To identify genetic events underlying the genesis and progression of multiple myeloma (MM), we conducted a high-resolution analysis of recurrent copy number alterations (CNAs) and expression profiles in a collection of MM cell lines and outcome-annotated clinical specimens. Attesting to the molecular heterogeneity of MM, unsupervised classification using nonnegative matrix factorization (NMF) designed for array comparative genomic hybridization (aCGH) analysis uncovered distinct genomic subtypes. Additionally, we defined 87 discrete minimal common regions (MCRs) within recurrent and highly focal CNAs. Further integration with expression data generated a refined list of MM gene candidates residing within these MCRs, thereby providing a genomic framework for dissection of disease pathogenesis, improved clinical management, and initiation of targeted drug discovery for specific MM patients.

Lung cancer is the leading cause of cancer mortality worldwide, yet there exists a limited view of the genetic lesions driving this disease. In this study, an integrated high-resolution survey of regional amplifications and deletions, coupled with gene-expression profiling of non-small-cell lung cancer subtypes, adenocarcinoma and squamous-cell carcinoma (SCC), identified 93 focal copynumber alterations, of which 21 span <0.5 megabases and contain a median of five genes. Whereas all known lung cancer genes͞loci are contained in the dataset, most of these recurrent copy-number alterations are previously uncharacterized and include high-amplitude amplifications and homozygous deletions. Notably, despite their distinct histopathological phenotypes, adenocarcinoma and SCC genomic profiles showed a nearly complete overlap, with only one clear SCC-specific amplicon. Among the few genes residing within this amplicon and showing consistent overexpression in SCC is p63, a known regulator of squamous-cell differentiation. Furthermore, intersection with the published pancreatic cancer comparative genomic hybridization dataset yielded, among others, two focal amplicons on 8p12 and 20q11 common to both cancer types. Integrated DNA-RNA analyses identified WHSC1L1 and TPX2 as two candidates likely targeted for amplification in both pancreatic ductal adenocarcinoma and non-small-cell lung cancer.array comparative genomic hybridization ͉ expression profiling ͉ lung adenocarcinoma ͉ squamous-cell lung carcinoma ͉ TP73L L ung cancer is the leading cause of cancer-related mortality in the United States, accounting for more than one-fourth of all cancer fatalities in 2004. Lung cancer is classified into two major subtypes, small-cell and non-small-cell lung cancer (NSCLC). NSCLC constitutes 75% of lung cancer cases and is subdivided further into three major histological subtypes: adenocarcinoma (AC), squamous-cell carcinoma (SCC), and large-cell carcinoma. The AC and SCC subtypes represent Ͼ85% of NSCLC cases. Although these NSCLC subtypes exhibit distinct pathological characteristics, the treatment approaches have remained generic and largely ineffective, despite advances in cytotoxic drugs, radiotherapy, and clinical management. For all stages of NSCLC, the 5-year survival rate has remained fixed at 15% for the last 15 years. The recent success of molecularly targeted therapies for a limited subset of cancer genotypes (1) has solidified the view that a more detailed knowledge of the spectrum of genetic lesions in lung cancer will, in turn, lead to meaningful therapeutic progress.To date, the majority of lung cancer genetic studies have cataloged mutations or the promoter methylation status of known cancer genes, performed genome-wide loss-of-heterozygosity surveys, and applied comparative genomic hybridization (CGH) to audit regional copy-number alterations (CNAs) on metaphase chromosomes or small-scale bacterial artificial chromosome (BAC) arrays. These concerted efforts have identified a core set of lesions, including activating...