scholarly journals The histologic phenotype of lung cancers is associated with transcriptomic features rather than genomic characteristics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ming Tang ◽  
Hussein A. Abbas ◽  
Marcelo V. Negrao ◽  
Maheshwari Ramineni ◽  
Xin Hu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Point Mutations ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Whole Exome ◽  
Microarray Profiling ◽  
Molecular Determinants ◽  
Mixed Histology ◽  
Therapeutic Decision Making ◽  
Histologic Subtypes

AbstractHistology plays an essential role in therapeutic decision-making for lung cancer patients. However, the molecular determinants of lung cancer histology are largely unknown. We conduct whole-exome sequencing and microarray profiling on 19 micro-dissected tumor regions of different histologic subtypes from 9 patients with lung cancers of mixed histology. A median of 68.9% of point mutations and 83% of copy number aberrations are shared between different histologic components within the same tumors. Furthermore, different histologic components within the tumors demonstrate similar subclonal architecture. On the other hand, transcriptomic profiling reveals shared pathways between the same histologic subtypes from different patients, which is supported by the analyses of the transcriptomic data from 141 cell lines and 343 lung cancers of different histologic subtypes. These data derived from mixed histologic subtypes in the setting of identical genetic background and exposure history support that the histologic fate of lung cancer cells is associated with transcriptomic features rather than the genomic profiles in most tumors.

scholarly journals The histologic phenotype of lung cancers may be driven by transcriptomic features rather than genomic characteristics

2021 ◽  
Author(s):  
Ming Tang ◽  
Hussein A Abbas ◽  
Marcelo Vailati Negrao ◽  
Maheshwari Ramineni ◽  
Xin Hu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Point Mutations ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Whole Exome ◽  
Microarray Profiling ◽  
Mixed Histology ◽  
Transcriptomic Level ◽  
Therapeutic Decision Making ◽  
Histologic Subtypes

AbstractHistology plays an essential role in therapeutic decision-making for lung cancer patients. However, the molecular determinants of lung cancer histology are largely unknown. We conducted whole-exome sequencing(WES) and microarray profiling on 19 micro-dissected tumor regions of different histologic subtypes from 9 patients with lung cancers of mixed histology. A median of 68.9% of point mutations and 83% of copy number aberrations were shared between different histologic components within the same tumors. Furthermore, different histologic components within the tumors demonstrated similar subclonal architecture. On the other hand, transcriptomic profiling revealed shared pathways between the same histologic subtypes from different patients, which was supported by the analyses of the transcriptomic data from 141 cell lines and 343 lung cancers of different histologic subtypes. These data suggest that histology of lung cancers may be determined at the transcriptomic level rather than the genomic level.

scholarly journals Role of Omentin in Obesity Paradox in Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 275
Author(s):  
Sheetal Parida ◽  
Sumit Siddharth ◽  
Dipali Sharma
Keyword(s):  
Lung Cancer ◽  
Obesity Paradox ◽  
Health Concern ◽  
Case Control Studies ◽  
Aberrant Expression ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Significant Enrichment ◽  
Normal Lungs ◽  
Related Mortality

Lung cancer remains the second-most-common cancer worldwide and is associated with the highest number of cancer-related mortality. While tobacco smoking is the most important risk factor for lung cancer, many other lifestyles and occupational factors significantly contribute. Obesity is a growing global health concern and contributes to ~30% cancer-related mortality, but unlike other lifestyle diseases, lung cancer is negatively associated with obesity. We meta-analyzed multiple case-control studies confirming increased survival and better outcomes in overweight and obese lung cancer patients. Tumor heterogeneity analysis showed significant enrichment of adipocytes and preadipocytes in normal lungs compared to lung cancers. Interestingly, one of the understudied adipokine, omentin, was significantly and consistently lower in lung neoplasms compared to normal lungs. Omentin has been examined in relation to osteoarthritis, inflammatory bowel disease, cardiovascular diseases, diabetes, chronic liver disease, psoriasis and some other cancers. Aberrant expression of omentin has been reported in solid tumors; however, little is known about its role in lung cancer. We found omentin to be consistently downregulated in lung cancers, and it exhibited a negative correlation with important transcription factors FOXA1, EN1, FOXC1 and ELK4. We, therefore, suggest that omentin may serve as a prognostic factor in lung cancer and explain the “obesity paradox” in lung cancer.

