Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer.
Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer.
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DOI：
10.1186/s13059-014-0428-9
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发表时间：
2014-08-27
期刊：
影响因子：
12.3
通讯作者：
Ji HP
中科院分区：
文献类型：
--
作者：
Nadauld LD;Garcia S;Natsoulis G;Bell JM;Miotke L;Hopmans ES;Xu H;Pai RK;Palm C;Regan JF;Chen H;Flaherty P;Ootani A;Zhang NR;Ford JM;Kuo CJ;Ji HP
胃癌是全球癌症死亡的第二大原因，转移性疾病是导致死亡的主要原因。为了确定参与肿瘤发生和肿瘤进化的候选驱动因素，我们对弥漫性胃癌的转移进展进行了广泛的基因组测序分析。本研究比较了遗传性弥漫性胃癌综合征先证者的原发肿瘤及其作为卵巢转移的复发。原发性肿瘤和卵巢转移均存在CDH1和TP53肿瘤抑制因子的双等位基因功能缺失，表明其具有共同的遗传起源。虽然原发肿瘤表现出成纤维细胞生长因子受体2 （FGFR2）基因的扩增，但转移明显缺乏FGFR2扩增，而是具有独特的转化生长因子- β受体2 （TGFBR2）双等位基因改变，这表明该患者中TGFBR2突变转移克隆群体的体内进化存在差异。由于TGFBR2突变之前尚未在胃癌中得到功能验证，因此我们在小鼠三维原代胃类器官培养中模拟了TGFBR2丢失的转移潜力。Cdh1-/-内Tgfbr2 shRNA敲低；Tp53-/-类器官在体外具有侵袭性，在体内具有强大的转移致瘤性，证实了Tgfbr2的转移抑制活性。我们记录了弥漫性胃癌的转移分化和遗传异质性，并揭示了TGFBR2功能缺失的潜在转移作用。为了支持这项研究，我们采用了一种能够概括体内转移性胃癌的小鼠原代类器官培养方法。总的来说，我们描述了一种综合的方法来识别和功能验证参与转移的推定癌症驱动因素。本文的在线版本（doi:10.1186/s13059-014-0428-9）包含补充材料，可供授权用户使用。
Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolution, we conduct an extensive genome sequencing analysis of metastatic progression in a diffuse gastric cancer. This involves a comparison between a primary tumor from a hereditary diffuse gastric cancer syndrome proband and its recurrence as an ovarian metastasis. Both the primary tumor and ovarian metastasis have common biallelic loss-of-function of both the CDH1 and TP53 tumor suppressors, indicating a common genetic origin. While the primary tumor exhibits amplification of the Fibroblast growth factor receptor 2 (FGFR2) gene, the metastasis notably lacks FGFR2 amplification but rather possesses unique biallelic alterations of Transforming growth factor-beta receptor 2 (TGFBR2), indicating the divergent in vivo evolution of a TGFBR2-mutant metastatic clonal population in this patient. As TGFBR2 mutations have not previously been functionally validated in gastric cancer, we modeled the metastatic potential of TGFBR2 loss in a murine three-dimensional primary gastric organoid culture. The Tgfbr2 shRNA knockdown within Cdh1-/-; Tp53-/- organoids generates invasion in vitro and robust metastatic tumorigenicity in vivo, confirming Tgfbr2 metastasis suppressor activity. We document the metastatic differentiation and genetic heterogeneity of diffuse gastric cancer and reveal the potential metastatic role of TGFBR2 loss-of-function. In support of this study, we apply a murine primary organoid culture method capable of recapitulating in vivo metastatic gastric cancer. Overall, we describe an integrated approach to identify and functionally validate putative cancer drivers involved in metastasis. The online version of this article (doi:10.1186/s13059-014-0428-9) contains supplementary material, which is available to authorized users.
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使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
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影响因子：
11.2
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Dulak AM;Schumacher SE;van Lieshout J;Imamura Y;Fox C;Shim B;Ramos AH;Saksena G;Baca SC;Baselga J;Tabernero J;Barretina J;Enzinger PC;Corso G;Roviello F;Lin L;Bandla S;Luketich JD;Pennathur A;Meyerson M;Ogino S;Shivdasani RA;Beer DG;Godfrey TE;Beroukhim R;Bass AJ
通讯作者：
Bass AJ