scholarly journals Genomic Profiling and Prognostic Value Analysis of Genetic Alterations in Chinese Resected Lung Cancer With Invasive Mucinous Adenocarcinoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Lei Cai ◽  
Jiangfeng Wang ◽  
Junrong Yan ◽  
Jian Zeng ◽  
Liang Zhu ◽  
...  
Keyword(s):  
Mucinous Adenocarcinoma ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Gradual Decrease ◽  
Stage Iii ◽  
Genomic Profiling ◽  
Primary Tumors ◽  
Genetic Characteristics ◽  
Value Analysis ◽  
Invasive Mucinous Adenocarcinoma

BackgroundInvasive mucinous adenocarcinoma (IMA) of the lung is a distinct histological subtype with unique clinical and pathological features. Despite previous genomic studies on lung IMA, the genetic characteristics and the prognosis-related biomarkers in Chinese surgically resected lung IMA remain unclear.MethodsWe collected 76 surgically resected primary tumors of invasive lung adenocarcinoma, including 51 IMA and 25 non-mucinous adenocarcinomas (non-IMA). IMA was further divided into pure-IMA (mucinous features≥90%) and mixed-IMA subgroups. Comprehensive genomic profiling based on targeted next-generation sequencing (NGS) of 425 genes was explored and genomic characteristics were evaluated for the correlation with postoperative disease-free survival (DFS).ResultsIMA had a unique genetic profile, with more diverse driver mutations and more tumor drivers/suppressors co-occurrence than that of non-IMA. The frequency of EGFR (72.0% vs. 40.0% vs. 23.1%, p=0.002) and ALK (undetected vs. 20.0% vs. 26.9%, p=0.015) alterations showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. The frequency of KRAS mutations in pure-IMA was higher than that in mixed-IMA, albeit statistically insignificant (23.1% vs. 4.0%, p=0.10). TP53 mutation was significantly less in pure-IMA compared to mixed-IMA and non-IMA (23.1% vs. 52.0% vs. 56.0%, p=0.03). Besides, IMA exhibited less arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, and the frequency of amplification and deletion also showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. Furthermore, prognosis analysis in stage III IMA patients showed that patients harboring alterations in EGFR (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) achieved prolonged DFS, while patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or with KRAS mutations (mDFS=13.0 vs. 20.0 months, HR=6.95, p=0.027) had shorter DFS. Multivariate analysis showed that KRAS mutations, PI3K pathway alterations, and tumor differentiation status were independent factors that have statistically significant influences on clinical outcomes of IMA patients.ConclusionOur study provided genomic insights into Chinese surgically resected lung IMA. We also identified several genomic features that may serve as potential biomarkers on postoperative recurrence in IMA patients with stage III disease.

Genetic Alterations in Chinese Resected Lung Cancer with Invasive Mucinous Adenocarcinoma: Genomic Profiling and Prognostic Value Analysis

2021 ◽  
Author(s):  
James D. Klingensmith
Keyword(s):  
Mucinous Adenocarcinoma ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Genetic Profile ◽  
Kras Mutations ◽  
Genetic Characteristics ◽  
Value Analysis ◽  
Invasive Mucinous Adenocarcinoma

Lung invasive mucinous adenocarcinoma (IMA) is a unique histological subtype with different clinical and pathological characteristics. Despite prior genomic investigations on lung IMA, little is known about the genetic features and prognosis-related biomarkers in Chinese surgically resected lung IMA. IMA showed a distinct genetic profile, with more diversified driver mutations and co-occurrence of tumor drivers/suppressors than non-IMA. From non-IMA to mixed-IMA to pure-IMA, the frequency of EGFR (72.0 percent vs. 40.0 percent vs. 23.1 percent, p=0.002) and ALK (undetected vs. 20.0 percent vs. 26.9%, p=0.015) changes exhibited a trend of steady decline and rise, respectively. KRAS mutations were more common in pure-IMA than in mixed-IMA, however the difference was statistically insignificant (23.1 percent vs. 4.0 percent, p=0.10). Pure-IMA had a lower rate of TP53 mutation than mixed-IMA and non-IMA (23.1 percent vs. 52.0 percent vs. 56.0 percent, p=0.03). Furthermore, IMA had fewer arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, with a steady drop in amplification and rise in deletion frequency from non-IMA to mixed-IMA to pure-IMA, respectively. Patients with EGFR mutations (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway mutations (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) had longer DFS than patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or KRAS mutations (mDFS=13 KRAS mutations, PI3K pathway changes, and tumor differentiation status were all shown to be independent predictors with statistically significant effects on IMA patients' clinical outcomes in multivariate analysis. Our research shed light on the genomics of Chinese lung IMA that had been surgically removed. In IMA patients with stage III illness, we also discovered many genetic characteristics that might be used as indicators for postoperative recurrence.