scholarly journals Soluble c-Met Is a Reliable and Sensitive Marker to Detect c-Met Expression Level in Lung Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Huilai Lv ◽  
Baoen Shan ◽  
Ziqiang Tian ◽  
Yong Li ◽  
Yuefeng Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Tissue Sample ◽  
Sample Collection ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Lung Cancer Therapy ◽  
Reliable Marker ◽  
Soluble C ◽  
Sensitive Marker

c-Met has been demonstrated as an attractive target in lung cancer therapy. Current studies showed that detection of c-Met status in tumor is critical in Met-targeted therapy. However not all patients are suitable for tissue sample collection. It is important to discover novel surrogate markers to detect c-Met status. In the study, soluble c-Met (s-Met) in plasma from 146 Chinese lung cancer patients and 40 disease-free volunteers was measured by enzyme-linked immunosorbent. In parallel, expression of c-Met in those tumors was also assessed by immunohistochemistry. Results showed that, in 146 lung cancer patients, 93 were c-Met expression positive and 74 of 93 were overexpressed. In c-Met-overexpressed patients, plasma s-Met was significantly increased. And further studies showed that plasma s-Met linearly correlated with c-Met expression in tumor. After tumor was removed in Met-overexpressed patients via resection, plasma s-Met significantly decreased to basal level. In addition, plasma s-Met showed to be poorly correlated with tumor size in Met-overexpressed patients. These results demonstrated that plasma s-Met is a sensitive and reliable marker to detect c-Met overexpression in lung cancers, and it is independent of tumor volume.

Comprehensive cancer genomics-based screening of new therapeutic targets and biomarkers for lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21031-e21031
Author(s):  
Yataro Daigo ◽  
Atsushi Takano ◽  
Yusuke Nakamura
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Therapeutic Target ◽  
Cancer Genomics ◽  
Cancer Biomarkers ◽  
Lung Cancer Cells ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Target Molecules

e21031 Background: Since the clinical outcome of advanced lung cancer patients is still poor after standard therapies, development of new anti-cancer drugs with minimum risk of adverse effects and cancer biomarkers for precision medicine is urgently required. Methods: We have been screening new therapeutic target molecules and molecular biomarkers for lung cancers as follows; i) To identify overexpressed genes in lung cancers by the gene expression profile analysis, ii) To verify the target genes for their scarce expression in normal tissues, iii) To validate the clinicopathologic importance of their protein expression by tissue microarray covering 263 lung cancers, and iv) To confirm their function for the growth and/or invasive ability of the lung cancer cells by siRNAs and gene transfection assays. Results: We identified dozens of candidate target molecules and selected a gene encoding protein with a GAP domain, LAPG1 (lung cancer-associated protein with Gap domain 1). Immunohistochemical analysis showed that LAPG1 expression was observed in 69.9% of lung cancers. Moreover positivity of LAPG1 expression was associated with poor prognosis of lung cancer patients. Knockdown of LAPG1 expression by siRNAs suppressed growth of lung cancer cells. Introduction of LAPG1 increased the invasive activity of mammalian cells, indicating that LAPG1 could be a prognostic biomarker and therapeutic target for lung cancers. Conclusions: Comprehensive cancer genomics-based screening could be useful for selection of new cancer biomarkers and molecular targets for developing small molecules, antibodies, nucleic acid drugs, and immunotherapies.

Delays in diagnosis and initiating treatment for patients with lung cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6102-6102
Author(s):  
R. L. Vandermeer ◽  
S. J. Dimitry ◽  
A. Arnold ◽  
P. M. Ellis
Keyword(s):  
Lung Cancer ◽  
Rapid Assessment ◽  
Wait Time ◽  
Term Survival ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Cancer Centre ◽  
Specialist Referral ◽  
Regional Cancer Centre ◽  
Delays In Diagnosis

