Transcriptome sequencing of malignant pleural mesothelioma tumors.
Cancers arise by the gradual accumulation of mutations in multiple genes. We now use shotgun pyrosequencing to characterize RNA mutations and expression levels unique to malignant pleural mesotheliomas (MPMs) and not present in control tissues. On average, 266 Mb of cDNA were sequenced from each of four MPMs, from a control pulmonary adenocarcinoma (ADCA), and from normal lung tissue. Previously observed differences in MPM RNA expression levels were confirmed. Point mutations were identified by using criteria that require the presence of the mutation in at least four reads and in both cDNA strands and the absence of the mutation from sequence databases, normal adjacent tissues, and other controls. In the four MPMs, 15 nonsynonymous mutations were discovered: 7 were point mutations, 3 were deletions, 4 were exclusively expressed as a consequence of imputed epigenetic silencing, and 1 was putatively expressed as a consequence of RNA editing. Notably, each MPM had a different mutation profile, and no mutated gene was previously implicated in MPM. Of the seven point mutations, three were observed in at least one tumor from 49 other MPM patients. The mutations were in genes that could be causally related to cancer and included XRCC6, PDZK1IP1, ACTR1A, and AVEN.
Sugarbaker
David J
DJ
International Mesothelioma Program, Division of Thoracic Surgery, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Richards
William G
WG
Gordon
Gavin J
GJ
Dong
Lingsheng
L
De Rienzo
Assunta
A
Maulik
Gautam
G
Glickman
Jonathan N
JN
Chirieac
Lucian R
LR
Hartman
Mor-Li
ML
Taillon
Bruce E
BE
Du
Lei
L
Bouffard
Pascal
P
Kingsmore
Stephen F
SF
Miller
Neil A
NA
Farmer
Andrew D
AD
Jensen
Roderick V
RV
Gullans
Steven R
SR
Bueno
Raphael
R
D030201:Activin Receptors, Type I / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D034961:Antigens, Nuclear / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D000072200:Ku Autoantigen; D008565:Membrane Proteins / Q000235:genetics; D008654:Mesothelioma / Q000235:genetics*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010997:Pleural Neoplasms / Q000235:genetics*; D017354:Point Mutation; D017393:RNA Editing; D012334:RNA, Neoplasm; D017384:Sequence Deletion
C412506:AVEN protein, human; D048868:Adaptor Proteins, Signal Transducing; D034961:Antigens, Nuclear; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C509768:PDZK1IP1 protein, human; D012334:RNA, Neoplasm; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen