Browsing by Author "Ding, Li"

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    Genomic Profiling of Lung Adenocarcinoma in Never-Smokers
    (American Society of Clinical Oncology, 2021) Devarakonda, Siddhartha; Li, Yize; Martins Rodrigues, Fernanda; Sankararaman, Sumithra; Kadara, Humam; Goparaju, Chandra; Lanc, Irena; Pepin, Kymberlie; Waqar, Saiama N.; Morgensztern, Daniel; Ward, Jeffrey; Masood, Ashiq; Fulton, Robert; Fulton, Lucinda; Gillette, Michael A.; Satpathy, Shankha; Carr, Steven A.; Wistuba, Ignacio; Pass, Harvey; Wilson, Richard K.; Ding, Li; Govindan, Ramaswamy; Medicine, School of Medicine
    Purpose: Approximately 10%-40% of patients with lung cancer report no history of tobacco smoking (never-smokers). We analyzed whole-exome and RNA-sequencing data of 160 tumor and normal lung adenocarcinoma (LUAD) samples from never-smokers to identify clinically actionable alterations and gain insight into the environmental and hereditary risk factors for LUAD among never-smokers. Methods: We performed whole-exome and RNA-sequencing of 88 and 69 never-smoker LUADs. We analyzed these data in conjunction with data from 76 never-smoker and 299 smoker LUAD samples sequenced by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium. Results: We observed a high prevalence of clinically actionable driver alterations in never-smoker LUADs compared with smoker LUADs (78%-92% v 49.5%; P < .0001). Although a subset of never-smoker samples demonstrated germline alterations in DNA repair genes, the frequency of samples showing germline variants in cancer predisposing genes was comparable between smokers and never-smokers (6.4% v 6.9%; P = .82). A subset of never-smoker samples (5.9%) showed mutation signatures that were suggestive of passive exposure to cigarette smoke. Finally, analysis of RNA-sequencing data showed distinct immune transcriptional subtypes of never-smoker LUADs that varied in their expression of clinically relevant immune checkpoint molecules and immune cell composition. Conclusion: In this comprehensive genomic and transcriptome analysis of never-smoker LUADs, we observed a potential role for germline variants in DNA repair genes and passive exposure to cigarette smoke in the pathogenesis of a subset of never-smoker LUADs. Our findings also show that clinically actionable driver alterations are highly prevalent in never-smoker LUADs, highlighting the need for obtaining biopsies with adequate cellularity for clinical genomic testing in these patients.
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    High-dimensional deconstruction of pancreatic cancer identifies tumor microenvironmental and developmental stemness features that predict survival
    (Springer Nature, 2023-10-19) Storrs, Erik P.; Chati, Prathamesh; Usmani, Abul; Sloan, Ian; Krasnick, Bradley A.; Babbra, Ramandeep; Harris, Peter K.; Sachs, Chloe M.; Qaium, Faridi; Chatterjee, Deyali; Wetzel, Chris; Goedegebuure, Peter; Hollander, Thomas; Anthony, Hephzibah; Ponce, Jennifer; Khaliq, Ateeq M.; Badiyan, Shahed; Kim, Hyun; Denardo, David G.; Lang, Gabriel D.; Cosgrove, Natalie D.; Kushnir, Vladimir M.; Early, Dayna S.; Masood, Ashiq; Lim, Kian-Huat; Hawkins, William G.; Ding, Li; Fields, Ryan C.; Das, Koushik K.; Chaudhuri, Aadel A.; Medicine, School of Medicine
    Numerous cell states are known to comprise the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). However, the developmental stemness and co-occurrence of these cell states remain poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) on a cohort of treatment-naive PDAC time-of-diagnosis endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) samples (n = 25). We then combined these samples with surgical resection (n = 6) and publicly available samples to increase statistical power (n = 80). Following annotation into 25 distinct cell states, cells were scored for developmental stemness, and a customized version of the Ecotyper tool was used to identify communities of co-occurring cell states in bulk RNA-seq samples (n = 268). We discovered a tumor microenvironmental community comprised of aggressive basal-like malignant cells, tumor-promoting SPP1+ macrophages, and myofibroblastic cancer-associated fibroblasts associated with especially poor prognosis. We also found a developmental stemness continuum with implications for survival that is present in both malignant cells and cancer-associated fibroblasts (CAFs). We further demonstrated that high-dimensional analyses predictive of survival are feasible using standard-of-care, time-of-diagnosis EUS-FNB specimens. In summary, we identified tumor microenvironmental and developmental stemness characteristics from a high-dimensional gene expression analysis of PDAC using human tissue specimens, including time-of-diagnosis EUS-FNB samples. These reveal new connections between tumor microenvironmental composition, CAF and malignant cell stemness, and patient survival that could lead to better upfront risk stratification and more personalized upfront clinical decision-making.