Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma.
Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma.
复制标题
非典型腺瘤增生的基因组景观揭示了与肺腺癌不同的模式。
DOI：
10.1158/0008-5472.can-17-1605
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发表时间：
2017-11-15
期刊：
影响因子：
11.2
通讯作者：
Kadara H
中科院分区：
文献类型：
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作者：
Sivakumar S;Lucas FAS;McDowell TL;Lang W;Xu L;Fujimoto J;Zhang J;Futreal PA;Fukuoka J;Yatabe Y;Dubinett SM;Spira AE;Fowler J;Hawk ET;Wistuba II;Scheet P;Kadara H
对于肺癌前病变的发病机制，尤其是非典型腺瘤性增生(AAH)的发病机制尚缺乏了解，AAH是目前已知的主要肺癌亚型腺癌(LUAD)的唯一前驱物。在本研究中，我们对一组AAH、LUAD和正常组织进行了深入的DNA和RNA测序分析。5/22(23%)的AAH患者存在体细胞BRAF变异，其中4/5的患者LUAD与驱动EGFR突变相匹配。除BRAF突变的病例外，队列中所有吸烟者中都存在KRAS突变(18%)。综合分析揭示了在AAH的KRAS突变病例(UBE2C，Rel)和BRAF突变病例(MAX)中表达的特征，或在这两组病例中共同表达的特征(抑制的Ax1)。与抗肿瘤信号抑制(Th1；IL12A，GZMB)和促肿瘤免疫信号(CCR2，CTLA-4)增强相关的基因集在AAH的发生和发展中被丰富。我们的结果揭示了AAH的BRAF或KRAS通路和免疫失调在这一癌前病变的发病机制中的潜在差异。
There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD and normal tissues. Somatic BRAF variants were found in 5/22 (23%) of AAH patients, 4/5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in all ever-smoker cases in the cohort (18%) exclusive of the cases with BRAF mutations. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF- mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed anti-tumor (Th1; IL12A, GZMB) and elevated pro-tumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways of AAH and immune dysregulation in the pathogenesis of this pre-malignant lung lesion.