Molecular Drivers of Lung Cancer in Hispanics

西班牙裔肺癌的分子驱动因素

• 批准号: 10543164
• 负责人: William Douglas Cress
• 金额: $ 19.3万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543164
• 关键词: Address; Affinity; African American population; Age; American Cancer Society; American Medical Association; Automobile Driving; Biological; Biology; Cancer Center; Cancer Etiology; Cancer Patient; Cancer cell line; Caucasians; Cell Culture Techniques; Cell Line; Cellular biology; Cessation of life; Chimeric Proteins; Chromosome 19; DNA sequencing; Data; Disease; Disparity; Epidemic; Epidermal Growth Factor Receptor; Event; Exons; Florida; Frequencies; Fusion Protein Expression; Gene Fusion; Genes; Genomics; Goals; Head; High Prevalence; Hispanic; Hispanic Populations; Indigenous American; Journals; KRAS2 gene; Latino; Latino Population; Literature; Low Prevalence; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Methodology; Minority; Modeling; Molecular; Mutation; Mutation Analysis; Not Hispanic or Latino; Oncogenic; Oncology; Oncoproteins; Paper; Patients; Pattern; Population; Property; Protein Isoforms; Proteins; Publishing; RNA; RNA Splicing; Reagent; Registries; Reporting; Resources; Role; STK11 gene; Sampling; Seminal; Series; Specimen; Tail; Testing; The Cancer Genome Atlas; Therapeutic; Transcript; Woman; Work; clinically relevant; cohort; driver mutation; exome sequencing; insight; lung cancer cell; men; mortality; never smoker; new therapeutic target; novel; overexpression; patient registry; repository; targeted treatment; transcriptome sequencing; tumor; tumorigenesis

Project Summary Lung malignancies are the leading cause of cancer death among Hispanic/Latino (H/L) men and second among H/L women1. While H/L have surpassed African Americans as a minority nationally, they account for only 3% (149 total) of patients characterized in the Cancer Genome Atlas (TCGA)2 and only 0.4% of patient- derived oncological models in existence3. Among lung cancer patients, compared to Caucasians, H/Ls (1) have double the mortality among never-smokers4-8; (2) present more frequently with late-stage disease7, 9; (3) and are often not identified as being candidates for targeted therapy due to the lack of proper genomic characterization of their lung cancers10-12. To address these disparities with respect to lung cancer, we collected 163 lung tumor samples from H/L patients and subjected them to exome sequencing13. Notably, we observed H/L lung adenocarcinoma patients have a very low prevalence of KRAS and STK11 mutations and a high prevalence of EGFR mutations - a pattern that we13 and others14 find associated with Indigenous American ancestry. We subjected 48 patients of those patients from the registry that lacked KRAS or EGFR driver mutations to RNA sequencing to assess if known or unknown fusion-events might account for lung cancer in this understudied population. Out of the 48 patient specimens, ten (21%) harbored potential oncogenic transcript fusions. Half (5) of these patients had known MET fusions or expressed known oncogenic isoforms of MET. Notably, the other five patient specimens expressed ADCK4-NUMBL fusion transcript (three copies of Exon 15: Exon 2 fusions and two copies of Exon 15: Exon 3 fusions). DNA sequencing does not reveal gene fusion; however, the ADCK4 and NUMBL genes are aligned head-to-tail in chromosome 19 supporting the hypothesis that intergenic cis-splicing of ADCK4 (Exon 15) with NUMBL (Exon 2) drives expression of ADCK4-NUMBL chimeric transcripts. Similar transcripts have been detected in a few cell lines but are not observed in the vast RNA sequencing data available via the TCGA, suggesting that these transcripts are expressed commonly only in H/L patient samples. Based on the limited literature15-18, we hypothesize that intergenic splicing of ADCK4 with NUMBL drives expression of ADCK4-NUMBL chimeric transcripts and that these transcripts express oncoproteins with unique biological properties. To test these hypotheses, we will 1) determine how expression of ADCK4-NUMBL chimeric proteins influence cell biology, 2) establish novel patient-derived cell lines from H/L never smokers and 3) explore the mechanisms leading to the expression of cis-spliced ADCK2-NUMBL transcripts. We anticipate that the results of these studies will provide insight into the mechanisms driving the elevated lung cancer mortality among H/Ls who do not smoke and identify novel therapeutic targets.

项目概要 肺部恶性肿瘤是西班牙裔/拉丁裔 (H/L) 男性癌症死亡的主要原因，其次是癌症死亡原因。 H/L 女性1。虽然 H/L 在全国范围内已超过非裔美国人，成为少数族裔，但他们占 只有 3%（总共 149 名）患者在癌症基因组图谱 (TCGA)2 中有特征，并且只有 0.4% 的患者- 现有的衍生肿瘤学模型3。在肺癌患者中，与白人相比，H/Ls (1) 从不吸烟者的死亡率增加一倍4-8； (2) 更频繁地出现晚期疾病7, 9； (3) 由于缺乏适当的基因组信息，通常不被确定为靶向治疗的候选者 肺癌的特征10-12。为了解决肺癌方面的这些差异，我们 从 H/L 患者身上收集了 163 个肺部肿瘤样本，并对它们进行了外显子组测序13。值得注意的是，我们 观察到的 H/L 肺腺癌患者 KRAS 和 STK11 突变的患病率非常低，并且 EGFR 突变的高发生率 - 我们13 和其他人14 发现这种模式与土著人相关 美国血统。我们对注册中缺乏 KRAS 或 EGFR 的患者中的 48 名患者进行了研究 RNA测序的驱动突变来评估已知或未知的融合事件是否可能解释肺部 这一研究不足的人群中的癌症。在 48 份患者样本中，有 10 份 (21%) 具有潜力 致癌转录物融合。这些患者中有一半 (5) 具有已知的 MET 融合或表达已知 MET 的致癌亚型。值得注意的是，其他五名患者标本表达了 ADCK4-NUMBL 融合 转录本（三份外显子 15：外显子 2 融合体和两份外显子 15：外显子 3 融合体）。脱氧核糖核酸 测序未显示基因融合；然而，ADCK4 和 NUMBL 基因在 19号染色体支持ADCK4（外显子15）与NUMBL（外显子）基因间顺式剪接的假设 2)驱动ADCK4-NUMBL嵌合转录物的表达。在一些地方也发现了类似的转录本 细胞系，但在通过 TCGA 提供的大量 RNA 测序数据中并未观察到，这表明这些 转录本通常仅在 H/L 患者样本中表达。基于有限的文献15-18，我们 假设 ADCK4 与 NUMBL 的基因间剪接驱动 ADCK4-NUMBL 嵌合体的表达 转录本，并且这些转录本表达具有独特生物学特性的癌蛋白。为了测试这些 假设，我们将 1) 确定 ADCK4-NUMBL 嵌合蛋白的表达如何影响细胞 生物学，2) 建立源自 H/L 从不吸烟者的新型患者细胞系，3) 探索 导致顺式剪接 ADCK2-NUMBL 转录物表达的机制。我们预计 这些研究的结果将有助于深入了解导致肺癌死亡率升高的机制 在不吸烟的 H/L 中寻找新的治疗靶点。