Identification and characterization of HPV-independent cervical cancers.
Identification and characterization of HPV-independent cervical cancers.
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DOI：
10.18632/oncotarget.14533
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发表时间：
2017-02-21
期刊：
影响因子：
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通讯作者：
Buckhaults PJ
中科院分区：
文献类型：
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作者：
Banister CE;Liu C;Pirisi L;Creek KE;Buckhaults PJ
人乳头瘤病毒（HPV）引发宫颈癌，HPV癌基因E6和E7的持续表达被认为是维持恶性生长所必需的。目前的疗法靶向增殖细胞，而不是特定的途径，大多数实验性疗法专门靶向E6/E7。我们研究了HPV在宫颈癌中的存在和表达，将HPV癌基因表达与这些肿瘤的临床和分子特征相关联，这些肿瘤可能与新的靶向治疗相关。虽然几乎所有宫颈癌都含有HPV DNA，并且大多数表达E6/E7（HPV活性），但HPV DNA阳性宫颈癌的一个子集（8%）不表达HPV转录本（HPV非活性）。HPV非活性肿瘤发生在老年女性（中位数54对45岁，p = 0.02），并与较差的生存期（中位数715对3046天，p = 0.0003）。HPV活性和非活性肿瘤的基因表达谱是不同的。HPV活性肿瘤表达E2 F靶基因并增加AKT/MTOR信号传导。HPV非活性肿瘤具有增加的WNT/β-连环蛋白和Sonic Hedgehog信号传导。观察到DNA甲基化的全基因组差异。HPV非活性肿瘤的DNA甲基化水平总体下降;然而，许多启动子相关的CpG高度甲基化。许多炎症反应基因的启动子甲基化和表达下降。体细胞突变景观差异显著。HPV活性肿瘤在驱动基因中携带很少的体细胞突变，而HPV非活性肿瘤富集特异性靶向TP 53、ARID、WNT和PI 3 K途径的非同义体细胞突变（p值<0.000001）。分析了癌症基因组图谱（TCGA）宫颈癌数据。HPV非活性肿瘤中发现的许多基因表达变化和体细胞突变改变了靶向治疗可用的途径。针对WNT、PI 3 K或TP 53突变的治疗策略可能对HPV非活性肿瘤有效，并可提高这些宫颈癌患者的生存率。
Human papillomavirus (HPV) initiates cervical cancer, and continuous expression of HPV oncogenes E6 and E7 is thought to be necessary to maintain malignant growth. Current therapies target proliferating cells, rather than specific pathways, and most experimental therapies specifically target E6/E7. We investigated the presence and expression of HPV in cervical cancer, to correlate HPV oncogene expression with clinical and molecular features of these tumors that may be relevant to new targeted therapies. While virtually all cervical cancers contained HPV DNA, and most expressed E6/E7 (HPV-active), a subset (8%) of HPV DNA-positive cervical cancers did not express HPV transcripts (HPV-inactive). HPV-inactive tumors occurred in older women (median 54 vs. 45 years, p = 0.02) and were associated with poorer survival (median 715 vs 3046 days, p = 0.0003). Gene expression profiles of HPV-active and -inactive tumors were distinct. HPV-active tumors expressed E2F target genes and increased AKT/MTOR signaling. HPV-inactive tumors had increased WNT/β-catenin and Sonic Hedgehog signaling. Substantial genome-wide differences in DNA methylation were observed. HPV-inactive tumors had a global decrease in DNA methylation; however, many promoter-associated CpGs were hypermethylated. Many inflammatory response genes showed promoter methylation and decreased expression. The somatic mutation landscapes were significantly different. HPV-active tumors carried few somatic mutations in driver genes, whereas HPV-inactive tumors were enriched for non-synonymous somatic mutations (p-value < 0.0000001) specifically targeting TP53, ARID, WNT, and PI3K pathways. The Cancer Genome Atlas (TCGA) cervical cancer data were analyzed. Many of the gene expression changes and somatic mutations found in HPV-inactive tumors alter pathways for which targeted therapeutics are available. Treatment strategies focused on WNT, PI3K, or TP53 mutations may be effective against HPV-inactive tumors and could improve survival for these cervical cancer patients.