Germline and somatic pathogenic variants (PVs) in DICER1, encoding a miRNA biogenesis protein, are associated with a wide variety of highly specific pathologic entities. The lung tumors pleuropulmonary blastoma, pulmonary blastoma (PB), and well-differentiated fetal lung adenocarcinoma (WDFLAC) are all known to harbor DICER1 biallelic variants (loss of function and/or somatic hotspot missense mutations), and all share pathologic features reminiscent of the immature lung. However, the role of DICER1 PVs in non-small cell lung cancer (NSCLC) is relatively unknown. Here, we aimed to establish the spectrum of lung pathologies associated with DICER1 hotspot PVs and to compare the mutational landscape of DICER1-mutated NSCLC with and without hotspots. We queried DNA sequencing data from 12,146 NSCLCs featuring somatic DICER1 variants. 235 (1.9%) cases harboring ≥ 1 DICER1 PV were found and 9/235 (3.8%) were DICER1 hotspot-positive cases. Histologic review of DICER1 hotspot-positive cases showed that all but one tumor were classified as within the histologic spectrum of PB/WDFLAC, whereas all the DICER1 non-hotspot double variants were classified as lung adenocarcinomas, not otherwise specified. Comparison between the mutational landscape of DICER1 hotspot-positive and hotspot-negative cases revealed a higher frequency of CTNNB1 mutations in the hotspot-positive cases (5/9 vs. 2/225; P<0.00001). We conclude that DICER1 somatic hotspots are not implicated in the most common forms of NSCLC but rather select for morphologic features of lung tumor types such as PB and WDFLAC. As a corollary, cases showing this tumor morphology should undergo testing for DICER1 variants, and if positive, genetic counseling should be considered.

中文翻译：

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胎儿类型形态学表明非小细胞肺癌中存在 DICER1 热点突变。

DICER1 编码 miRNA 生物发生蛋白，其种系和体细胞致病性变异 (PV) 与多种高度特异性的病理实体相关。已知肺部肿瘤胸膜肺母细胞瘤、肺母细胞瘤 (PB) 和分化良好的胎儿肺腺癌 (WDFLAC) 均含有 DICER1 双等位基因变异（功能丧失和/或体细胞热点错义突变），并且所有肿瘤都具有类似的病理特征不成熟的肺。然而，DICER1 PV 在非小细胞肺癌 (NSCLC) 中的作用相对未知。在这里，我们的目的是建立与 DICER1 热点 PV 相关的肺部病理谱，并比较有和没有热点的 DICER1 突变 NSCLC 的突变情况。我们查询了 12,146 例具有体细胞 DICER1 变异的 NSCLC 的 DNA 测序数据。发现 235 例 (1.9%) 病例携带 ≥ 1 DICER1 PV，其中 9/235 (3.8%) 为 DICER1 热点阳性病例。DICER1 热点阳性病例的组织学检查表明，除一个肿瘤外，所有肿瘤均被归类为 PB/WDFLAC 的组织学谱内，而所有 DICER1 非热点双变体均被归类为肺腺癌，未另有说明。比较 DICER1 热点阳性和热点阴性病例的突变情况，发现热点阳性病例中 CTNNB1 突变频率较高（5/9 vs. 2/225；P<0.00001）。我们得出的结论是，DICER1 体细胞热点与最常见的 NSCLC 类型无关，而是选择肺肿瘤类型（如 PB 和 WDFLAC）的形态特征。作为推论，显示这种肿瘤形态的病例应接受 DICER1 变异检测，如果呈阳性，应考虑遗传咨询。