Defining the spatial landscape of KRAS mutated congenital pulmonary airway malformations: a distinct entity with a spectrum of histopathologic features.
Defining the spatial landscape of KRAS mutated congenital pulmonary airway malformations: a distinct entity with a spectrum of histopathologic features.
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DOI：
10.1038/s41379-022-01129-0
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发表时间：
2022-12
期刊：
影响因子：
7.5
通讯作者：
Pogoriler, Jennifer
中科院分区：
文献类型：
--
作者：
Nelson, Nya D.;Xu, Feng;Chandrasekaran, Prashant;Litzky, Leslie A.;Peranteau, William H.;Frank, David B.;Li, Marilyn;Pogoriler, Jennifer
先天性肺气道畸形（CPAMs）的不同形态的潜在发病机制尚未确定分子，但已被证明含有粘液细胞（MCC）簇的子集。这些簇被认为是潜在的浸润性粘液腺癌的前体，并且它们与KRAS密码子12突变相关。为了评估KRAS突变在MCC中的普遍性，我们对来自18名患者的61个MCC中的KRAS外显子2进行了测序，并且我们在所有61个MCC中发现了KRAS密码子12突变。此外，来自单个患者的所有MCC总是具有相同的KRAS突变，并且在非粘液性病变组织中也发现了相同的KRAS突变。7个MCC的下一代测序显示没有其他突变或拷贝数变异。另外46个含有MCC的CPM的测序显示，在所有病例中，非粘液性病变组织中存在KRAS突变。RNA原位杂交证实了具有突变KRAS RNA的细胞的广泛分布，甚至延伸到细支气管型上皮细胞之外。我们确定了另外25个总体组织学结构与KRAS突变但没有可识别的MCC的CPM相似的CPM，我们在17个（68%）中发现了KRAS突变。这些KRAS突变的CPM的组织学特征包括1型和3型形态，以及具有中间组织学外观的病变，并且分析显示特异性氨基酸取代与组织形态学之间存在强相关性。这些研究结果与先前发表的模式生物数据一起表明，1型和3型CPM的形成是由发育早期肺上皮中出现的镶嵌KRAS突变驱动的，并将其置于镶嵌RASopathies的生长区域内。广泛上皮突变的存在解释了未完全切除患者的晚期转移性疾病，并加强了完全切除这些病变的建议。
The potential pathogenetic mechanisms underlying the varied morphology of congenital pulmonary airway malformations (CPAMs) have not been molecularly determined, but a subset have been shown to contain clusters of mucinous cells (MCC). These clusters are believed to serve as precursors for potential invasive mucinous adenocarcinoma, and they are associated with KRAS codon 12 mutations. To assess the universality of KRAS mutations in MCCs, we sequenced exon 2 of KRAS in 61 MCCs from 18 patients, and we found a KRAS codon 12 mutation in all 61 MCCs. Furthermore, all MCCs from a single patient always had the same KRAS mutation, and the same KRAS mutation was also found in non-mucinous lesional tissue. Next generation sequencing of seven MCCs showed no other mutations or copy number variations. Sequencing of 46 additional CPAMs with MCCs revealed KRAS mutations in non-mucinous lesional tissue in all cases. RNA in situ hybridization confirmed widespread distribution of cells with mutant KRAS RNA, even extending outside of the bronchiolar type epithelium. We identified 25 additional CPAMs with overall histologic architecture similar to CPAMs with KRAS mutations but without identifiable MCCs, and we found KRAS mutations in 17 (68%). The histologic features of these KRAS mutated CPAMs included type 1 and type 3 morphology, as well as lesions with an intermediate histologic appearance, and analysis revealed a strong correlation between the specific amino acid substitution and histomorphology. These findings, together with previously published model organism data, suggests that the formation of type 1 and 3 CPAMs is driven by mosaic KRAS mutations arising in the lung epithelium early in development and places them within the growing field of mosaic RASopathies. The presence of widespread epithelial mutation explains late metastatic disease in incompletely resected patients and reinforces the recommendation for complete resection of these lesions.
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影响因子：
18.4
作者：
Haigis KM
通讯作者：
Haigis KM
影响因子：
3.3
作者：
Hermelijn, Sergei M.;Wolf, Janina L.;von der Thusen, Jan H.
通讯作者：
von der Thusen, Jan H.
影响因子：
3.1
作者：
Koopman, Timco;Rottier, Bart L.;Timens, Wim
通讯作者：
Timens, Wim
DOI：
10.1158/1078-0432.ccr-21-0423
发表时间：
2021-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Chang JC;Offin M;Falcon C;Brown D;Houck-Loomis BR;Meng F;Rudneva VA;Won HH;Amir S;Montecalvo J;Desmeules P;Kadota K;Adusumilli PS;Rusch VW;Teed S;Sabari JK;Benayed R;Nafa K;Borsu L;Li BT;Schram AM;Arcila ME;Travis WD;Ladanyi M;Drilon A;Rekhtman N
通讯作者：
Rekhtman N
DOI：
10.1165/rcmb.2007-0290oc
发表时间：
2008-09-01
影响因子：
6.4
作者：
Gonzaga, Silvia;Henriques-Coelho, Tiago;Flake, Alan W.
通讯作者：
Flake, Alan W.