We present a deep proteogenomic profiling study of 87 lung adenocarcinoma (LUAD) tumors from the United States, integrating whole-genome sequencing, transcriptome sequencing, proteomics and phosphoproteomics by mass spectrometry, and reverse-phase protein arrays. We identify three subtypes from somatic genome signature analysis, including a transition-high subtype enriched with never smokers, a transversion-high subtype enriched with current smokers, and a structurally altered subtype enriched with former smokers, TP53 alterations, and genome-wide structural alterations. We show that within-tumor correlations of RNA and protein expression associate with tumor purity and immune cell profiles. We detect and independently validate expression signatures of RNA and protein that predict patient survival. Additionally, among co-measured genes, we found that protein expression is more often associated with patient survival than RNA. Finally, integrative analysis characterizes three expression subtypes with divergent mutations, proteomic regulatory networks, and therapeutic vulnerabilities. This proteogenomic characterization provides a foundation for molecularly informed medicine in LUAD.

PURPOSE: Linked cancer registry and medical claims data have increased the capacity for cancer research. However, few efforts have described methods to select information between data sources, which may affect data use. We developed a systematic process to evaluate and consolidate cancer diagnosis and treatment information between the linked Department of Defense Central Cancer Registry (CCR) and Military Health System Data Repository (MDR) administrative claims database, called Military Cancer Epidemiology Data System (MilCanEpi). METHODS: MilCanEpi contains information on cancer diagnosis and treatment of patients receiving care from 1998 to 2014. We used an iterative process guided by knowledge of data features, current literature, and logical comparisons between the CCR and MDR data to evaluate and consolidate cancer diagnosis and treatment received (yes or no) and their dates. We applied the processes to breast cancer data as an example. Agreement between diagnosis and treatment dates in the two data sources was evaluated using Cohen’s κ with 95% CIs. RESULTS: In MilCanEpi, we identified 15,965 patients with a breast cancer diagnosis and 15,145 patients who underwent breast cancer surgery; 97.9% and 84.1% of patients had records in both CCR and MDR for diagnosis and surgery, respectively. Exact agreement was 13.7% for diagnosis dates (Cohen’s κ = 0.14; 95% CI, 0.13 to 0.14) and 68.9% for surgery dates (Cohen’s κ = 0.69; 95% CI, 0.68 to 0.70) between the two data sources. After applying systematic processes, 98.1% of patients with a breast cancer diagnosis and 99.7% of patients with surgery had information selected for analytic data sets. CONCLUSION: The developed processes resulted in high consolidation rates of breast cancer data in MilCanEpi and may serve as a data selection template for other tumor sites and linked data sources.

Background: Approximately 85% of the U.S. military active duty population is male and less than 50 years of age, with elevated levels of known risk factors for oropharyngeal squamous cell carcinoma (OPSCC), including smoking, excessive use of alcohol, and greater numbers of sexual partners, and elevated prevalence of human papilloma virus (HPV). Given the recent rise in incidence of OPSCC related to the HPV, the Department of Defense Serum Repository provides an unparalleled resource for longitudinal studies of OPSCC in the military for the identification of early detection biomarkers.Methods: We identified 175 patients diagnosed with OPSCC with 175 matched healthy controls and retrieved a total of 978 serum samples drawn at the time of diagnosis, 2 and 4 years prior to diagnosis, and 2 years after diagnosis. Following immunoaffinity depletion, serum samples were analyzed by targeted proteomics assays for multiplexed quantification of a panel of 146 candidate protein biomarkers from the curated literature.Results: Using a Random Forest machine learning approach, we derived a 13-protein signature that distinguishes cases versus controls based on longitudinal changes in serum protein concentration. The abundances of each of the 13 proteins remain constant over time in control subjects. The AUC for the derived Random Forest classifier was 0.90.Conclusions: This 13-protein classifier is highly promising for detection of OPSCC prior to overt symptoms.Impact: Use of longitudinal samples has significant potential to identify biomarkers for detection and risk stratification.

We performed a deep proteogenomic analysis of bulk tumor and laser microdissection enriched tumor cell populations from high-grade serous ovarian cancer (HGSOC) tissue specimens spanning a broad spectrum of purity. We identified patients with longer progression-free survival had increased immune-related signatures and validated proteins correlating with tumor-infiltrating lymphocytes in 65 tumors from an independent cohort of HGSOC patients, as well as with overall survival in an additional 126 HGSOC patient cohort. We identified that homologous recombination deficient (HRD) tumors are enriched in pathways associated with metabolism and oxidative phosphorylation that we validated in independent patient cohorts. We further identified that polycomb complex protein BMI-1 is elevated in HR proficient (HRP) tumors, that elevated BMI-1 correlates with poor overall survival in HRP but not HRD HGSOC patients, and that HRP HGSOC cells are uniquely sensitive to BMI-1 inhibition.