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 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.

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.

scholarly journals MUC5AC enhances tumor heterogeneity in lung adenocarcinoma with mucin production and is associated with poor prognosis

2020 ◽  
Vol 50 (6) ◽  
pp. 701-711
Author(s):  
Yujie Dong ◽  
Lijuan Zhou ◽  
Dan Zhao ◽  
Kun Li ◽  
Zichen Liu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Lung Adenocarcinoma ◽  
Poor Prognosis ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Kras Mutations ◽  
Mucin Production ◽  
Thyroid Transcription Factor 1 ◽  
Thyroid Transcription Factor ◽  
Transcription Factor 1

Abstract Objective The clinicopathological significance of Mucin5AC (MUC5AC) in lung adenocarcinoma with mucin production is still unclear. This study aimed to explore MUC5AC expression in lung adenocarcinoma with mucin production and its correlation with histological subtypes, common driver mutations and its impact on prognosis. Methods MUC5AC and thyroid transcription factor 1 immunohistochemistry was performed on surgical samples from 90 patients with lung adenocarcinoma with mucin production. Common driver mutations including EGFR and KRAS mutations and ALK rearrangement were detected by established methods. Results MUC5AC was significantly associated with lymphovascular invasion (P = 0.023) and tumors with intra-cytoplasmic mucin (P < 0.001). Moreover, MUC5AC was more significant in invasive mucinous adenocarcinoma (P < 0.001), as well as in tumors with KRAS mutations (P = 0.005) and a lack of thyroid transcription factor 1 expression (P < 0.001). Conversely, MUC5AC was less significantly detected in acinar predominant adenocarcinoma (P = 0.036) and tumors with EGFR mutations (P = 0.001). Notably, MUC5AC in non-pure mucinous subtype of lung adenocarcinoma with mucin production showed more aggressive behavior, distinct expression pattern and a lack of significant correlation with thyroid transcription factor 1 (P = 0.113) when compared with pure mucinous subtype. MUC5AC-positive tumors were significantly associated with a worse prognosis compared to MUC5AC-negative tumors (P < 0.001). A multivariate survival analysis showed that MUC5AC was an independent prognosis factor for poor prognosis (P = 0.006). Conclusions The clinicopathological features of non-pure mucinous subtype of lung adenocarcinoma with mucin production were distinct and should be distinguished from pure mucinous subtype. MUC5AC was associated with poor prognosis and could be a potential therapeutic target for this distinct type of lung adenocarcinoma that has few effective treatments.

Ethnic difference of driver mutation frequencies and correlations between driver mutations and histologic subtypes in lung adenocarcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1552-1552
Author(s):  
Yuki Yamane ◽  
Koichi Goto ◽  
Akikazu Kawase ◽  
Katsuya Tsuchihara ◽  
Sachiyo Mimaki ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Ethnic Difference ◽  
The United States ◽  
Driver Mutation ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Cancer Center ◽  
Histological Subtypes ◽  
Kras Mutations ◽  
Met Amplification

1552 Background: The frequencies of known driver mutation in lung adenocarcinoma from patients in the United States have been reported by the NCI’s Lung Cancer Mutation Consortium (LCMC), indicating driver mutations were detected in 54% (280/516) of tumors. In this report, mutations found: EGFR 17%, KRAS 22%, HER2 0.6%, PIK3CA 1.2%, BRAF 2%, MET amplification 0.6%, MAP2K1 0.4%, NRAS 0.4%, AKT 0%, ALK rearrangements 7%. However little is known about ethnic difference of driver mutation frequencies and correlations between driver mutations and histological subtypes in lung adenocarcinoma. Methods: Known driver mutations in tumors from 97 Japanese patients with lung adenocarcinoma who underwent surgical resection between 1999 and 2003 in National Cancer Center Hospital East were analyzed by next-generation sequencing and confirmed by Sanger sequencing. Correlations between driver mutations and histological subtypes were also assessed. Results: Driver mutations were detected in 72% of tumors. Mutations found: EGFR 57%, KRAS9%, HER2 2%, PIK3CA 2%, BRAF 1%, MET amplification 1%, MAP2K1 0%, NRAS 0%, AKT 0%. Due to the limitation of rearrangement detection by exon-sequencing, ALK rearrangements were not analyzed. Compared with the report by LCMC, the frequency of EGFR mutations was high and that of KRAS mutations was low in the present study. All mutations were mutually exclusive. The number of predominant histological subtypes of tumors harbored EGFR mutations were papillary 28, acinar 3, solid 5, lepidic 19. That with KRAS mutations showed papillary 2, acinar 2, solid 2, lepidic 3, and HER2 mutations showed papillary 1 and acinar 1. Two tumors harbored PIK3CA mutations showed both histological acinar pattern. Each of BRAF mutation and MET amplification showed lepidic and papillary pattern, respectively. Conclusions: It was suggested that there should be ethnic difference of driver mutation frequencies in lung adenocarcinoma between Asian and non-Asian patients, although the details of ethnic distribution included in LCMC study has not been opened. In addition, each driver mutations did not correspond to specific histological subtypes of lung adenocarcinoma.

