Genomic and Immunological Features of Micropapillary Pattern in Lung Adenocarcinoma

Abstract Background: Lung adenocarcinoma (LUAD) usually contain heterogeneous histological subtypes, among which the micropapillary (MIP) subtype was associated with poor prognosis while the lepidic (LEP) subtype possessed the most favorable outcome. A more comprehensive analysis involving discovery and public validation cohorts on the two subtypes could better decipher the key biological and evolutionary mechanisms.Methods: We firstly retrospectively studied the survival status of 286 LUAD patients with different subtypes. MIP and LEP components were micro-dissected for whole-exome sequencing (WES). Shared and private alterations as well as genomic alternation characteristics between the two components were investigated. Four public cohorts containing LEP and MIP samples were further selected for genomic profile comparison, novel therapeutic target investigation and immune infiltration quantification.Results: LEP and MIP subtypes exhibited largest disease free survival (DFS) in our patients. A total of 2035 SNV and 2757 InDels were identified in the sequenced LEP and MIP components. EGFR was found with highest mutation frequency. Distinct biological processes or pathways were involved in the evolutionary of the two components. Besides, analyses on copy number variation (CNV) and intratumor heterogeneity further discovered the possible immunosurveillance escape, the discrepancy between mutation and CNV level ITH and the pervasive DNA Damage Response as well as WNT pathway gene alternations in MIP component. Phylogenetic analysis on 5 pairs of LEP and MIP components further confirmed the presence of ancestral EGFR mutations. Through comprehensive analysis in our samples and public cohorts, PTP4A3, NAPRT and RECQL4 were identified as novel therapeutic and diagnostic targets in MIP subtype. Immunosuppression prevalence in MIP component was finally confirmed by multi-omics data.Conclusion: We identified genetic differences responsible for variated prognosis. The subtype evolution trajectory was additionally unraveled. Novel gene targets and the immunological analyses also provided therapeutic suggestions for MIP subtype.

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Prognostic Value of the Hemoglobin/Red Cell Distribution Width Ratio in Resected Lung Adenocarcinoma

Cancers ◽

10.3390/cancers13040710 ◽

2021 ◽

Vol 13 (4) ◽

pp. 710

Author(s):

Francesco Petrella ◽

Monica Casiraghi ◽

Davide Radice ◽

Andrea Cara ◽

Gabriele Maffeis ◽

...

Keyword(s):

Prognostic Factor ◽

Lung Adenocarcinoma ◽

Disease Free Survival ◽

Red Cell Distribution Width ◽

Red Cell ◽

Cell Distribution ◽

Distribution Width ◽

Free Survival ◽

Node Involvement ◽

Disease Free

Background: The ratio of hemoglobin to red cell distribution width (HRR) has been described as an effective prognostic factor in several types of cancer. The aim of this study was to investigate the prognostic role of preoperative HRR in resected-lung-adenocarcinoma patients. Methods: We enrolled 342 consecutive patients. Age, sex, surgical resection, adjuvant treatments, pathological stage, preoperative hemoglobin, red cell distribution width, and their ratio were recorded for each patient. Results: Mean age was 66 years (SD: 9.0). There were 163 females (47.1%); 169 patients (49.4%) had tumors at stage I, 71 (20.8%) at stage II, and 102 (29.8%) at stage III. In total, 318 patients (93.0%) underwent lobectomy, and 24 (7.0%) pneumonectomy. Disease-free survival multivariable analysis disclosed an increased hazard ratio (HR) of relapse for preoperative HRR lower than 1.01 (HR = 2.20, 95%CI: (1.30–3.72), p = 0.004), as well as for N1 single-node (HR = 2.55, 95%CI: (1.33–4.90), p = 0.005) and multiple-level lymph node involvement compared to N0 for both N1 (HR = 9.16, 95%CI:(3.65–23.0), p < 0.001) and N2 (HR = 10.5, 95%CI:(3.44–32.2, p < 0.001). Conclusion: Pre-operative HRR is an effective prognostic factor of disease-free survival in resected-lung-adenocarcinoma patients, together with the level of pathologic node involvement.