6102 Background: Many patients with lung cancer report delays in the diagnosis of their disease. This situation may contribute to advanced stage at diagnosis and poor long term survival. This study explores the delays experienced by patients referred to a regional cancer centre with lung cancer. Methods: A prospective cohort of patients referred to a regional cancer centre with newly diagnosed lung cancer were surveyed over a 3 month period. Surgically resected patients were not included as they were treated at another site. Patients were asked when they first experienced symptoms, when they saw their doctor, what tests were done, when they saw a specialist and when they started treatment. A medical record review was employed to validate the data patients provided. Descriptive statistics were used to summarize the different time intervals. Results: 56 of 73 patients consented (RR 77%). However, only 52 patients (30M, 22F) were interviewed as two expired before being interviewed and two could not be contacted. The mean age was 68 yrs. Stage distribution was as follows: IB/IIA 10%, IIIA 20%, IIIB/IV 70%. The initial treatment was as follows: 10% of patients supportive care alone, 19% chemotherapy, 44% radiation and 27% had combined chemoradiation. Patients waited a median of 21 days (IQR 7–51d) before seeing a doctor and a further 22d (IQR 0–38d) to complete any investigations. The median time from presentation to specialist referral was 27d (IQR 12–49d) and a further 63d (IQR 44–102d) to complete investigations. The median wait time to start treatment once patients were seen at the cancer centre was 10d (IRQ 2–28d). The overall time from development of first symptoms to starting treatment was 139d (IQR 100–174d). Conclusions: Lung cancer patients experience substantial delays from development of symptoms to first initiating treatment. There is a need to develop and evaluate rapid assessment clinics for patients with suspected lung cancers. No significant financial relationships to disclose.

Systematic approach for development of new immunotherapeutics for lung cancers through cancer genomics analysis.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3092-3092
Author(s):  
Yataro Daigo ◽  
Atsushi Takano ◽  
Yusuke Nakamura
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Clinical Studies ◽  
Critical Role ◽  
Phase I Clinical Trials ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
High Immunogenicity

3092 Background: Oncoantigens are defined to be proteins that are very specifically expressed in cancer cells and that have the oncogenic activity and high immunogenicity, and are considered to be promising targets for immunotherapy such as therapeutic cancer vaccines. Methods: We have established a strategy as follows to identify new oncoantigens; i) screening of highly transactivated genes in the majority of 120 lung cancers using cDNA microarray representing 27,648 genes coupled with enrichment of tumor cells by laser microdissection, ii) verification of no expression of each candidate gene in normal tissues by northern-blot analysis, iii) validation of the clinicopathological significance of its high level of expression with tissue microarray containing 300 lung cancers, iv) verification of a critical role of each gene in the growth or invasiveness of cancer cells by RNAi and cell growth/invasion assays, v) screening of the epitope peptides recognized by HLA-A*0201- or A*2402-restricted cytotoxic T lymphocyte (CTL). We conducted phase I clinical trials of these therapeutic peptide vaccines for lung cancer patients. Results: We identified 35 oncoantigens and screened dozens of 10-amino-acid peptides, each of which corresponded to a part of TTK, LY6K, IMP-3, CDCA1, KIF20A, CDC45L, and FOXM1, and was a candidate to be presented on the surface of HLA-A*0201 or HLA-A*2402 that induced in vitro CTL response. Phase I clinical studies indicated that five epitope peptides could strongly induce the CTL activity in cancer patients. For example, we conducted a phase I study for HLA-A*2402-positive, advanced non-small cell lung cancer patients who failed to standard therapy, using the combination of 1, 2 or 3 mg/body of each peptides from LY6K, CDCA1, and KIF20A mixed with adjuvant once a week. This cancer vaccine therapy demonstrated tolerability and had very high immunogenicity of even 1 mg/body dose to induce antigen-specific CTLs in cancer patients. Conclusions: Through systematic genomics-based approach and clinical study, we have identified five epitope peptides, which could induce CTLs very effectively in cancer patients, and therefore it warrants further clinical studies. Clinical trial information: NCT01069575.

Multiregion whole exome seuquencing of pre- and early neoplastic lung lesions.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20042-e20042
Author(s):  
Jianjun Zhang ◽  
Dan Su ◽  
Junya Fujimoto ◽  
Lisa Ying ◽  
Chi-Wan Chow ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Gene Mutations ◽  
Lung Cancer Screening ◽  
Adenocarcinoma In Situ ◽  
Invasive Adenocarcinoma ◽  
Lung Cancers ◽  
Molecular Events ◽  
Whole Exome ◽  
Incidence And Mortality ◽  
Early Carcinogenesis

