Molecular Drivers of Lung Cancer in Hispanics

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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.