Multiple Myeloma Sequencing Reveals Subclonality and Timing of Genetic Alterations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2897-2897
Author(s):  
Jens Lohr ◽  
Petar Stojanov ◽  
Michael S Lawrence ◽  
Daniel Auclair ◽  
Scott Carter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Time Course ◽  
Somatic Mutations ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Classification Systems ◽  
Driver Mutations ◽  
Kras Mutations

Abstract Abstract 2897 Multiple myeloma is considered to be a homogenous disease within a given patient, and current classification systems and treatment algorithms are based on this assumption. We have asked if there is genetic heterogeneity of multiple myeloma within a patient and if this heterogeneity can be quantified. To address this question, we have used massively parallel whole exome and whole genome sequencing of tumors and matched normal controls of 64 patients with multiple myeloma. We present an analytic strategy to distinguish potential driver mutations based on their clonality. We demonstrate that in some patients there are many somatic mutations that are only present in a subclonal fraction of the malignant plasma cells, and the subclonal fraction comprises up to 50%. These mutations are therefore less likely to confer a selective clonal advantage and are less attractive therapeutic targets because they only affect a small fraction of the myeloma cells. As an example, we found KRAS to be one of the most prevalent mutated genes in multiple myeloma, and KRAS mutations are significantly more likely clonal than subclonal, while other mutations in other genes are predominantly subclonal. We also used this approach to investigate how copy number variations are related to somatic mutations, i.e. to define the temporal sequence of these events. This question is particularly relevant for hyperdiploidy in multiple myeloma, since this is associated with trisomies of odd numbered chromosomes. However, these trisomies do not occur with the same frequency in all odd numbered chromosomes and some hyperdiploid samples are also associated with trisomies of various even numbered chromosomes. It is unclear if these trisomies occur as a single catastrophic event, or rather in a sequential fashion. By assuming a constant rate of somatic mutations and utilizing this rate as a “timer” for chromosomal duplications we demonstrate that trisomies of odd-numbered chromosomes appear to occur early in a distinct order, whereas trisomies of even-numbered chromosomes and chromosome 1q occur late. Our analyses allow us to determine which somatic mutations occurred before chromosomal duplication and may therefore give insight in the time course of pathogenic genetic alterations in multiple myeloma. Our work may also play an important role in prioritizing somatic mutations for therapeutic targeting in multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

Somatic mutation spectrum of non-small cell lung cancers (NSCLCs) from African Americans (AAs).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6038-6038
Author(s):  
Philip Edward Lammers ◽  
Velmalia Matthews-Smith ◽  
Ya-Lin Yun ◽  
Yumei Pan ◽  
Snjezana Zaja-Milatovic ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
North American Population ◽  
Molecular Testing ◽  
Chi Square ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Anaplastic Lymphoma ◽  
Ffpe Tumor

6038 Background: In the AA population, previous studies have presented conflicting data on the frequency of EGFR mutations (Reinersman JTO 2011;Leidner JCO 2009), while frequencies of other gene mutations and translocations, including anaplastic lymphoma kinase (ALK), have not been described. Methods: 161 archival FFPE tumor specimens from self reported AA patients with any stage NSCLC from 1997-2010 were collected from 3 sites in Tennessee (132 samples) and one site in Michigan (29 samples). Samples were evaluated for known recurrent driver mutations in EGFR, KRAS, BRAF, NRAS, AKT1, PI3KCA, PTEN, HER-2, MEK1 by standard SNaPshot/sizing assays, and translocations in ALK by FISH. Clinical data was collected on 119 patients. Chi-square was used to compare the frequency of mutations in subgroups and Kaplan-Meier and log rank were used to calculate and compare PFS between groups. Results: 5.0% of tumors had EGFR mutations, 14.9% had KRAS mutations, 0.6% had a BRAF, AKT1, PI3KCA, or HER2 mutation, and 0% had NRAS, PTEN, or MEK1 mutations. Of 35 ‘pan-negative’ non-squamous specimens, 0 had ALK translocations. PFS was the same in those with and without KRAS mutation (p=0.74) and showed a trend towards improvement in those with EGFR mutation (p=0.08). The frequency of EGFR mutations was higher in samples from Detroit versus those from Tennessee (17% vs 2.3%, p<0.01), as was the frequency of adenocarcinoma (62% vs 44%, p<0.05). The frequency of EGFR mutations in never smokers was higher in the samples from Detroit versus Tennessee (83% vs 7.1%, p<0.01). Conclusions: In the largest tumor mutational profiling study of NSCLC from AAs to date, EGFR mutations occurred less frequently than would be expected from a North American population. We noted a regional difference, with fewer EGFR mutations in Tennessee than in Michigan, a finding that may have been the result of more adenocarcinoma samples from Michigan. The rates of other mutations and translocations including ALK were low. While lung cancer tumors should continue to undergo routine molecular testing to prioritize therapy, future comprehensive genotyping efforts should focus on identifying novel driver mutations in this population. Funding: 5RC1CA162260 R01CA060691 R01CA87895.