e20042 Background: The widespread use of CT for lung cancer screening and other reasons has resulted in a dramatic increase in the number of indeterminate ground glass opacities (GGOs). While many of GGOs can be resected with minimal morbidity, the cost has been called into question. Furthermore, multifocality is a relatively common, which makes decisions on extent of surgical resection and potential benefit less clear. Chemoprevention is a theoretically appealing approach to reduce lung cancer incidence and mortality. However, randomized trials have been disappointing to date. This may be due to the constellation of many factors including lack of reliable biomarkers to identify high-risk patients, lack of appropriate molecular targets and appropriate drugs because of our rudimentary knowledge on early carcinogenesis of lung cancers. It has been postulated that atypical adenomatous hyperplasia (AAH) represents preneoplastic lesion that can progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). However, the biology of these lesions is poorly understood and the definition and management of these lesions remain controversial. Methods: Study on early carcinogenesis is hampered by the small size of lesions and challenge of obtaining longitudinal samples at different stages of disease progression. Multiregion sequencing can depict genomic events relative to molecular time with early events ubiquitously present in all regions and late mutations confined to spatially separated regions of lesions. Using this approach, our recent work has reported that 20/21 canonical cancer gene mutations were early genetic events. Results: With intent to delineate the pivotal molecular events driving early carcinogenesis of lung cancer, we have collected 154 resected GGOs with including AAH (N = 40), AIS (N = 39), MIA (N = 55) and ADC (N = 20) based on the IASLC/ATS/ERS classification from 89 patients including 38 patients presenting with multifocal GGOs and 18 patients carry more than one type of pathology. Two to five spatially separated regions from each of the 154 lesions are subjected to whole exome sequencing. Conclusions: The data will be ready to present at the meeting.

Pathogenic germline mutation profile in Chinese lung cancers and related-driver mutation pattern.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13003-e13003
Author(s):  
Wenying Peng ◽  
Lin Wu ◽  
Lianpeng Chang ◽  
Jin Li ◽  
Jing Bai ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Somatic Mutation ◽  
Germline Mutation ◽  
Therapy Response ◽  
Therapeutic Interventions ◽  
Onset Age ◽  
Germline Variants ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Predisposition Genes

e13003 Background: Many cancers could be driven by germline mutation exampled as BRCA1/2 in breast or ovarian cancer. However, the candidate predisposition variants for Chinese lung cancer are largely unknown. Methods: We reviewed 1797 Chinese lung cancer patients with paired tumor-normal samples sequenced by a 1021 gene panel. The annotation of germline variants within 95 selected susceptible genes was based on ACMG 2015 version guideline. Results: The frequency of patients identified with pathogenic or likely pathogenic (P/LP) germline variants were 5.95% (107 in 1797), which elevated to 10.1% (9 in 89) in patients younger than 40. Totally, 112 mutations from 35 genes were screened out. Recurrent pathogenic germline genes were BRCA2 (n = 14), FANCA (n = 9), RAD51D (n = 7), MUTYH (n = 7), ATM (n = 7) and TP53 (n = 5). The average age at diagnosis was numerically 2 years earlier in patients with P/LP (mean, 58.2 vs. 60.0, p = 0.22) than other patients without significance, but different genes contribute to discordant effects. Significantly early onset age was found in germline BRCA1/ 2 mutation (median, 52.5 versus 60.0 yrs in patients without P/LP, p = 0.0080) while later onset age was associated with germline PMS2 mutation (median, 74 versus 60.0 yrs, p = 0.0214 ). In terms of clinical actionable somatic mutation, the frequency of KRAS (15/89, 16.85% versus 121/1429, 8.47%, p = 0.012) and c-MET (6/89, 6.74% versus 31/1429, 2.17%, p = 0.018) in germline mutant patients were significantly higher, while TP53 (41/89, 46.07% versus 847/1429, 59.27%, p = 0.019) was apparently less mutated in P/LP lung cancer. As for frequency of EGFR, ALK, ROS-1, RET and BRAF, mutation frequency were not significantly different in lung cancer with germline mutation. Conclusions: Our study delineated the pathogenic germline mutation landscape in Chinese lung cancers for the first time. Predisposition genes demonstrated clinical actionable roles in onset age and therapeutic interventions. Further follow up may clarify the contribution of germline mutation to somatic mutation driven targeted therapy response and prognosis.

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