Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

/pdf/gene-set-enrichment-analysis-a-knowledge-based-approach-for-mbpti6qljw.pdf

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

A genetic model for colorectal tumorigenesis

The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.

Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal

8059 Background: Case reports have shown that EGFR-TKI’s can be effective against brain mets from NSCLC. It is unclear, however, what effect these agents might have on the rate and time to occurren...

Rates of central nervous system progression in non-small cell lung cancer patients treated with EGFR-TKI's vs. chemotherapy

2165 Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) have recently been found to closely correlate with tumor responses to the EGFR-TK inhibitor, gefitinib (‘Iressa’), in patients with NSCLC. However, little is known about the efficacy of the EGFR directed antibody, cetuximab, in EGFR mutant NSCLCs. We examined the effects of gefitinib (3.3 nM to 10 μM) and cetuximab (33 ng/ml to 100 μg/ml) on in vitro cell growth by MTS assay in NSCLC cell lines with different EGFR genotypes: wild type (EGFRWT; A549, H441, and H1666); exon 21 L858R missense mutant (EGFRL858R; H3255); and exon 19 deletion mutant (EGFRdel; DFCILU-011). In the H1666 EGFRWT cell line, both gefitinib and cetuximab caused partial growth inhibition (47% and 43% growth inhibition using 1 μM and 10 μg/ml, respectively). In contrast, both H441 and A549 were resistant to both agents. Both gefitinib and cetuximab led to only partial inhibition of EGFR phosphorylation in H1666. Treatment with either 1 μM gefitinib or 10 μg/ml cetuximab induced apoptosis in H1666 (gefitinib:9.3+/− 1.0 %; cetuximab:11.2 +/− 2.5 %) but not in H441 cells. However, both cell lines harboring the EGFR mutations were very sensitive to gefitinib (IC50 for H3255 and DFCILU-011, 63 and 20 nM, respectively) and resistant to cetuximab (IC50 > 100 μg/ml). Consistent with these observations, 1 μM gefitinib led to significantly greater increase in apoptosis than 10 μg/ml cetuximab (H3255: gefitinib: 23.6 +/− 9.2 %, cetuximab 3.7 +/− 1.1 %; DFCILU-011: gefitinib 11 +/− 1.5%, cetuximab 0 +/− 0.9%). Gefitinib treatment also led to complete inhibition of EGFR phosphorylation while cetuximab had minimal effects on EGFR phosphorylation. To further evaluate the differences between wildtype and mutant EGFRs, we examined the effects of these agents in NIH-3T3 cells stably expressing EGFR that was either wild type or contained the L858R or exon 19 deletion mutations. In NIH-3T3/EGFRWT cells, both gefitinib and cetuximab led only to partial blockade of phophorylation of EGFR. However in NIH-3T3/EGFRL858R and NIH-3T3/EGFRdel cells gefitinib completely abrogated phosphorylation of EGFR at 0.1 μM but cetuximab led to only partial inhibition even at 100 μg/ml. We also sequenced EGFR from 3 NSCLC patients who received treatment with both cetuximab and gefitinib. Two patients who initially had stable disease with single agent cetuximab but subsequently developed disease progression achieved partial responses when treated with gefitinib. The third patient had a complete response to gefitinib but subsequently progressed, and was then treated with cetuximab with disease progression. All three patients had somatic mutations (exon 19 deletions) in EGFR.These findings suggest that gefitinib and cetuximab have differential effects on EGFR mutant NSCLCs and that patients with EGFR TK mutations should be treated with EGFR TKIs.

Differential effects of gefitinib and cetuximab on EGFR mutant non-small cell lung cancers (NSCLC)

The role of and significance of autocrine growth factors and neuroendocrine markers in the development of small cell lung cancer

BRAF mutations are rare in patients with NSCLC, and treatment options are limited. Dabrafenib plus trametinib (dab-tram) was approved for BRAFV600-mutated advanced NSCLC (aNSCLC), based on results from a phase 2 study (NCT01336634). This retrospective analysis compared the effectiveness of dab-tram, based on previously reported clinical trial data, versus real-world standard of care in patients with BRAF-mutated aNSCLC.Real-world cohorts were derived from a deidentified real-world database (2011-2020) and included patients with BRAF-mutated aNSCLC receiving first-line platinum-based chemotherapy (PBC), first-line immune checkpoint inhibitors (ICIs) plus PBC, or second-line ICIs. Weighting by odds was used to estimate the average treatment effect of the treated.For first-line dab-tram versus PBC, the hazard ratio (HR; 95% confidence interval) for death in unweighted and weighted analyses was 0.65 (0.39-1.1) and 0.51 (0.29-0.92; p = 0.03), respectively; unweighted and weighted median overall survival was 17.3 (12.3-40.2) versus 14.5 (9.2-19.6) months and 17.3 (14.6-not reached) versus 9.7 (6.4-19.6) months, respectively. Hazard ratio of death in unweighted and weighted analyses was 0.56 (0.29-1.1) and 0.57 (0.28-1.17), respectively, with first-line dab-tram versus PBC plus ICI, and 0.65 (0.39-1.07) and not reported (Cox proportional-hazards assumption violated), respectively, with second-line dab-tram versus ICI.In this indirect comparison in patients with BRAF-mutated aNSCLC, the risk of death was lower and median overall survival was longer with first-line dab-tram versus PBC. In analyses of dab-tram versus first-line PBC plus ICI or second-line ICI, sample sizes were small and findings were inconclusive with overlapping confidence intervals. Despite some limitations, the study provides useful data for this rare patient population. 

https://doi.org/10.1016/j.jtocrr.2022.100324

Bruce E. Johnson

Papers

Rates of central nervous system progression in non-small cell lung cancer patients treated with EGFR-TKI's vs. chemotherapy

Differential effects of gefitinib and cetuximab on EGFR mutant non-small cell lung cancers (NSCLC)

The role of and significance of autocrine growth factors and neuroendocrine markers in the development of small cell lung cancer

Clinical Outcomes With Dabrafenib Plus Trametinib in a Clinical Trial Versus Real-World Standard of Care in Patients With BRAF-Mutated Advanced NSCLC

Toxicity and supportive care in small cell lung cancer: a consensus report