Highlights d Comprehensive LUAD proteogenomics exposes multi-omic clusters and immune subtypes d Phosphoproteomics identifies candidate ALK-fusion diagnostic markers and targets d Candidate drug targets: PTPN11 (EGFR), SOS1 (KRAS), neutrophil degranulation (STK11) d Phospho and acetyl modifications denote tumor-specific markers and druggable proteins
A B S T R A C T PurposeMounting evidence suggests that tumor-infiltrating immune cells have prognostic value for patients with solid organ malignancies. Our aim was to investigate the prognostic significance of the immune microenvironment in patients with stage I lung adenocarcinoma (ADC). Patients and MethodsUsing tissue microarray and immunohistochemistry, we investigated eight types of tumorinfiltrating immune cells in the tumor nest and tumor-associated stroma as well as tumor expression of five cytokines in a uniform cohort of 956 patients with stage I lung ADC (478 each in training and validation cohorts). ResultsAlthough a high density of stromal forkhead box P3 (FoxP3) -positive cells was associated with shorter recurrence-free probability (RFP; P ϭ .043), the relative proportion of stromal FoxP3 to CD3 was a stronger predictor of recurrence (5-year RFP, 85% for high v 77% for low ratio; P ϭ .004). High expression of tumor interleukin-12 receptor 2 (IL-12R2) was associated with better outcome (5-year RFP, 90% for high v 80% for low expression; P ϭ .026), whereas high expression of tumor IL-7R was associated with worse outcome (5-year RFP, 76% for high v 86% for low expression; P ϭ .001). In multivariate analysis, these immune markers were independently associated with recurrence. Although IL-7R remained significant for poor overall survival, all the markers remained prognostic for recurrence in patients with stages IA and IB disease as well as for patients with tumors Յ 2 cm. ConclusionOur investigation confirms the biologic and prognostic significance of the tumor immune microenvironment for patients with stage I lung ADC and provides support for its use to stratify clinical outcome and immunotherapeutic interventions.
Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant pleural mesothelioma in which only staging is prognostic for survival. In this study of epithelioid diffuse malignant pleural mesothelioma, we investigate the prognostic utility of nuclear features. The slides of 232 epithelioid diffuse malignant pleural mesothelioma patients (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed for the following seven nuclear features: nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, intranuclear inclusions, prominence of nucleoli, mitotic count, and atypical mitoses. MIB-1 immunohistochemistry was performed using tissue microarray, and MIB-1 labeling index was recorded as the percentage of positive tumor cells. Median overall survival of all patients was 16 months and correlated with nuclear atypia (P<0.001), chromatin pattern (P=0.031), prominence of nucleoli (P<0.001), mitotic count (P<0.001), and atypical mitoses (P<0.001) by univariate analysis. Multivariate analysis revealed nuclear atypia (P=0.012) and mitotic count (P<0.001) as independent prognostic factors, and these two factors were utilized to create a three-tier nuclear grade score. The resulting nuclear grade stratified patients into three distinct prognostic groups: grade I (n=107, median overall survival = 28 months), grade II (n=91, 14 months), and grade III (n=34, 5 months). Not only was nuclear grade an independent predictor of overall survival (P<0.001), but it was also a stronger discriminator of survival than all currently available factors. Furthermore, nuclear grade was associated with time to recurrence (P=0.004) in patients who underwent complete surgical resection (n=159). MIB-1 labeling index correlated with mitotic count (P<0.001) and nuclear atypia (P=0.037) and stratified overall survival (P<0.001) and time to recurrence (P=0.048), confirming the prognostic value of the nuclear grade. Nuclear grading in epithelioid mesothelioma provides a simple, practical, and cost-effective prognostic tool that better stratifies clinical outcome and time to recurrence than currently available clinicopathologic factors.
Highlights d Unsupervised clustering revealed subtype with EMT and phosphoprotein signatures d Potential therapeutic vulnerabilities included survivin, NSD3, LSD1, and EZH2 d Rb phosphorylation nominated as a biomarker for trials with CDK4/6 inhibitors d Detailed immune landscape analysis highlighted targetable points of immuneregulation
The IASLC/ATS/ERS has recently proposed a new lung adenocarcinoma classification. We investigated whether nuclear features can stratify prognostic subsets. Slides of 485 stage I lung adenocarcinoma patients were reviewed. We evaluated nuclear diameter, nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, prominence of nucleoli, intranuclear inclusions, mitotic count/10 high-power fields (HPF) or 2.4 mm2, and atypical mitoses. Tumors were classified into histologic subtypes according to the IASLC/ATS/ERS classification and grouped by architectural grade into low (adenocarcinoma in situ, minimally invasive adenocarcinoma or lepidic predominant), intermediate (papillary or acinar), and high (micropapillary or solid). Log-rank tests and Cox regression models evaluated the ability of clinicopathologic factors to predict recurrence-free probability. In univariate analyses, nuclear diameter (p=0.007), nuclear atypia (p=0.006), mitotic count (p<0.001), and atypical mitoses (p<0.001) were significant predictors of recurrence. The recurrence-free probability of patients with high mitotic count (≥5/10HPF: n=175) was the lowest (5-year recurrence-free probability=73%), followed by intermediate (2–4/10HPF: n=106, 80%), and low (0–1/10HPF: n=204, 91%, p<0.001). Combined architectural/mitotic grading system stratified patient outcomes (p<0.001): low grade (low architectural grade with any mitotic count and intermediate architectural grade with low mitotic count: n=201, 5-year recurrence-free probability=92%), intermediate grade (intermediate architectural grade with intermediate-high mitotic counts: n=206, 78%), and high grade (high architectural grade with any mitotic count: n=78, 68%). The advantage of adding mitotic count to architectural grade is in stratifying patients with intermediate architectural grade into two prognostically distinct categories (p=0.001). After adjusting for clinicopathologic factors including sex, stage, pleural/lymphovascular invasion, and necrosis, mitotic count was not an independent predictor of recurrence (p=0.178). However, patients with the high architectural/mitotic grade remained at significantly increased risk of recurrence (high vs. low: p=0.005) after adjusting for clinical factors. We proposed this combined architectural/mitotic grade for lung adenocarcinoma as a practical method that can be applied in routine practice.
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