We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.

These results confirm that lung metastasectomy is a safe and potentially curative procedure. Resectability, disease-free interval, and number of metastases enabled us to design a simple system of classification valid for different tumor types.

The identification of lung tumor-initiating cells and associated markers may be useful for optimization of therapeutic approaches and for predictive and prognostic information in lung cancer patients. CD133, a surface glycoprotein linked to organ-specific stem cells, was described as a marker of cancer-initiating cells in different tumor types. Here, we report that a CD133 ؉ , epithelial-

The efficacy of computed tomography (CT) screening for early lung cancer detection in heavy smokers is currently being tested by a number of randomized trials. Critical issues remain the frequency of unnecessary treatments and impact on mortality, indicating the need for biomarkers of aggressive disease. We explored microRNA (miRNA) expression profiles of lung tumors, normal lung tissues and plasma samples from cases with variable prognosis identified in a completed spiral-CT screening trial with extensive follow-up. miRNA expression patterns significantly distinguished: (i) tumors from normal lung tissues, (ii) tumor histology and growth rate, (iii) clinical outcome, and (iv) year of lung cancer CT detection. Interestingly, miRNA profiles in normal lung tissues also displayed remarkable associations with clinical features, suggesting the influence of a permissive microenvironment for tumor development. miRNA expression analyses in plasma samples collected 1-2 y before the onset of disease, at the time of CT detection and in disease-free smokers enrolled in the screening trial, resulted in the generation of miRNA signatures with strong predictive, diagnostic, and prognostic potential (area under the ROC curve ≥ 0.85). These signatures were validated in an independent cohort from a second randomized spiral-CT trial. These results indicate a role for miRNAs in lung tissues and plasma as molecular predictors of lung cancer development and aggressiveness and have theoretical and clinical implication for lung cancer management.circulating biomarkers | risk prediction | miRNA ratios D espite recent advances in the management of resected lung cancer and the use of molecular targeted agents in specific clinical settings, the cure rate of non-small-cell lung cancer (NSCLC) remains low due to drug-refractory recurrent and metastatic disease.Early detection studies using chest X-rays (1) and, more recently, spiral-computed tomography (CT; refs. 2 and 3), have reported a significant increase in the number of lung cancer diagnoses, without apparent major decrease in advanced cancers or reduction of mortality in smokers (4). A recent press release (http://www.cancer.gov) reporting the findings of the largest randomized trial comparing spiral-CT to chest X-rays showed a 6.9% reduction in all-cause mortality (−20.3% lung cancer mortality), but a full report of the results of this trial is not yet available. A likely explanation of the limited impact of CT screening on mortality is that perhaps not all aggressive lung tumors arise from identifiable slow-growing precursors, suggesting a possible paradigm shift in our understanding of the natural history of lung cancer (5, 6). In this respect, the identification of biologic and molecular features of indolent and aggressive disease would be critical to define clinically useful predictors of high-risk lesions. microRNAs (miRNAs) are small RNA molecules with regulatory function and marked tissue specificity that can modulate multiple targets belonging to several pathways. They are fr...

Lung cancer screening with low-dose CT can save lives. This European Union (EU) position statement presents the available evidence and the major issues that need to be addressed to ensure the successful implementation of low-dose CT lung cancer screening in Europe. This statement identified specific actions required by the European lung cancer screening community to adopt before the implementation of low-dose CT lung cancer screening. This position statement recommends the following actions: a risk stratification approach should be used for future lung cancer low-dose CT programmes; that individuals who enter screening programmes should be provided with information on the benefits and harms of screening, and smoking cessation should be offered to all current smokers; that management of detected solid nodules should use semi-automatically measured volume and volume-doubling time; that national quality assurance boards should be set up to oversee technical standards; that a lung nodule management pathway should be established and incorporated into clinical practice with a tailored screening approach; that non-calcified baseline lung nodules greater than 300 mm, and new lung nodules greater than 200 mm, should be managed in multidisciplinary teams according to this EU position statement recommendations to ensure that patients receive the most appropriate treatment; and planning for implementation of low-dose CT screening should start throughout Europe as soon as possible. European countries need to set a timeline for implementing lung cancer screening.