Inclusion And Ethical Considerations
The inclusion criteria were all cases with a component of Non-Small Cell Lung cancer and/or adenocarcinomatous differentiation or those in which a pulmonary carcinoma or adenocarcinomatous component could not be excluded, verified by a pathologist before being included in the study. Approval from the Institutional Ethical Committee was obtained prior to data collection during data collection from all three institutions, no other clinicopathologic data were collected for this analysis except those necessary for this study.
Clinical Characteristics And Genomic Profiling Of Lung Cancer With Metex14 Alterations
The prevalence of METex14 alterations was much higher in ASC than other subtypes, including LCC , ADC and SCC . The median age of lung cancer patients with METex14 was 68 , and females and males take up 48.6% and 47.4% , respectively.
Comparatively, gene alterations in 9 non-lung cancer cases revealed a different mutational spectrum, including a much higher occurrence of TP53 alterations , and the absence of MDM2/CDK4 amplification. Moreover, KRAS mutations and non-METex14 alterations were found in 44% of cases , suggesting the companion mutations might be different across cancer types.
Extended Data Fig 6 Dominant Endogenous Processes In Sherlock
a, Density plot of cosine similarity between original mutational profile and reconstructed mutational profile using reference signatures from : 65 COSMIC SBS signatures, 22 COSMIC SBS signatures for endogenous processes, 53 MutaGene SBS signatures of environmental exposures, and a combined set of signatures including the 22 endogenous and 53 environmental exposure signatures. b, Comparison of the cosine similarity between the original mutational profiles and reconstructed mutational profiles using endogenous and exogenous signatures . Each dot represents one sample. The size and color represent the total number of mutations and tumor histological type, respectively.
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Validation Of This Assay Kit
The performance characteristics of this kit were validated by real-time PCR assay and the results were interpreted according to the Ct values of the samples. ALK, ROS1 and RET gene fusions status were analyzed in tubes 14. If FAM Ct value of tube 14 is < 35, the sample was determined as positive, otherwise it was negative. The kit allows detection of 450 copies of gene fusions armored RNA in 0.094.5g FFPE sample RNA . For tubes 511, DNA gene mutation status were analyzed. If FAM or VIC Ct value of tube 512 is< 31, the sample was determined as positive. The sensitivity was 1% for each gene mutation status .
Figure 1 Analyze the mutation/fusion assay for each gene.Notes: The performance characteristics of this kit were validated by real-time PCR assay and the results were interpreted according to the Ct values of the samples. ALK, ROS1 and RET gene fusions status were analyzed in tubes 14. Tube1 FAM signal: ALK Tube2 FAM signal: ROS-1 Tube3 FAM signal: ROS-1 Tube4 FAM signal: RET DNA gene mutation status were analyzed in tubes 511. Tube5 FAM signal: 19 Del Tube5 VIC signal: S768I Tube6 FAM signal: L858R Tube6 VIC signal: G719X Tube7 FAM signal: T790M Tube7 VIC signal: L861Q Tube8 FAM signal: KRAS Tube8 VIC signal: BRAF Tube9 FAM signal: KRAS Tube9 VIC signal: HER2 Tube10 FAM signal: NRAS Tube10 VIC signal: HER2 Tube11 FAM signal: NRAS Tube11 VIC signal: PIK3CA.Abbreviations: PC, positive control NTC, negative control.
Resistance To Egfr Inhibitors In Egfr Mutated Nsclc
The main limitation of the widespread benefits of EGFR TKIs is the development of acquired resistance in patients with EGFR mutated NSCLC treated with this class of drugs. Resistant mutations that disrupt kinase-drug binding contacts and activation of shared downstream signaling pathways through other aberrant kinases are the predominant models for acquired resistance under pressure of a TKI in preclinical models and clinical samples . A simple consensus clinical criterion that defines acquired resistance has been loosely used for clinical trial development .
Bypass signaling tracks as mechanisms of acquired resistance to EGFR TKIs are more varied . The validated oncogenes that participate in these bypass mechanisms comprise hepatocyte growth factor receptor , ERBB2 , and others . These changes are individually uncommon , and they can be co-identified with the gatekeeper EGFR-T790M change in the same specimen . Successful treatments for these bypass tracks await clinical trials . Some biopsies of NSCLCs with acquired resistance to first-generation EGFR TKIs show histological transformation to poorly differentiated neuroendocrine tumors . This proposed transformation to small-cell lung cancer may be mediated in part by activation of pathways that alter the stem cell potential of the TKI-resistant cell .