scholarly journals Clinical Relevance of PD-L1 Expression and CD8+ T Cells’ Infiltration in Patients With Lung Invasive Mucinous Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoling Xu ◽  
Na Li ◽  
Ding Wang ◽  
Wei Chen ◽  
Yun Fan
Keyword(s):  
Mucinous Adenocarcinoma ◽  
Target Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Egfr Mutations ◽  
Chi Square ◽  
Genetic Characteristics ◽  
Kaplan Meier ◽  
Chi Square Test ◽  
Cox Proportional Hazard Regression ◽  
Invasive Mucinous Adenocarcinoma

BackgroundInvasive mucinous adenocarcinoma (IMA) of the lung is a rare and distinct subtype of adenocarcinoma. At present, people have no idea whether IMA patients can benefit from immunotherapy and target therapy; thus there is an urgent need to clarify the immune microenvironment and genetic characteristics of this cohort.MethodsA total of 31 IMA patients matched with 27 non-mucinous adenocarcinoma (non-IMA) patients were enrolled in this study, and clinical data was collected. The expression of PD-L1, CD8+ tumor-infiltrating lymphocytes (TILs) and ALK was determined by immunohistochemistry. Polymerase Chain Reaction was used to determine the mutations of EGFR. The Chi-square test, Kaplan–Meier method and Cox proportional hazard regression model were used to explore the correlations between these clinicopathological variables, survival and identify risk factors.ResultsOf the patients with IMA 9.7% (3/31) revealed positive PD-L1 expression and 35.5% (11/31) showed CD8+ TIL infiltration, which were markedly lower than that of non-IMA group [PD-L1: 48.1% (13/27); CD8: 81.5% (22/27)]. Moreover, five (16.1%) patients in IMA group and 10 (37.0%) patients in non-IMA group had EGFR mutations, and nine (29.0%) patients in IMA group and zero (0.0%) patient in non-IMA group had ALK rearrangements. Additionally, we observed that IMA patients with CD8+ TIL infiltration had a worse prognosis than CD8-negative group (P = 0.024). Multivariate analyses showed that CD8 was an independent prognostic factor for patient’s survival (HR = 5.60, 95% CI: 1.35–23.22, P = 0.017).ConclusionPatients with IMA have down-regulated expression of PD-L1 and less CD8+ TIL infiltration in tumor microenvironment. Besides, a lower frequency of EGFR mutations was detected in patients with IMA than non-IMA patients while a higher rate of ALK rearrangements was found. Our results provide important reference for therapy of lung IMA.

Multiple Lung Cancers: Independent Primary Tumors or Intrapulmonary Metastases, A Case Report

2020 ◽  
Author(s):  
Anna Sarah Erem ◽  
Matthew J Cecchini ◽  
Jennifer M. Boland
Keyword(s):  
Mucinous Adenocarcinoma ◽  
Adenosquamous Carcinoma ◽  
Lower Lobe ◽  
Interesting Case ◽  
Primary Tumors ◽  
Lung Cancers ◽  
Direct Invasion ◽  
Adenocarcinoma Component ◽  
Invasive Mucinous Adenocarcinoma ◽  
The Right

Abstract Background The prevalence of multiple primary lung cancers is rising, highlighting the need for tools to distinguish independent primary tumors from metastases. Molecular markers and hisopathologic comparison are useful to aid in this distinction, but they have significant limitations. Case Presentation A 76-year old woman presented with recurrent bronchorrhea, non-productive cough, and dyspnea upon exertion. She was a former smoker (15 pack-year history). Computerized tomography imaging revealed multiple lung masses: 1.9 × 2.3 cm nodule in the right upper lobe, and a 6.5 cm mass in the right lower lobe. Histologic examination of the tumors showed that the right lower lobe mass was an adenosquamous carcinoma with a mucinous adenocarcinoma component. This tumor showed visceral pleural invasion, and direct invasion of one intrapulmonary peribronchial lymph node. The upper lobe lesion was characterized by pure invasive mucinous adenocarcinoma with no squamous component. Abdominal and pelvic imaging was performed to rule out alternative primary sites, and no evidence of disease was identified outside of the chest. A cancer mutation and rearrangement panel on the adenosquamous carcinoma did not reveal any mutations. Conclusions In this interesting case, a patient presented with two lung tumors which had some morphologic similarities, but also some important differences, and no specific genetic mutations were present to establish the relationship between the tumors. Although current tools are useful, this case highlights an example of a case where it remains extremely difficult to determine whether two lung cancers are independent primary tumors or intrapulmonary metastases.

