Direct Comparison of HPV16 Viral Genomic Integration, Copy Loss, and Structural Variants in Oropharyngeal and Uterine Cervical Cancers Reveal Distinct Relationships to E2 Disruption and Somatic Alteration.
Direct Comparison of HPV16 Viral Genomic Integration, Copy Loss, and Structural Variants in Oropharyngeal and Uterine Cervical Cancers Reveal Distinct Relationships to E2 Disruption and Somatic Alteration.
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HPV 16导致大约60%的宫颈癌和95%的HPV驱动的口咽癌。尽管两者都与HPV相关，但这些肿瘤非常不同。我们直接比较了这两种疾病中HPV16基因组整合到人类基因组中的情况，发现病毒基因E2在宫颈癌中经常丢失，但通常在口咽癌中保持不变。我们还发现，具有整合的口咽癌每个肿瘤具有更多的整合位点，并且这些整合位点更频繁地发生在具有高密度基因的基因组区域。由HPV 16型（HPV 16 + OPSCC）引起的口咽鳞状细胞癌是美国最常见的HPV相关恶性肿瘤，与宫颈鳞状细胞癌（UCSCC）有许多分子差异。我们对HPV肿瘤发生的理解依赖于UCSCC的研究，这些研究揭示了一个共识模型，该模型依赖于HPV整合和E2缺失。在这里，我们通过分析104例OPSCC和44例UCSCC肿瘤中HPV16基因组的亲和捕获测序，比较了UCSCC和OPSCC中HPV整合的模式。使用相同的策略同时对这些群组进行测序。使用不一致读取对聚类和基于组装的方法鉴定整合。检查病毒整合位点、结构变异和拷贝丢失。虽然HPV 16基因的大规模深度丢失在UCSCC中很常见，并且与E2丢失相关，但HPV 16基因组的深度拷贝丢失在HPV 16 + OPSCC中并不常见。类似地，HPV 16内的结构变异有利于UCSCC而不是OPSCC中的E2损失。HPV16整合位点是非随机的，具有鉴定的复发性整合热点。与UCSCC相比，OPSCC肿瘤每个肿瘤具有更多的整合位点，并且在具有高基因密度的基因组区域中具有更多的整合位点。这些数据表明，病毒整合和E2破坏在UCSCC和OPSCC中是不同的。我们的研究结果也增加了越来越多的文献表明，HPV在OPSCC的肿瘤发生并不遵循基于UCSCC开发的模型。
HPV16 causes approximately 60% of uterine cervical cancer and 95% of HPV-driven oropharynx cancers. Despite both being HPV-associated, these tumors are very different. We directly compare integration of the HPV16 genome into the human genome in these two diseases, finding that the viral gene E2 is frequently lost in cervical cancer, but usually maintained in oropharyngeal cancer. We also found that oropharyngeal cancers with integration have many more integration sites per tumor and these more frequently occur in genomic regions with a high density of genes. Squamous cell carcinoma of the oropharynx caused by HPV type 16 (HPV16+ OPSCC) is the most common HPV-associated malignancy in the USA and has many molecular differences from uterine cervical squamous cell carcinoma (UCSCC). Our understanding of HPV oncogenesis relied on studies of UCSCC revealing a consensus model reliant on HPV integration with a loss of E2. Here, we compare patterns of HPV integration in UCSCC and OPSCC by analysis of affinity capture sequencing of the HPV16 genome in 104 OPSCC and 44 UCSCC tumors. These cohorts were contemporaneously sequenced using an identical strategy. Integration was identified using discordant read pair clustering and assembly-based approaches. Viral integration sites, structural variants, and copy losses were examined. While large-scale deep losses of HPV16 genes were common in UCSCC and were associated with E2 loss, deep copy losses of the HPV16 genome were infrequent in HPV16+ OPSCC. Similarly, structural variants within HPV16 favored E2 loss in UCSCC but not OPSCC. HPV16 integration sites were non-random, with recurrent integration hot-spots identified. OPSCC tumors had many more integration sites per tumor when compared to UCSCC and had more integration sites in genomic regions with high gene density. These data show that viral integration and E2 disruption are distinct in UCSCC and OPSCC. Our findings also add to growing literature suggesting that HPV tumorigenesis in OPSCC does not follow the model developed based on UCSCC.
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影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
男性同性恋和对Y连锁蛋白NLGN4Y的母体免疫反应。
DOI：
10.1073/pnas.1705895114
发表时间：
2018-01-09
影响因子：
11.1
作者：
Bogaert AF;Skorska MN;Wang C;Gabrie J;MacNeil AJ;Hoffarth MR;VanderLaan DP;Zucker KJ;Blanchard R
通讯作者：
Blanchard R
影响因子：
4.1
作者：
Feng Yang-chun;Wang Sen-yu;Huang Yan-chun
通讯作者：
Huang Yan-chun
影响因子：
11.5
作者：
Begum, S;Cao, DF;Westra, WH
通讯作者：
Westra, WH
影响因子：
5.4
作者：
Jakobsdottir, G. Maria;Brewer, Daniel S.;Cooper, Colin;Green, Catherine;Wedge, David C.
通讯作者：
Wedge, David C.