Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms.
Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms.
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DOI：
10.1186/s12885-015-1421-8
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发表时间：
2015-05-19
期刊：
影响因子：
3.8
通讯作者：
Anglesio MS
中科院分区：
文献类型：
--
作者：
Mackenzie R;Kommoss S;Winterhoff BJ;Kipp BR;Garcia JJ;Voss J;Halling K;Karnezis A;Senz J;Yang W;Prigge ES;Reuschenbach M;Doeberitz MV;Gilks BC;Huntsman DG;Bakkum-Gamez J;McAlpine JN;Anglesio MS
卵巢粘液性肿瘤是上皮性卵巢癌的一种独特的组织类型。卵巢癌是五种主要组织类型中最罕见的(2-4%)，其基因组图谱仍很少被描述。我们对69个卵巢粘液性肿瘤中常见的50个人类癌症突变基因进行了热点测序。我们的目标是使用高灵敏的下一代测序技术，在一个大的队列中建立癌症热点突变的总频率，特别是那些以前被认为是“RAS途径改变阴性”的肿瘤，以及进一步探索少数在RAS途径激活改变中具有明显异质性的病例。使用Ion Torrent PGM平台，我们使用v2癌症热点面板进行下一代测序分析。对两例先前证实为ERBB2扩增/过表达异质性的粘液性癌(MC)进行了不同ERBB2扩增状态的区域独立测序，以评估独立或同时含有KRAS突变或ERBB2扩增的亚克隆群体的假设。我们检测了KRAS、TP53、CDKN2A、PIK3CA、PTEN、BRAF、FGFR2、STK11、CTNNB1、SRC、Smad4、GNA11和ERBB2的突变。KRAS突变仍然是MC(64.9%)和粘液性交界性肿瘤(MBOT)中最常见的改变(92.3%)。TP53突变在癌中的发生率高于交界性肿瘤(分别为56.8%和11.5%)，IHC和突变联合数据显示，大约68%的MC和多达20%的MBOT发生改变。已证实的和潜在的RAS通路激活变化在除一例MC外的所有MC中都观察到。相当数量的病例(7/63)同时发现ERBB2扩增和KRAS突变，KRAS和BRAF突变同时存在(1例)。对含有KRAS突变的肿瘤ERBB2扩增区域的显微解剖表明，这些变化发生在相同的细胞群体中，而ERBB2扩增区域和非扩增区域KRAS等位基因频率的一致性表明，这种突变发生在扩增事件之前。总体而言，RAS改变的流行和显著的共同出现的途径“双重打击”支持在这种卵巢恶性肿瘤的肿瘤进展中起关键作用。鉴于RAS激活突变的频谱，很明显，靶向这一途径可能是复发或晚期粘液性卵巢癌患者可行的治疗选择，但考虑到非多余RAS激活改变的频率，在选择一种或多种个性化治疗方案时应谨慎行事。本文的在线版本(doi：10.1186/s12885-0151421-8)包含补充材料，授权用户可以使用。
Mucinous ovarian tumors represent a distinct histotype of epithelial ovarian cancer. The rarest (2-4 % of ovarian carcinomas) of the five major histotypes, their genomic landscape remains poorly described. We undertook hotspot sequencing of 50 genes commonly mutated in human cancer across 69 mucinous ovarian tumors. Our goals were to establish the overall frequency of cancer-hotspot mutations across a large cohort, especially those tumors previously thought to be “RAS-pathway alteration negative”, using highly-sensitive next-generation sequencing as well as further explore a small number of cases with apparent heterogeneity in RAS-pathway activating alterations. Using the Ion Torrent PGM platform, we performed next generation sequencing analysis using the v2 Cancer Hotspot Panel. Regions of disparate ERBB2-amplification status were sequenced independently for two mucinous carcinoma (MC) cases, previously established as showing ERBB2 amplification/overexpression heterogeneity, to assess the hypothesis of subclonal populations containing either KRAS mutation or ERBB2 amplification independently or simultaneously. We detected mutations in KRAS, TP53, CDKN2A, PIK3CA, PTEN, BRAF, FGFR2, STK11, CTNNB1, SRC, SMAD4, GNA11 and ERBB2. KRAS mutations remain the most frequently observed alteration among MC (64.9 %) and mucinous borderline tumors (MBOT) (92.3 %). TP53 mutation occurred more frequently in carcinomas than borderline tumors (56.8 % and 11.5 %, respectively), and combined IHC and mutation data suggest alterations occur in approximately 68 % of MC and as many as 20 % of MBOT. Proven and potential RAS-pathway activating changes were observed in all but one MC. Concurrent ERBB2 amplification and KRAS mutation were observed in a substantial number of cases (7/63 total), as was co-occurrence of KRAS and BRAF mutations (one case). Microdissection of ERBB2-amplified regions of tumors harboring KRAS mutation suggests these alterations are occurring in the same cell populations, while consistency of KRAS allelic frequency in both ERBB2 amplified and non-amplified regions suggests this mutation occurred in advance of the amplification event. Overall, the prevalence of RAS-alteration and striking co-occurrence of pathway “double-hits” supports a critical role for tumor progression in this ovarian malignancy. Given the spectrum of RAS-activating mutations, it is clear that targeting this pathway may be a viable therapeutic option for patients with recurrent or advanced stage mucinous ovarian carcinoma, however caution should be exercised in selecting one or more personalized therapeutics given the frequency of non-redundant RAS-activating alterations. The online version of this article (doi:10.1186/s12885-015-1421-8) contains supplementary material, which is available to authorized users.
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通讯作者：
Futreal PA