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Identification the Clinical Value of PLOD Family Members in Lung Adenocarcinoma: A Comprehensive Analysis

SSRN Electronic Journal ◽

10.2139/ssrn.3922643 ◽

2021 ◽

Author(s):

Yiming Meng ◽

Jing Sun ◽

Guirong Zhang ◽

Tao Yu ◽

Haozhe Piao

Keyword(s):

Lung Adenocarcinoma ◽

Family Members ◽

Comprehensive Analysis ◽

Clinical Value

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Comparative Multiomic Analysis Reveals Low T Cell Infiltration as the Primary Feature of Tobacco Use in HPV(+) Oropharyngeal Cancer

10.1101/2021.03.23.436478 ◽

2021 ◽

Author(s):

Benjamin M Wahle ◽

Paul Zolkind ◽

Ricardo Ramirez ◽

Zachary L Skidmore ◽

Angela Mazul ◽

...

Keyword(s):

T Cell ◽

Tobacco Use ◽

Disease Free Survival ◽

Oncologic Outcomes ◽

Cell Infiltration ◽

Tobacco Exposure ◽

Primary Tumors ◽

T Cell Infiltration ◽

Mutational Burden ◽

Whole Exome

Purpose: Tobacco use is an independent adverse prognostic feature in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Despite this, the biologic features associated with tobacco use have not been systematically investigated in this population. We sought to characterize the genomic and immunologic features of HPV(+) OPSCC associated with tobacco use and adverse oncologic outcomes. Experimental Design: Whole exome sequencing of 47 primary HPV(+) OPSCC tumors was performed to investigate mutational differences associated with tobacco exposure. To characterize the tumor immune microenvironment (TIME), targeted mRNA hybridization was performed and immunohistochemical (IHC) staining was used to validate these findings. Results: Low expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at the time of diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T>C substitutions and a lower proportion of mutational signatures typically observed in HPV(+) OPSCC tumors, but was not associated with increases in mutational burden or the rate of recurrent oncogenic mutations. Conclusions: In HPV(+) OPSCC, low T cell infiltration of primary tumors is associated with current tobacco use and worse oncologic outcomes. Rather than an increased mutational burden, tobacco's primary and clinically relevant association is immunosuppression of the primary TIME. An objective clinical assay like the TGEP, which quantifies immune infiltration of the primary TIME, may have value for HPV(+) OPSCC risk stratification in future clinical trials.

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P70.05 Identification of Germline Mutations in Young Never Smokers With Lung Adenocarcinoma by Whole Exome Sequencing

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.08.714 ◽

2021 ◽

Vol 16 (10) ◽

pp. S1211

Author(s):

Y. Zhang ◽

F. Fu ◽

H. Chen

Keyword(s):

Lung Adenocarcinoma ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Germline Mutations ◽

Whole Exome ◽

Never Smokers

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Prognostic implications of programmed death ligand 1 expression in resected lung adenocarcinoma: a systematic review and meta-analysis

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezaa172 ◽

2020 ◽

Vol 58 (5) ◽

pp. 888-898

Author(s):

Donglai Chen ◽

Yiming Mao ◽

Qifeng Ding ◽

Wei Wang ◽

Feng Zhu ◽

...

Keyword(s):

