA repair susceptibility genes identified by whole exome sequencing in head and neck cancer
Assessment of DNA repair susceptibility genes identified by whole exome sequencing in head and neck cancer
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DOI：
10.1016/j.dnarep.2018.04.005
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发表时间：
2018-06-01
期刊：
影响因子：
3.8
通讯作者：
Ghosh, Sankar Kumar
中科院分区：
文献类型：
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作者：
Das, Raima;Kundu, Sharbadeb;Ghosh, Sankar Kumar
头颈癌 (HNC) 是全球第六大常见癌症，在印度位居第二。在印度东北部（NE），它是男性第六大常见死因，女性第七大常见死因。长期吸烟和饮酒是 HNC 发生的主要病因，可引起 DNA 损伤。因此，DNA修复途径是维持基因组完整性和预防癌变的关键系统。目前的工作旨在预测 DNA 修复基因的显着种系变异对疾病易感性的影响。在 Ion Proton (TM) 平台上对来自 HNC 流行州曼尼普尔邦、米佐拉姆邦和那加兰邦的 15 个病例对照样本进行了全外显子组测序。变异注释在 Ion Reporter (TM) 和 wANNOVAR 中完成。随后的统计和生物信息学分析确定了与 HNC 相关的显着外显子和内含子变异。在我们观察到的变异中，78.6% 发生在 ExAC 中，94% 发生在 dbSNP 中，5.8% 和 9.3% 的变异分别存在于 ClinVar 和 HGMD 中。总变异分散在199个基因中，其中DSBR和FA途径是突变最多的途径。等位基因关联检验表明，HLTF和RAD52基因的内含子变异与HNC风险显着相关（P < 0.05）（OR > 5），而PARP4、RECQL5、EXO1和PER）基因的内含子变异和TDP2基因的外显子变异对HNC具有保护作用（OR < 1）。 MDR 分析提出，MSH6、BRCA2、PALB2 和 TP53 基因中的外显子变异和 RECQL5 基因区域中的内含子变异在 HNC 因果关系的 DNA 修复机制的特定阶段共同作用。此外，其他内含子和 3'UTR 变异导致与 HNC 相关的转录因子结合位点和 miRNA 靶位点发生修饰。为了识别与 HNC 相关的真正因果变异，有必要在东北印度人群中进行大规模验证、深入的结构预测以及对我们公认的多态性的后续模拟。
Head and neck cancer (HNC), the sixth most common cancer globally, stands second in India. In Northeast (NE) India, it is the sixth most common cause of death in males and seventh in females. Prolonged tobacco and alcohol consumption constitute the major etiological factors for HNC development, which induce DNA damage. Therefore, DNA repair pathway is a crucial system in maintaining genomic integrity and preventing carcinogenesis. The present work was aimed to predict the consequence of significant germline variants of the DNA repair genes in disease predisposition. Whole exome sequencing was performed in Ion Proton (TM) platform on 15 case-control samples from the HNC-prevalent states of Manipur, Mizoram, and Nagaland. Variant annotation was done in Ion Reporter (TM) as well as wANNOVAR. Subsequent statistical and bioinformatics analysis identified significant exonic and intronic variants associated with HNC. Amongst our observed variants, 78.6% occurred in ExAC, 94% reported in dbSNP and 5.8% & 9.3% variants were present in ClinVar and HGMD, respectively. The total variants were dispersed among 199 genes with DSBR and FA pathway being the most mutated pathways. The allelic association test suggested that the intronic variants in HLTF and RAD52 gene significantly associated (P < 0.05) with the risk (OR > 5), while intronic variants in PARP4, RECQL5, EXO1 and PER) genes and exonic variant in TDP2 gene showed protection (OR < 1) for HNC. MDR analysis proposed the exonic variants in MSH6, BRCA2, PALB2 and TP53 genes and intronic variant in RECQL5 genetic region working together during certain phase of DNA repair mechanism for HNC causation. In addition, other intronic and 3'UTR variations caused modifications in the transcription factor binding sites and miRNA target sites associated with HNC. Large-scale validation in NE Indian population, in-depth structure prediction and subsequent simulation of our recognized polymorphisms is necessary to identify true causal variants related to HNC.