Integrative analysis of the melanoma transcriptome.
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.
Berger
Michael F
MF
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Levin
Joshua Z
JZ
Vijayendran
Krishna
K
Sivachenko
Andrey
A
Adiconis
Xian
X
Maguire
Jared
J
Johnson
Laura A
LA
Robinson
James
J
Verhaak
Roel G
RG
Sougnez
Carrie
C
Onofrio
Robert C
RC
Ziaugra
Liuda
L
Cibulskis
Kristian
K
Laine
Elisabeth
E
Barretina
Jordi
J
Winckler
Wendy
W
Fisher
David E
DE
Getz
Gad
G
Meyerson
Matthew
M
Jaffe
David B
DB
Gabriel
Stacey B
SB
Lander
Eric S
ES
Dummer
Reinhard
R
Gnirke
Andreas
A
Nusbaum
Chad
C
Garraway
Levi A
LA
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
D020033:Protein Isoforms