Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis.

Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.

Feasibility of using low-volume tissue samples for gene expression profiling of advanced non-small cell lung cancers.

PURPOSE: The majority of patients with non-small cell lung cancer (NSCLC) present at an advanced clinical stage, when surgery is not a recommended therapeutic option. In such cases, tissues for molecular research are usually limited to the low-volume samples obtained at the time of diagnosis, usually via fine-needle aspiration (FNA). We tested the feasibility of performing gene expression profiling of advanced NSCLCs using amplified RNA from lung FNAs. EXPERIMENTAL DESIGN AND RESULTS: A total of 46 FNAs was tested, of which 18 yielded RNA of sufficient quality for microarray analysis. Expression profiles of these 18 samples were compared with profiles of 17 pairs of tumor and normal lung tissues that had been surgically obtained. Using a variety of unsupervised and supervised analytical approaches, we found that the FNA profiles were highly distinct from the normal samples and similar to the tumor profiles. CONCLUSIONS: We conclude that when RNA amplification is successful, gene expression profiles from NSCLC FNAs can determine malignancy and suggest that with additional refinement and standardization of sample collection and RNA amplification protocols, it will be possible to conduct additional and more detailed molecular analysis of advanced NSCLC using lung FNAs.

Using whole genome amplification (WGA) of low-volume biopsies to assess the prognostic role of EGFR, KRAS, p53, and CMET mutations in advanced-stage non-small cell lung cancer (NSCLC).

BACKGROUND: Progression of non-small cell lung cancer (NSCLC) from early- to late-stage may signify the accumulation of gene mutations. An advanced-stage tumor's mutation profile may also have prognostic value, guiding treatment decisions. Mutation detection of multiple genes is limited by the low amount of deoxyribonucleic acid extracted from low-volume diagnostic lung biopsies. We explored whole genome amplification (WGA) to enable multiple molecular analyses. METHODS: Eighty-eight advanced-stage NSCLC patients were enrolled. Their low-volume lung biopsies underwent WGA before direct sequencing for epidermal growth factor receptor (EGFR), KRAS (rat sarcoma virus), p53, and CMET (mesenchymal-epithelial transition factor) mutations. Overall survival impact was examined. Surgically-resected tumors from 133 early-stage NSCLC patients were sequenced for EGFR, KRAS and p53 mutations. We compared the mutation frequencies of both groups. RESULTS: It is feasible for low-volume lung biopsies to undergo WGA for mutational analysis. KRAS and CMET mutations have a deleterious effect on overall survival, hazard ratios 5.05 (p = 0.009) and 23.65 (p = 0.005), respectively. EGFR and p53 mutations, however, do not have a survival impact. There also does not seem to be significant differences in the frequency of mutations in EGFR, KRAS, and p53 between early- and advanced-stage disease: 20% versus 24% (p = 0.48), 29% versus 27% (p = 0.75), 10% versus 6% (p = 0.27), respectively. CONCLUSIONS: In advanced-stage NSCLC, KRAS, and CMET mutations suggest poor prognosis, whereas EGFR and p53 mutations do not seem to have survival impact. Mutations in EGFR, KRAS and p53 are unlikely to be responsible for the progression of NSCLC from early- to late-stage disease. WGA may be used to expand starting deoxyribonucleic acid from low-volume lung biopsies for further analysis of advanced-stage NSCLC.

Surgical coronary revascularization in severe left ventricular dysfunction.

Surgical revascularization in patients with coronary artery disease and severe left ventricular dysfunction is a common practice and poses a surgical challenge. From September 2002 to May 2004, 50 patients (47 men and 3 women; mean age, 59 +/- 9 years) with a mean preoperative ejection fraction of 19.7% +/- 3.2% underwent surgical revascularization. The mean EuroSCORE was 7.2 +/- 3.4. Indications for surgery were congestive heart failure in 8 patients (16%), angina in 20 (40%), ventricular arrhythmias in 4 (8%), and critical left main stem disease in 12 (24%). Twenty-two patients (44%) had emergency surgery for critical anatomy and unstable symptoms. The number of grafts per patient was 3.7 +/- 0.8. Seventeen patients (34%) required intra-aortic balloon pump support, 16 (32%) needed pacing, and 48 (96%) had inotropic support postoperatively. Morbidity included re-operation for bleeding (2%), acute renal failure (10%), hemodialysis (4%), and fatal multiorgan failure (4%). Postoperative (4.9 +/- 3.7 months) 2-dimentional echocardiography was available in 18 patients of whom 11 (61%) showed improved left ventricular function (range, 5% to 45%). Thirty-day hospital mortality was 8%. These data indicate that surgical revascularization can be performed safely with acceptable hospital mortality in high-risk patients with severe left ventricular dysfunction.