THE ROLE OF PHOSPHATIDYLINOSITOL-3-KINASE IN CARCINOGENESIS

2017 ◽  
Vol 63 (4) ◽  
pp. 545-556
Author(s):  
Natalya Oskina ◽  
Aleksandr Shcherbakov ◽  
Maksim Filipenko ◽  
Nikolay Kushlinskiy ◽  
L. Ovchinnikova
Keyword(s):  
Genetic Disease ◽  
Intracellular Signaling ◽  
Somatic Mutations ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Phosphatidylinositol 3 Kinase ◽  
Intracellular Signaling Pathway ◽  
Metabolic Activities ◽  
Carcinogenic Process

Currently it is established that cancer is a genetic disease and that somatic mutations are the initiators of the carcinogenic process. The PI3K/AKT/mTOR pathway is an important intracellular signaling pathway regulating the cell growth and metabolic activities. Aberrant activation of the PI3K pathway is commonly observed in many different cancers. In this review we analyze the genetic alterations of PI3K pathway in a variety of human malignancies and discuss their possible implications for diagnosis and therapy.

scholarly journals Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2048
Author(s):  
Antónia Afonso Póvoa ◽  
Elisabete Teixeira ◽  
Maria Rosa Bella-Cueto ◽  
Rui Batista ◽  
Ana Pestana ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Patient Outcomes ◽  
Genetic Alterations ◽  
Papillary Thyroid ◽  
Tissue Samples ◽  
Primary Tumors ◽  
Persistent Disease ◽  
Increased Risk ◽  
Structural Disease

Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002–2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTpmut showed increased risk of structural disease (HR = 7.0, p < 0.001) and DSM (HR = 10.1, p = 0.001). Combined genotypes, BRAFwt/TERTpmut (HR = 6.8, p = 0.003), BRAFmut/TERTpmut (HR = 3.2, p = 0.056) and BRAFmut/TERTpwt (HR = 2.2, p = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAFwt/TERTpmut (HR = 24.2, p < 0.001) and BRAFmut/TERTpmut (HR = 11.5, p = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTpmut regardless of BRAF status (BRAFmut/TERTpmut, log-rank p < 0.001; BRAFwt/TERTpmut, log-rank p < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients’ outcome. BRAFmut/TERTpwt tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTpmut tumors were predisposed to recurrent structural disease and DSM.

scholarly journals Antigenic and Genotypic Similarity between Primary Glioblastomas and Their Derived Neurospheres

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Valentina Caldera ◽  
Marta Mellai ◽  
Laura Annovazzi ◽  
Angela Piazzi ◽  
Michele Lanotte ◽  
...  
Keyword(s):  
Stem Cells ◽  
Genetic Alterations ◽  
Tumor Stem Cells ◽  
Primary Tumors ◽  
Immunodeficient Mice ◽  
Brain Tumor Stem Cells ◽  
Tumor Phenotype ◽  
Fetal Bovine ◽  
Primary Glioblastomas

Formation of neurospheres (NS) in cultures of glioblastomas (GBMs), with self-renewal, clonogenic capacities, and tumorigenicity following transplantation into immunodeficient mice, may denounce the existence of brain tumor stem cells (BTSCs) in vivo. In sixteen cell lines from resected primary glioblastomas, NS showed the same genetic alterations as primary tumors and the expression of stemness antigens. Adherent cells (AC), after adding 10% of fetal bovine serum (FBS) to the culture, were genetically different from NS and prevailingly expressed differentiation antigens. NS developed from a highly malignant tumor phenotype with proliferation, circumscribed necrosis, and high vessel density. Beside originating from transformed neural stem cells (NSCs), BTSCs may be contained within or correspond to dedifferentiated cells after mutation accumulation, which reacquire the expression of stemness antigens.

Genomic analysis of primary malignant melanoma of the esophagus.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21515-e21515
Author(s):  
Jingjing Li ◽  
Shi Yan ◽  
Wenyan Guan ◽  
Xiao Xiao ◽  
Bing Liu ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Somatic Mutations ◽  
Genome Instability ◽  
Mapk Signaling ◽  
Primary Malignant Melanoma ◽  
Base Substitution ◽  
Pathway Enrichment Analysis ◽  
Driver Genes ◽  
Primary Tumors ◽  
Genetic Characteristics

