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Top 10 correlated genes to BIM (BCL2L11)

PDF file - 69KB, FGFR3-TACC3 fusion variants and BAG4-FGFR1 fusion in NSCLCs.

Supplementary Figure 1 Legend. Describing the qPCR assay and variant allele frequency data that are included in the figure.

Supplemental legend

PDF file - 56KB, Correlation between FGFR fusion and expression.

PDF file, 37K, Patient Characteristics.

PDF file, 36K, Primers for qRT-PCR.

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PDF file - 80KB, Detailed Clinicopathologic Characteristics of 1328 patients with non-small cell lung cancer.

Purpose: A secondary EGFR mutation, T790M, is the most common resistance mechanism in EGFR-mutant adenocarcinomas that have progressed on erlotinib. Third-generation EGFR inhibitors capable of inhibiting mutant EGFR with T790M produce responses in nearly two thirds of patients. However, acquired resistance mechanisms in patients treated with these drugs are yet to be described.Experimental Design: To study acquired resistance to third-generation EGFR inhibitors, T790M-positive cells derived from an erlotinib-resistant cancer were made resistant to a third-generation TKI and then characterized using cell and molecular analyses.Results: Cells resistant to a third-generation TKI acquired an additional EGFR mutation, C797S, which prevented suppression of EGFR. Our results demonstrate that the allelic context in which C797S was acquired may predict responsiveness to alternative treatments. If the C797S and T790M mutations are in trans, cells will be resistant to third-generation EGFR TKIs, but will be sensitive to a combination of first- and third-generation TKIs. If the mutations are in cis, no EGFR TKIs alone or in combination can suppress activity. If C797S develops in cells wild-type for T790 (when third-generation TKIs are administered in the first-line setting), the cells are resistant to third-generation TKIs, but retain sensitivity to first-generation TKIs.Conclusions: Mutation of C797S in EGFR is a novel mechanism of acquired resistance to third-generation TKIs. The context in which the C797S develops with respect to the other EGFR alleles affects the efficacy of subsequent treatments. Clin Cancer Res; 21(17); 3924–33. ©2015 AACR.See related commentary by Ayeni et al., p. 3818

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PDF file, 38K, Sensitivity and specificity of different primer sets using FISH as the gold standard.

ZEB1 binding sites found in 1975R2 cells compared to 1975 parental cells

PDF file - 91KB, Independent predictors of FGFR1/3 fusions in 1328 patients with NSCLCs in multivariate analysis.

Purpose: Our previous study revealed that 90% [47 of 52; 95% confidence interval (CI), 0.79–0.96] of Chinese never-smokers with lung adenocarcinoma harbor known oncogenic driver mutations in just four genes EGFR, ALK, HER2, and KRAS. Here, we examined the status of known driver mutations specifically in female never-smokers with lung adenocarcinoma.Experimental Design: Tumors were genotyped for mutations in EGFR, KRAS, ALK, HER2, and BRAF. Data on age, stage, tumor differentiation, histologic subtypes, and molecular alterations were recorded from 349 resected lung adenocarcinomas from female never-smokers. We further compared the clinicopathologic parameters according to mutational status of these genes.Results: Two hundred and sixty-six (76.2%) tumors harbored EGFR mutations, 16 (4.6%) HER2 mutations, 15 (4.3%) EML4-ALK fusions, seven (2.0%) KRAS mutations, and two (0.6%) BRAF mutations. In univariate analysis, patients harboring EGFR mutations were significantly older (P < 0.001), whereas patients harboring HER2 mutations were significantly younger (P = 0.036). Higher prevalence of KRAS (P = 0.028) and HER2 (P = 0.021) mutations was found in invasive mucinous adenocarcinoma (IMA). The frequency of EGFR mutations was positively correlated with acinar predominant tumors (P = 0.002). Multivariate analysis revealed that older age at diagnosis (P = 0.013) and acinar predominant subtype (P = 0.005) were independent predictors of EGFR mutations. Independent predictors of HER2 mutations included younger age (P = 0.030) and IMA (P = 0.017). IMA (P = 0.006) and poor differentiation (P = 0.028) were independently associated with KRAS mutations.Conclusions: The frequency of driver mutations in never-smoking female lung adenocarcinoma varies with histologic subtypes and age at diagnosis. These data have implications for both clinical trial design and therapeutic strategies. Clin Cancer Res; 18(7); 1947–53. ©2012 AACR.

