BackgroundColon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses.Methods and FindingsFresh-frozen primary tumor samples from a large multicenter cohort of 750 patients with stage I to IV CC who underwent surgery between 1987 and 2007 in seven centers were characterized for common DNA alterations, including BRAF, KRAS, and TP53 mutations, CpG island methylator phenotype, mismatch repair status, and chromosomal instability status, and were screened with whole genome and transcriptome arrays. 566 samples fulfilled RNA quality requirements. Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes. These subtypes were associated with distinct clinicopathological characteristics, molecular alterations, specific enrichments of supervised gene expression signatures (stem cell phenotype–like, normal-like, serrated CC phenotype–like), and deregulated signaling pathways. Based on their main biological characteristics, we distinguished a deficient mismatch repair subtype, a KRAS mutant subtype, a cancer stem cell subtype, and three chromosomal instability subtypes, including one associated with down-regulated immune pathways, one with up-regulation of the Wnt pathway, and one displaying a normal-like gene expression profile. The classification was validated in the remaining 123 samples plus an independent set of 1,058 CC samples, including eight public datasets. Furthermore, prognosis was analyzed in the subset of stage II–III CC samples. The subtypes C4 and C6, but not the subtypes C1, C2, C3, and C5, were independently associated with shorter relapse-free survival, even after adjusting for age, sex, stage, and the emerging prognostic classifier Oncotype DX Colon Cancer Assay recurrence score (hazard ratio 1.5, 95% CI 1.1–2.1, p = 0.0097). However, a limitation of this study is that information on tumor grade and number of nodes examined was not available.ConclusionsWe describe the first, to our knowledge, robust transcriptome-based classification of CC that improves the current disease stratification based on clinicopathological variables and common DNA markers. The biological relevance of these subtypes is illustrated by significant differences in prognosis. This analysis provides possibilities for improving prognostic models and therapeutic strategies. In conclusion, we report a new classification of CC into six molecular subtypes that arise through distinct biological pathways. Please see later in the article for the Editors' Summary

In EGFR-TKIs naive NSCLC patients, MET amplification is a frequent event, which could be associated with EGFR amplification, but not with K-Ras mutation. MET amplification may identify a subset of NSCLC for new targeted therapy. It will also be important to evaluate MET copy number to properly interpret future clinical trials.

The majority of lung cancer patients have tumor-derived genetic alterations in circulating plasma DNA that could be exploited as a diagnostic tool. We used fluorescent microsatellite analysis to detect alterations in plasma and tumor DNA in 34 patients who underwent bronchoscopy for lung cancer, including 11 small cell lung cancer (SCLC) and 23 nonsmall cell lung cancer (NSCLC) (12 adenocarcinomas, 11 squamous cell carcinomas) and 20 controls. Allelotyping was performed with a selected panel of 12 microsatellites from 9 chromosomal regions 3p21, 3p24, 5q, 9p, 9q, 13q, 17p, 17q and 20q. Plasma DNA allelic imbalance (AI) was found in 88% (30 of 34 Key words: plasma DNA alterations; lung cancer; microsatellite analysis; histologic type; prognosisLung cancer is one of the most common tumors in the world. The World Health Organization's (WHO) pathologic description of malignant tumors classifies lung cancer into 4 main groups: 1 small cell lung cancer (SCLC), squamous cell carcinoma (SQC), adenocarcinoma (ADC) and large cell carcinoma (LCC). For prognostic and therapeutic purposes, SQC, ADC and LCC are pooled together in the nonsmall cell lung cancer (NSCLC) group. NSCLC and SCLC represent about 80% and 20% of all primary lung cancers, respectively. 2 Surgery offers the best probability of cure for patients with NSCLC, but surgery cannot be proposed for locally advanced or metastatic stages. In spite of aggressive therapy, however, prognosis of lung cancer patients is generally very poor. Survival at 5 years is 35% for NSCLC operated patients and Ͻ 5% for inoperable NSCLC. Survival is Ͻ 20% at 2 years for limited SCLC and Ͻ 2% for extensive disease. 3-5 Thus, the development of novel diagnostic techniques to identify lung cancer may facilitate earlier diagnosis of primary or recurring cancers and lead to more effective treatments and improved prognosis.As in other cancers, accumulation of genetic alterations is common in lung cancer and can include gene mutations, allelic losses, allelic instabilities and aberrant gene methylation that target oncogenes or tumor suppressor genes (TSG). 6,7 Among microsatellite (MS) alterations, primary lung cancers seldom show microsatellite instability (MSI) but are more often characterized by frequent loss of heterozygosity (LOH). 8 Remarkably, the frequency of MS alterations reported in lung cancers varies substantially and obviously depends on the markers analyzed. For lung cancer, frequent LOH has been reported in regions of chromosomes 3, 5, 9, 13 and 17, with the highest frequency occurring at 3p. 9 -14 Nevertheless, comparison of allelotypes have identified some consistent differences in LOH frequencies such as 50 -80% and 80 -100% at 17p13, 20 -30% and 80 -90% at 13q, 60% and 0 -10% at 9p21, 50% and 90% at 3p in NSCLC and in SCLC, respectively. 14 -17 It has long been known that the concentration of free-circulating DNA in plasma is higher in tumor patients than in healthy people. 18 Microsatellite analysis, mutation analysis in genomic or mitochondrial DNA and gene promot...