title: Integrative analysis of the melanoma transcriptome.
abstract: Global studies of transcript structure and abundance in cancer cells enable the systematic discovery of aberrations that contribute to carcinogenesis, including gene fusions, alternative splice isoforms, and somatic mutations. We developed a systematic approach to characterize the spectrum of cancer-associated mRNA alterations through integration of transcriptomic and structural genomic data, and we applied this approach to generate new insights into melanoma biology. Using paired-end massively parallel sequencing of cDNA (RNA-seq) together with analyses of high-resolution chromosomal copy number data, we identified 11 novel melanoma gene fusions produced by underlying genomic rearrangements, as well as 12 novel readthrough transcripts. We mapped these chimeric transcripts to base-pair resolution and traced them to their genomic origins using matched chromosomal copy number information. We also used these data to discover and validate base-pair mutations that accumulated in these melanomas, revealing a surprisingly high rate of somatic mutation and lending support to the notion that point mutations constitute the major driver of melanoma progression. Taken together, these results may indicate new avenues for target discovery in melanoma, while also providing a template for large-scale transcriptome studies across many tumor types.
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.forename: Joshua Z
authors.initials: JZ
authors.lastname: Levin
authors.forename: Krishna
authors.initials: K
authors.lastname: Vijayendran
authors.forename: Andrey
authors.initials: A
authors.lastname: Sivachenko
authors.forename: Xian
authors.initials: X
authors.lastname: Adiconis
authors.forename: Jared
authors.initials: J
authors.lastname: Maguire
authors.forename: Laura A
authors.initials: LA
authors.lastname: Johnson
authors.forename: James
authors.initials: J
authors.lastname: Robinson
authors.forename: Roel G
authors.initials: RG
authors.lastname: Verhaak
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.forename: Robert C
authors.initials: RC
authors.lastname: Onofrio
authors.forename: Liuda
authors.initials: L
authors.lastname: Ziaugra
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Laine
authors.forename: Jordi
authors.initials: J
authors.lastname: Barretina
authors.forename: Wendy
authors.initials: W
authors.lastname: Winckler
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: David B
authors.initials: DB
authors.lastname: Jaffe
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.forename: Andreas
authors.initials: A
authors.lastname: Gnirke
authors.forename: Chad
authors.initials: C
authors.lastname: Nusbaum
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D023281:Genomics / Q000379:methods; D006801:Humans; D020014:K562 Cells; D016555:Matched-Pair Analysis; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000235:genetics; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018511:Systems Integration; D014407:Tumor Cells, Cultured
chemical_list: D020033:Protein Isoforms