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Extended Data Fig 2 Genomic Alterations Of Tp53 Pathway In Sherlock
a, Oncoplot showing the mutual exclusivity between TP53 mutations and MDM2 amplification, which was used to define the TP53 proficient and deficient groups. The bottom bar shows tumor histological types. b, Comparison of genomic features between TP53-proficient and TP53-deficient tumors. Left three panels: tumor mutation burden, percentage of genome with SCNA and SV burden. P-values are calculated using the two-sided Mann-Whitney U test. Middle four panels: enrichments for BRCA1 LOH, Kataegis events, WGD events, and HLA LOH. P-values and OR are calculated using Fishers exact test . Right panel: Contributions of each SBS signature.
Is It Possible To Prevent Lung Cancer
- Cessation of smoking and eliminating exposure to tobacco smoke is the most important measure that can prevent lung cancer. Many products, such as nicotine gum, nicotine sprays, or nicotine inhalers, may be helpful to people trying to quit smoking.
- Minimizing exposure to passive smoking also is an effective preventive measure.
- Using a home radon test kit can identify and allow correction of increased radon levels in the home.
- Methods that allow early detection of cancers, such as the low-dose CT scan, also may be of value in the identification of small cancers that can be cured by surgical resection and prevented from becoming widespread, incurable metastatic cancer.
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Dna Isolation And Mutational Analysis
Genomic DNA were isolated from Formalin-Fixed Paraffin-Embedded samples according to standard protocols . EGFR , HER2 , KRAS , BRAF and TERT promoter region were PCR amplified using DNA and directly sequenced. Multiplex PCR analysis was done with rTaq DNA polymerase . Primers used in these experiments are listed in . ALK fusions were screened using FISH with FFPE slides.
Extended Data Fig 1 Genomic Alterations Of Rtk
a, Oncoplot showing mutual exclusivity of genes within the RTK-RAS pathway, which were used to define the RTK-RAS status. The bottom bar shows tumor histological types. b, Comparison of genomic features between RTK-RAS negative and positive tumors. Left four panels: tumor mutational burden, percentage of genome with SCNAs, SV burden and T/N TL ratio. P-values are calculated using the two-sided Mann-Whitney U test Middle three panels: enrichments for Kataegis events, WGD events, and BRCA2 LOH. P-values and OR are calculated using Fishers exact test Right panel: Contributions of each SBS signature.
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Pathological Presentation Of Mutation
It was observed that majority of patients presented with LUAD lesions n = 1231 , SQCC n = 29 , ASC n = 13 , LCC n = 10 , SCC n = 6 , ACC n = 3 , sarcomatous carcinoma n = 1 and there were n = 436 patients whose pathological types could not be ascertained at the time of this study.
LUAD lesions were most rampant among our cohort, where EGFR n = 847 , ALK n = 25 , KRAS n = 110 , HER2 n = 35 , MET n = 12 , BRAF n = 17 , PIK3CA n = 30 , and CTNNB1 n = 16 all had predominantly adenocarcinomatous presentations while a single patient harboring HRAS gene mutation presented with SQCC. Details in Table 2. LUADs, SQCCs, LCCs, and ACCs were found to be more common among females while ASCs, LCCs, SCCs, and SCs were predominant among males. Details in Table 3. On-the-other-hand, LUAD, SQCC, and LCC occurred frequently among non-smokers, while ASC, SCC, ACC, and SCs occurred mostly among smokers as seen in Table 3.
Table 2. Illustrates the correlation between the individual genetic mutations, and various pathological types observed in our study population.
Table 3. Illustrates the distribution of the pathologic presentations between gender and smoking histories.
Extended Data Fig 8 Homologous Recombination Deficiency In Sherlock
a, HRDetect scores of Sherlock-Lung samples. HRD-high: > 0.7, HRD-low: < 0.005. b, Comparison of the number of total indels, microhomology deletions, SVs, and SNVs between samples with HRDetect score below 0.7 and above 0.7 . P-values are calculated using the two-sided Mann-Whitney U test. For box plots, center lines show the medians box limits indicate the 25th and 75th percentiles whiskers extend 1.5 times the interquartile range from the 25th and 75th percentiles.
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Tumor Genomic Alterations In Melanoma Cohort
Of the 332 melanoma patients from previous genomic immune studies, 98 were recognized as immune responders. LRP1B was one of the most frequently mutated genes in the aggregated melanoma cohort, accounting for 122 of 332 patients . The mutation plots of LRP1B in different immune response status are shown in . Melanoma samples with LRP1B mutations had higher mutation rate than samples without LRP1B mutation . The well-known melanoma driver oncogenes , genomic integrity maintenance and DNA replication proofreading associated genes and common LRPs in relation to LRP1B mutation were illustrated in waterfall plot . Mutations in LRP1B, MRE11A were correlated with improved immune response .
