title: Landscape of somatic allelic imbalances and copy number alterations in human lung carcinoma.
abstract: Lung cancer is the worldwide leading cause of death from cancer and has been shown to be a heterogeneous disease at the genomic level. To delineate the genomic landscape of copy number alterations, amplifications, loss-of-heterozygosity (LOH), tumor ploidy and copy-neutral allelic imbalance in lung cancer, microarray-based genomic profiles from 2,141 tumors and cell lines including adenocarcinomas (AC, n = 1,206), squamous cell carcinomas (SqCC, n = 467), large cell carcinomas (n = 37) and small cell lung carcinomas (SCLC, n = 88) were assembled from different repositories. Copy number alteration differences between lung cancer histologies were confirmed in 285 unrelated tumors analyzed by BAC array comparative genomic hybridization. Tumor ploidy patterns were validated by DNA flow cytometry analysis of 129 unrelated cases. Eighty-nine recurrent copy number alterations (55 gains, 34 losses) were identified harboring genes with gene expression putatively driven by gene dosage through integration with gene expression data for 496 cases. Thirteen and 26 of identified regions discriminated AC/SqCC and AC/SqCC/SCLC, respectively, while 48 regions harbored recurrent (n > 15) high-level amplifications comprising established and putative oncogenes, differing in frequency and coamplification patterns between histologies. Lung cancer histologies displayed differences in patterns/frequency of copy number alterations, genomic architecture, LOH, copy-neutral allelic imbalance and tumor ploidy, with AC generally displaying less copy number alterations and allelic imbalance. Moreover, a strong association was demonstrated between different types of copy number alterations and allelic imbalances with tumor aneuploidy. In summary, these analyses provide a comprehensive overview of the landscape of genomic alterations in lung cancer, highlighting differences but also similarities between subgroups of the disease.
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Barngatan 2B, Lund, Sweden. johan.staaf@med.lu.se
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.forename: Sofi
authors.initials: S
authors.lastname: Isaksson
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.forename: Mats
authors.initials: M
authors.lastname: Jönsson
authors.forename: Leif
authors.initials: L
authors.lastname: Johansson
authors.forename: Per
authors.initials: P
authors.lastname: Jönsson
authors.forename: Johan
authors.initials: J
authors.lastname: Botling
authors.forename: Patrick
authors.initials: P
authors.lastname: Micke
authors.forename: Bo
authors.initials: B
authors.lastname: Baldetorp
authors.forename: Maria
authors.initials: M
authors.lastname: Planck
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D022981:Allelic Imbalance; D018196:Carcinoma, Adenosquamous / Q000235:genetics / Q000473:pathology; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011003:Ploidies; D011379:Prognosis; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology