Abstract：
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm with biological heterogeneity. Mutations in multiple genes have been identified in LCNEC. However, associations between gene alterations, histopathological characteristics, and prognosis remain ambiguous. Here, we investigated the clinicopathologic, immunohistochemical, and genomic characteristics of 19 patients with LCNEC and 9 patients with atypical carcinoid (AC). We revealed high mutation frequencies of TP53 (89.5 %), RB1 (42.1 %), APC (31.6 %), and MCL1 (31.6 %) in LCNEC, while genetic alterations were rarely found in AC. APC alterations mainly occurred to the exon 16 and were only identified in LCNEC with wild-type RB1. The 19 LCNEC were further subgrouped into APC wild-type (LCNEC-APCMT, 6/19) and APC-mutated (LCNEC-APCWT, 13/19) subgroups. In comparison with LCNEC-APCWT, LCNEC-APCMT displayed lower TMB (median: 12.64 vs 4.20, P = 0.045), and relatively mild cytologic atypia. In addition, LCNEC-APCMT distinguished itself from AC and LCNEC-APCWT by obviously downregulated expression of neuroendocrine markers (CD56 and Syn, P < 0.01) and significantly altered expression of genes downstream of APC (β-catenin migrating into the cytoplasm and nucleus, P < 0.001; c-Myc upregulating, P = 0.005). The OS of LCNEC-APCMT was numerically intermediate between AC and LCNEC-APCWT. We first proposed that APC alterations were common in LCNEC with wild-type RB1 and that LCNEC-APCMT was associated with lower TMB and better OS in comparison with LCNEC-APCWT.
摘要：
肺大细胞神经内分泌癌(LCNEC)是一种高度侵袭性肿瘤,具有生物学异质性。已经在LCNEC中鉴定了多个基因中的突变。然而,基因改变之间的关联，组织病理学特征，和预后仍然模棱两可。这里,我们调查了临床病理，免疫组织化学，19例LCNEC和9例非典型类癌（AC）患者的基因组特征。我们揭示了TP53的高突变频率（89.5％），RB1（42.1%），APC（31.6%），LCNEC的MCL1（31.6％），而在AC中很少发现遗传改变。APC改变主要发生在外显子16,并且仅在具有野生型RB1的LCNEC中鉴定。将19个LCNEC进一步细分为APC野生型（LCNEC-APCMT，6/19）和APC突变（LCNEC-APCWT，13/19）子组。与LCNEC-APCWT相比，LCNEC-APCMT显示出较低的TMB（中位数：12.64vs4.20，P=0.045），和相对轻度的细胞学异型性。此外,LCNEC-APCMT与AC和LCNEC-APCWT的区别在于明显下调神经内分泌标志物的表达（CD56和Syn，P<0.01）和APC下游基因的表达显着改变（β-catenin迁移到细胞质和细胞核中，P<0.001；c-Myc上调，P=0.005)。LCNEC-APCMT的OS在数值上介于AC和LCNEC-APCWT之间。我们首先提出APC改变在具有野生型RB1的LCNEC中很常见，并且与LCNEC-APCWT相比，LCNEC-APCMT与更低的TMB和更好的OS相关。