PDF file - 47KB, Kaplan-Meier survival curves for relapse free and overall survival according to EGFR, KRAS, BRAF, HER2, FGFR or wild-type status.

PDF file - 77KB, Clinicopathologic Characteristics of 734 Patients with NSCLC in Survival analysis.

Purpose: Approximately 3% to 7% of non–small cell lung cancers (NSCLC) harbor an ALK fusion gene, thus defining a tumor group that may be responsive to targeted therapy. The breakpoint in ALK consistently occurs at exon 20 and EML4 or other fusion partners, thus driving a strong expression of ALK kinase domain and resulting in an unbalanced expression in 5′ and 3′ portions of ALK transcripts. We have developed a rapid and accurate method by simultaneously detecting the expression in 5′ and 3′ portions of ALK mRNA.Experimental Design: Quantitative real-time reverse transcriptase PCR (qRT-PCR) was used to examine expression levels of the 5′ and 3′ portions of ALK transcripts in177 NSCLCs, in which EGFR, KRAS, HER2, and BRAF mutations were absent. If unbalanced ALK mRNA expression was seen, ALK rearrangement was assumed to exist. ALK FISH was used to confirm the accuracy of qRT-PCR. RT-PCR and 5′ RACE coupling sequencing identified the fusion variants.Results: Real-time RT-PCR showed excellent sensitivity and specificity (100% and 100%, respectively) for detection of ALK rearrangements in resected specimens. In addition, six novel ALK fusion variants were identified, including one KIF5B-ALK (E17;A20) and five EML4-ALK variants (E6a;A19, E6a/b ins 18;A20, E17b ins 39;A20, E10a/b, E13;A20, and E17 ins 65;A20).Conclusions: Real-time RT-PCR is a rapid and accurate method for diagnosing ALK-rearranged lung cancers. Coupling of 5′ RACE to this method should further facilitate rapid identification of novel ALK fusion genes. Clin Cancer Res; 18(17); 4725–32. ©2012 AACR.

PDF file - 150KB, Representative positive/negative expression of FGFR1 (A/B), FGFR3c(C/D),FGFR3a(E/F) in NSCLC.

Table 5:Correlation between FGFR fusion and expression Table 6: Clinicopathologic Characteristics of 734 Patients with NSCLC in Survival analysis

PDF file, 10567K, Identification of novel variants of EML4-ALK.

Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it.Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR-mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance.Results: We observed that mesenchymal EGFR-mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance “free” cellular BIM levels both led to resensitization of mesenchymal EGFR-mutant cancers to EGFRi. This relationship between EMT and loss of BIM is not restricted to EGFR-mutant lung cancers, as it was also observed in KRAS-mutant lung cancers and large datasets, including different cancer subtypes.Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. Clin Cancer Res; 24(1); 197–208. ©2017 AACR.

PDF file - 81KB, Primers Used for Sequencing of FGFR Fusion.

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PDF file, 8019K, Heatmaps of normalized Exon Array expression values for ALK in lung adenocarcinomas.

Supplementary Figure 1. EGFR amplification status and variant allele frequencies of T790M and C797S mutations for MGH121 parental and MGH121 resistant #1 cells.

PDF file, 12461K, Immunohistochemical staining patterns.

PDF file - 130KB, Clinicopathologic Characteristics in NSCLC Patients with FGFR, ALK, RET and ROS1 fusions.

PDF file, 305K, Normalized mRNA expression in 3' portion in ALK-rearranged lung cancer samples with varied tumor content.

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Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53, arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment., The genomic and immune landscape of pre-invasive lung adenocarcinoma is poorly understood. Here, the authors perform exome and transcriptome sequencing on precursor legions and invasive lung adenocarcinomas, identifying recurrently mutated genes in pre/minimally invasive cases, and arm level alteration events linked to immune infiltration.