TGFβ receptor 1: an immune susceptibility gene in HPV-associated cancer.
TGFβ receptor 1: an immune susceptibility gene in HPV-associated cancer.
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DOI：
10.1158/0008-5472.can-14-0602-t
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发表时间：
2014-12-01
期刊：
影响因子：
11.2
通讯作者：
Sikora AG
中科院分区：
文献类型：
--
作者：
Levovitz C;Chen D;Ivansson E;Gyllensten U;Finnigan JP;Alshawish S;Zhang W;Schadt EE;Posner MR;Genden EM;Boffetta P;Sikora AG
只有少数接触人乳头瘤病毒 (HPV) 的人会患上 HPV 相关的宫颈癌和口咽癌。由于宿主免疫会影响感染和癌症进展，因此我们通过对来自头颈癌全基因组关联研究 (GWAS) 的口咽癌数据进行多层综合计算分析，检验了免疫相关基因的遗传变异是口咽癌和其他 HPV 相关癌症易感性决定因素的假设。独立分析，包括单基因、基因互连、蛋白质-蛋白质相互作用、基因表达和通路分析，确定了与口咽癌显着相关的免疫基因和通路。 TGFβR1 贯穿所有分析层，因此被选择进行验证，在仅限于 HPV 血清阳性病例的头颈癌 GWAS 和独立的宫颈癌 GWAS 中显着复制。含有p38-MAPK通路的TGFβR1与口咽癌和宫颈癌显着相关，并且TGFβR1在口咽癌、宫颈癌和HPV+头颈癌肿瘤中过表达。这些一致的分析表明 TGFβR1 信号传导是 HPV 相关癌症中失调的过程。这项研究表明，免疫相关基因的遗传变异与口咽癌的易感性相关，并暗示 TGFβR1/TGFβ 信号传导参与口咽癌和宫颈癌的发展。更好地了解 HPV 相关癌症易感性的免疫遗传学基础，可能有助于深入了解少数 HPV 暴露个体进展为癌症的宿主/病毒相互作用和免疫过程失调。
Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein–protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFβR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFβR1 containing p38–MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV+ head and neck cancer tumors. These concordant analyses implicate TGFβR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFβR1/TGFβ signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer.