BACKGROUND The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). PATIENTS AND METHODS We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. RESULTS In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors. CONCLUSIONS We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.

中文翻译：

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非吸烟相关肺癌细胞的全基因组分析揭示了与 EGFR 突变肿瘤的组织病理学转化相关的常见 RB1 重排。

背景 非吸烟者肺腺癌 (LuADs) 的病因学和分子基础目前尚不清楚。此外，可用原代培养物的稀缺性继续阻碍我们对非吸烟相关肺腺癌 (NSK-LuADs) 的生物学理解。患者和方法 我们从转移性 NSK-LuAD 中建立了患者来源的癌细胞 (PDC) 培养物，包括对酪氨酸激酶抑制剂 (TKI) 耐药前后的两对匹配的 EGFR 突变 PDC，然后进行全外显子组和 RNA 测序描绘它们的基因组结构。为了验证，我们分析了主要 LuAD 的独立队列。结果 除了已知的与吸烟者无关的改变（例如 RET、ALK、EGFR 和 ERBB2）外，我们还发现了新的融合和反复突变的基因，包括 ATF7IP、基因表达的调节剂，在 5% 的原发性 LuAD 病例中失活。我们还在主要熟悉的癌症基因上发现了种系突变，突出了遗传易感性在 NSK-LuAD 子集起源中的重要性。此外，在未经治疗的 EGFR 突变 LuADs 中，RB1 的失活改变过多，主要是通过复杂的基因内重排。三种 EGFR 突变型和一种 EGFR 野生型肿瘤分别获得了对 EGFR-TKI 和化疗的耐药性，重新活检的组织学显示小细胞肺癌/鳞状细胞癌 (SCLC/LuSCC) 转化的发展。这些特征与 EGFR 突变肿瘤中的 RB1 失活和获得性 EGFR-T790M 突变或 FGFR3-TACC3 融合一致。结论 我们发现 LuAD 的反复变化值得进一步探索。我们的工作还表明，NSK-LuADs 的一个子集出现在癌症易感综合征中。在 EGFR 突变肿瘤中发现的通过复杂重排优先发生 RB1 失活似乎有利于在生长抑制压力下的 SCLC/LuSCC 转化。因此，RB1 失活可以预测 LuAD 转化为更具侵袭性的肺癌类型的风险，并且可能需要被视为 NSK-LuADs 患者临床管理的一部分。在 EGFR 突变肿瘤中发现似乎有利于在生长抑制压力下进行 SCLC/LuSCC 转化。因此，RB1 失活可以预测 LuAD 转化为更具侵袭性的肺癌类型的风险，并且可能需要被视为 NSK-LuADs 患者临床管理的一部分。在 EGFR 突变肿瘤中发现似乎有利于在生长抑制压力下进行 SCLC/LuSCC 转化。因此，RB1 失活可以预测 LuAD 转化为更具侵袭性的肺癌类型的风险，并且可能需要被视为 NSK-LuADs 患者临床管理的一部分。