e21515 Background: Primary malignant melanoma of the esophagus (PMME) is an exceedingly rare disease but behave more aggressively and have a poorer prognosis. No specific histopathological classification and therapy strategies have been established for this type of disease due to lack of both tumor biological and genetics perception to PMME. Methods: We performed whole exome sequencing on 29 dissections including 23 primary tumors and 6 metastatic lymph nodes from 18 PMME patients. The genetic characteristics including somatic mutations and copy number variation (CNV) of PMME were compared to 398 skin cutaneous melanoma (SKCM), 67 mucosal melanoma (MM) and 79 uveal melanoma (UVM). Using multi-region sequencing, we reconstructed the phylogenetic structure and inferred the evolutionary mode. Results: We found that PMME/MM have similar genomic patterns to SKCM but distinct from UVM. Frequently mutated driver genes such as MUC16, BRAF, NRAS, NF1, KMT2C, POLE, PTPRT, RANBP2 appeared in both SKCM and PMME/MM cohorts. Of note, pathway enrichment analysis using identified driver genes revealed that melanoma pathway and MAPK signaling pathway were among the top affected pathways in MM/PMME as well as in SKCM. UVR-associated single base substitution signature 7 (SBS7) was not a dominant signature (median: 0.17, range:0̃0.79) in PMME/MM but 99 percent (89/90) of them do have it. An overall concordant trend in genome instability was found between PMME and SKCM. Significant CNV events at arm level showed the similar changes in PMME and SKCM, including amplification regions of 1q, 6p, 7p, 8q, 15q, 20p and deletion of 10p, 10q, 11p. CDKN2A loss appeared as a shared focal event by PMME and SKCM. To elucidate the evolution trajectory of spatially separated samples, we also performed multi-region sequencing, and the phylogenetic analysis suggested that whole genome doubling (WGD) was an early and clonal event, which preceded the majority of somatic mutations and CNV. Most driver genes such as NF1, RANBP2 and MUC16 mutated after WGD except TP53. Above findings suggested that WGD might be capable of promoting ongoing genome instability and shaping the evolution in PMME. Moreover, parallel evolution of RANBP2 was recurrently observed indicating the existence of constraints and selection. Conclusions: Our data showed that PMME/MM exhibited genetic features very similar to SKCM so it might not be excluded from treatments currently used for common SKCM.

Improvements in access to cancer clinical trials facilitated by comprehensive genomic profiling in non-small cell lung cancer.

2021 ◽  
Vol 39 (28_suppl) ◽  
pp. 59-59
Author(s):  
Woojung Lee ◽  
Scott Spencer ◽  
Josh John Carlson ◽  
Tam Dinh ◽  
Victoria Dayer ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Genomic Profiling ◽  
Small Cell Lung ◽  
Eligibility Criteria ◽  
Comprehensive Genomic Profiling

59 Background: The use of comprehensive genomic profiling (CGP) in cancer patients could lead to additional enrollment in clinical trials that study novel genetic biomarkers, potentially reducing treatment costs for payers and improving health outcomes for patients. Our objective was to estimate the number of additional clinical trials in which patients with non-small cell lung cancer (NSCLC) could potentially enroll due to the use of CGP vs. a comparator panel of 50 genes or less. Methods: Clinical trials in NSCLC that started between 2015 - 2020 were identified from the Aggregate Analysis of ClinicalTrials.gov (AACT) database. Trials with unknown status or study sites outside the United States only were excluded. We abstracted information on required genetic alterations based on the study eligibility criteria. We calculated the incremental number of trials available to patients due to results generated by CGP (FoundationOne CDx, 324 genes) vs. a commercially available comparator panel that was 50 genes or less (Oncomine Dx Target Test, 23 genes) by phase and calendar year. The additional trials were characterized by disease severity, type of therapy, and setting. Results: Enrollment eligibility was dependent on genetic variant status in 35% (250/709) of all identified NSCLC trials. There were 29 (248 vs. 219) additional clinical trials available to patients through the use of CGP, 12% of all gene-specific trials for NSCLC. We identified 45 uses of genetic markers in the 29 additional clinical trials. The most frequent genetic marker in the incremental trials was microsatellite instability, accounting for 44% of all identified markers (20/45). The incremental number of trials available to patients due to the use of CGP did not vary significantly over time but varied by phase – most of the additional clinical trials were in phase 1 or 2 (28/29, 97%). Most of the incremental trials were in metastatic disease (22/29, 76%) and were conducted in academic or advanced community settings (18/29, 62%). The most frequently studied type of intervention in these studies was targeted monotherapy (8/29, 28%), followed by immuno-monotherapy (7/29, 24%). Conclusions: Clinical trials in NSCLC initiated over the past 5 years have consistently included CGP-specific genes or markers in eligibility criteria. Patients with NSCLC have the potential to benefit from the use of CGP as compared to smaller gene panels through improved access to clinical trials.[Table: see text]

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