Mutational patterns of recurrently mutated melanoma genes, Genomic Instability associated genes and LRPs gene family in relation to LRP1B mutation in the pooled melanoma patients. . Mutation rates per megabase stratified by synonymous and non-synonymous mutations. . The left panel is mutation frequency and the middle panel depicts genes mutation patterns across each cases with different mutation types color coded differently. Clinical features of immune response status, age, gender and stage displays in bottom. Immune response related genes were highlighted in bold.
Prognostic Value Of Gene Alternation Status
One hundred and one patients relapsed and 70 patients died due to the disease at final follow-up . The median follow-up period was 45 months . OS and DFS were evaluated according to gene mutation status. In Kaplan-Meier analysis, no associations between survival and EGFR , KRAS , and ALK status were observed . However, patients with two or more alternations exhibited shorter DFS compared to those with single mutations , whilst had no significant difference in OS . In further univariate analysis, tumor differentiation and TNM stage showed association with OS and TNM stage, concurrent mutation were correlated with DFS. Finally, multivariate analysis showed that only TNM stage was an independent predictor of OS as well as DFS in our cohort .
Table 3 Univariate and Multivariate Survival Analysis
Figure 4 KaplanMeier survival analysis for each genotype status.Notes: OS and DFS analysis stratified by EGFR status , KRAS status , ALK status , and dual mutation status .Abbreviations: OS, overall survival DFS, disease-free survival.
In the population of patients with EGFR sensitizing mutation, it was found that patients harboring the L858R mutation had longer DFS compared to other sensitizing mutation types . Besides, patients with L858R mutation tended to have better OS although the differences were not significant .
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Catalog Of Lung Cancer Gene Mutations Among Chinese Patients
- 1Department of Respiratory and Critical Care, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- 2Department of Radiology, Jinzhou Medical University, Jinzhou, China
- 3Internal Medicine Department, Xuhui Changqiao Community Health Care Centre, Shanghai, China
- 4Department of Pathology, Chinese PLA General Hospital, Beijing, China
- 5Department of Radiology, Affiliated Hospital of Qingdao University, Qingdao, China
- 6Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- 7Department of Respiratory and Critical Care, Second Affiliated Hospital of Anhui Medical University, Anhui, China
- 8Department of Chest Surgery, Chinese PLA General Hospital, Beijing, China
- 9Department of Laboratory, Chinese PLA General Hospital, Beijing, China
- 10Department of Respiratory and Critical Care, Affiliated Hospital of Weifang Medical University, Shandong, China
- 11Department of Chest Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- 12Department of Radiology, Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- 13Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, China
Patients and Methods: A retrospective data acquisition was conducted spanning 6 years among all patients who underwent lung cancer surgeries not bronchial or percutaneous lung biopsy at three major tertiary hospitals. Finally, we identified 1,729 patients who matched our inclusion criteria.
Frequency Of Kras G12c Mutations In Chinese Nsclc Patients
In the mCohort, 3998 NSCLC patients had KRAS mutations 25 patients had two KRAS mutation subtypes, and the frequency of KRAS mutations was 9.8%. Of the patients with KRAS mutations, 1179 were confirmed to harbor G12C mutations . The proportions of the other three major KRAS codon 12 subtypes were as follows: G12V, 18.3% G12D, 17.3% and G12A, 8.4% .
Flow charts of NSCLC patient enrollment in the study. Patients included from multiple centers cohort a. Patients included and excluded from Guangdong Lung Cancer Institute cohort b. pts.: patients
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The Correlation Between Clinico
As expected, the frequency of EGFR mutation was much higher in female patients , never-smokers , the ADC subtype and early-stage disease . KRAS mutations were associated with smoking history . ALK fusion patients were significantly younger than wild-type patients, and ALK fusion was well correlated with differentiated tumors.
Table 2 Frequencies of Genetic Alterations with Clinical Characteristics
Ucsf Internal Medicine Chief Resident Hub
Thank you to the great Sam Brondfield for joining us AND presenting a fascinating case! We discussed an older woman with metastatic lung adenocarcinoma on erlotinib transferred from OSH with shock with markedly elevated uric acid, LDH, and renal failure.
Lung Cancer Targeted Treatment
Refresher on the Etiologies of Shock
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