Gene Expression ◽

Protein Expression ◽

Lung Adenocarcinoma ◽

Messenger Rna ◽

Disease Free Survival ◽

Pooled Analysis ◽

The Cancer Genome Atlas ◽

Free Survival ◽

L1 Protein ◽

Disease Free

Abstract OBJECTIVES Conflicting results have been reported about the prognostic value of programmed death ligand 1 (PD-L1) protein and gene expression in lung adenocarcinoma. METHODS We performed a comprehensive online search to explore the association between PD-L1 expression (protein and messenger RNA) and overall survival (OS) or disease-free survival. Outcomes also included pooled rates of high PD-L1 protein expression in different cell types, per threshold used and per antibody used. A pooled gene expression analysis was also performed on 3 transcriptomic data sets that were obtained from The Cancer Genome Atlas database and the Gene Expression Omnibus database. RESULTS A total of 6488 patients from 25 studies were included. The pooled results suggested that high PD-L1 expression was associated with shorter OS [hazard ratio (HR) 1.57; P < 0.001] and disease-free survival (HR 1.341; P = 0.037) in the overall population. The overall pooled rate of high PD-L1 protein expression was 29% (95% confidence interval 23–34%) in tumour cells. In subgroup analysis, high PD-L1 protein expression in tumour cells predicted worse OS and disease-free survival. A pooled analysis of The Cancer Genome Atlas and Gene Expression Omnibus data sets revealed that higher levels of PD-L1 messenger RNA predicted poorer OS in the entire population. CONCLUSIONS This study is, to our knowledge, the largest pooled analysis on the subject to shed light on the high expression rate of PD-L1 and the prognostic value of high PD-L1 expression in resected lung adenocarcinomas. PD-L1 gene expression is a promising prognostic factor for patients with surgically resected lung adenocarcinoma. Standardization of staining should be underscored prior to routine implementation.

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Solid component ratio influences prognosis of GGO-featured IA stage invasive lung adenocarcinoma

Cancer Imaging ◽

10.1186/s40644-020-00363-6 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Fenghao Sun ◽

Yiwei Huang ◽

Xiaodong Yang ◽

Cheng Zhan ◽

Junjie Xi ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Prognostic Value ◽

Disease Free Survival ◽

Ground Glass Opacity ◽

Solid Component ◽

Component Ratio ◽

Tumor Diameter ◽

Cox Proportional Hazard ◽

Cox Proportional Hazard Models ◽

Invasive Lung Adenocarcinoma

Abstract Background The computed tomography (CT) characteristic of ground glass opacity (GGO) were shown to be associated with clinical significance in lung adenocarcinoma. We evaluated the prognostic value of the solid component ratio of GGO IA invasive lung adenocarcinoma. Methods We retrospectively analyzed the records of GGO IA patients who received surgical resection from April 2012 to December 2015. The solid component ratio was calculated based on thin-slice CT scans. Baseline features were compared stratified by the ratio. Cox proportional hazard models and survival analyses were adopted to explore potential prognostic value regarding overall survival (OS) and disease-free survival (DFS). Results Four hundred fifteen patients were included. The higher ratio was significantly associated with larger tumor diameter, pathological subtypes and choice of surgical type. There was a significantly worse DFS with a > 50% ratio. The subgroups of 0% and ≤ 50% ratio showed close survival curves of DFS. Similar trends were observed in OS. Multivariate analyses revealed that the ratio was a significant predictor for DFS, but not for OS. No significant prognostic difference was observed between lobectomy and limited resections. Conclusion A higher solid component ratio may help to predict a significantly worse prognosis of GGO IA lung adenocarcinoma.

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The Genetic Control of Stoichiometry Underlying Autism

Annual Review of Neuroscience ◽

10.1146/annurev-neuro-100119-024851 ◽

2020 ◽

Vol 43 (1) ◽

pp. 509-533 ◽

Cited By ~ 1

Author(s):

Robert B. Darnell

Keyword(s):

Large Scale ◽

Biochemical Analysis ◽

Critical Role ◽

Gene Mutations ◽

Loss Of Function ◽

Case Control Studies ◽

Neurologic Disorder ◽

Regulatory Variants ◽

Whole Exome ◽

Number Variation

Autism is a common and complex neurologic disorder whose scientific underpinnings have begun to be established in the past decade. The essence of this breakthrough has been a focus on families, where genetic analyses are strongest, versus large-scale, case-control studies. Autism genetics has progressed in parallel with technology, from analyses of copy number variation to whole-exome sequencing (WES) and whole-genome sequencing (WGS). Gene mutations causing complete loss of function account for perhaps one-third of cases, largely detected through WES. This limitation has increased interest in understanding the regulatory variants of genes that contribute in more subtle ways to the disorder. Strategies combining biochemical analysis of gene regulation, WGS analysis of the noncoding genome, and machine learning have begun to succeed. The emerging picture is that careful control of the amounts of transcription, mRNA, and proteins made by key brain genes—stoichiometry—plays a critical role in defining the clinical features of autism.

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