scholarly journals Clinicopathological Features and Survival Outcomes of Primary Pulmonary Invasive Mucinous Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4103
Author(s):  
Chien-Hung Gow ◽  
Min-Shu Hsieh ◽  
Yi-Nan Liu ◽  
Yi-Hsuan Lee ◽  
Jin-Yuan Shih
Keyword(s):  
Mucinous Adenocarcinoma ◽  
Early Stage ◽  
Clinicopathological Features ◽  
Stage I ◽  
Driver Mutations ◽  
Survival Outcomes ◽  
Grading System ◽  
Low Grade ◽  
High Grade ◽  
Invasive Mucinous Adenocarcinoma

Pulmonary invasive mucinous adenocarcinoma (IMA) has unique histological patterns. This study aimed to comprehensively evaluate the clinicopathological features, prognosis, and survival outcomes of IMAs. We retrospectively identified 77 patients with pulmonary IMA and reviewed their clinical and pathological features. Another 520 patients with non-IMA-type ADC were retrieved for comparison with patients with IMA. A new two-tier grading system (high-grade and low-grade IMAs) modified from the pancreatic intraepithelial neoplasia classification system was used for survival analyses. Compared to patients with non-IMA-type ADC, patients with IMA tended to have never smoked (p = 0.01) and had early-stage IMA at initial diagnosis (p < 0.001). For stage I–II diseases, the five-year overall survival (OS) rates were 76% in IMAs and 50% in non-IMA-type ADCs, and a longer OS was observed in patients with IMA (p = 0.002). KRAS mutations were the most commonly detected driver mutations, which occurred in 12 of the 28 (43%) patients. High-grade IMAs were associated with a shorter recurrence-free survival (RFS) for stage I–IIIA diseases (p = 0.010) than low-grade IMAs but not for OS. In conclusion, patients with stage I and II IMA had better OS than those with non-IMA-type ADC. A new two-tier grading system might be useful for predicting RFS in stage I–IIIA IMAs.

Multiplex testing of driver mutations in non-small cell lung cancer (NSCLCs) of African-American (AA) patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7561-7561
Author(s):  
Shirish M. Gadgeel ◽  
Michele L Cote ◽  
Ann G. Schwartz ◽  
Aliccia Bollig-Fischer ◽  
Susan Land ◽  
...  
Keyword(s):  
Smoking Status ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Therapeutic Interventions ◽  
Driver Mutations ◽  
Specific Gene ◽  
Kras Mutations ◽  
Institutional Review ◽  
Multiplex Testing ◽  
White Patients

7561 Background: Recently driver genetic alterations have been identified in NSCLC that can be targeted for therapeutic interventions. Previous reports have suggested that rates of certain mutations may vary according to ethnic background. We conducted multiplex testing of NSCLCs of AA and white patients to assess variability in the mutation rates by race. Methods: We identified tumor tissues of 136 AA and 320 white NSCLC patients collected as part of three different institutional review board approved studies. Using the Sequenom MassArray system and a multiplexed panel, we analyzed tumor DNA for 214 oncogenic mutations in 26 genes previously identified in NSCLC. Estimated risk (Odds Ratios (OR)) of any mutation and specific gene mutations among AA patients compared to white patients were calculated after adjusting for age, sex, smoking status and histology (adenocarcinoma versus non-adenocarcinoma). Information on smoking status was unavailable on 46 patients and was not included in calculations of ORs for some genes (ORª). Results: The median age at diagnosis was 60 vs 66 years in AA vs white patients; 43% of AA patients and 66% of white patients were males; 69% of AA patients and 52% of white patients had adenocarcinoma; 66% of AA patients and 85% of white patients had stage I/II NSCLC and 10% of AA patients and 6% of white patients were never smokers. 43% of the AA patients and 47% of white patients had at least one mutation detected (OR = 0.78; 0.5-1.2). 19% of AA patients and 6% of white patients had more than 1 mutation detected (OR 2.3; 1.1-4.9). AA patients were more likely to harbor mutations in STK11 (LKB1) (OR=8.4; 3.2-21.8) and NOTCH1 (ORª=8.1; 2.2-30.8), and they were less likely to have MET mutations (ORª= 0.12; 0.02-0.9) then white patients. While not statistically significant, AA had lower prevalence of Kras mutations (OR=0.64, 0.3-1.4) and p53 mutations (OR= 0.82; 0.4-1.6). Conclusions: Our analysis of NSCLCs shows that AAs were more likely to have multiple genetic mutations than whites and the mutation profile differs by race.

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