A genetic basis for the variation in the vulnerability of cancer to DNA damage.
Radiotherapy is not currently informed by the genetic composition of an individual patient's tumour. To identify genetic features regulating survival after DNA damage, here we conduct large-scale profiling of cellular survival after exposure to radiation in a diverse collection of 533 genetically annotated human tumour cell lines. We show that sensitivity to radiation is characterized by significant variation across and within lineages. We combine results from our platform with genomic features to identify parameters that predict radiation sensitivity. We identify somatic copy number alterations, gene mutations and the basal expression of individual genes and gene sets that correlate with the radiation survival, revealing new insights into the genetic basis of tumour cellular response to DNA damage. These results demonstrate the diversity of tumour cellular response to ionizing radiation and establish multiple lines of evidence that new genetic features regulating cellular response after DNA damage can be identified.
Department of Translational Hematology Oncology Research, Cleveland Clinic, 9500 Euclid Avenue/R40, Cleveland, Ohio 44195, USA.
Brian D
BD
Yard
Department of Genetics, Case Western Reserve University, 2109 Adelbert Road/BRB, Cleveland, Ohio 44106, USA.
Drew J
DJ
Adams
Department of Translational Hematology Oncology Research, Cleveland Clinic, 9500 Euclid Avenue/R40, Cleveland, Ohio 44195, USA.|Department of Radiation Oncology, Seoul National University College of Medicine, 101, Daehak-Ro, Jongno-Gu, Seoul 110-774, Korea.
Eui Kyu
EK
Chie
Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Pablo
http://orcid.org/0000-0002-9360-4668
P
Tamayo
Department of Translational Hematology Oncology Research, Cleveland Clinic, 9500 Euclid Avenue/R40, Cleveland, Ohio 44195, USA.
Jessica S
JS
Battaglia
Department of Translational Hematology Oncology Research, Cleveland Clinic, 9500 Euclid Avenue/R40, Cleveland, Ohio 44195, USA.
Priyanka
P
Gopal
Department of Translational Hematology Oncology Research, Cleveland Clinic, 9500 Euclid Avenue/R40, Cleveland, Ohio 44195, USA.
Kevin
K
Rogacki
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
Bradley E
BE
Pearson
Department of Translational Hematology Oncology Research, Cleveland Clinic, 9500 Euclid Avenue/R40, Cleveland, Ohio 44195, USA.
James
J
Phillips
Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Avenue/J4-1, Cleveland, Ohio 44195, USA.
Daniel P
DP
Raymond
Department of Hematology and Medical Oncology, Cleveland Clinic, 9500 Euclid Avenue/R40, Cleveland, Ohio 44195, USA.
Nathan A
NA
Pennell
Department of Pulmonary Medicine, Cleveland Clinic, 9500 Euclid Avenue/M2-141, Cleveland, Ohio 44195, USA.
Francisco
F
Almeida
Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Jaime H
JH
Cheah
Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Paul A
PA
Clemons
Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.
Alykhan
A
Shamji
Department of Translational Hematology Oncology Research, Cleveland Clinic, 9500 Euclid Avenue/R40, Cleveland, Ohio 44195, USA.
Craig D
CD
Peacock
Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Center for the Science of Therapeutics, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.|Howard Hughes Medical Institute, Broad Institute, Cambridge, Massachusetts 02142, USA.
Stuart L
http://orcid.org/0000-0003-1922-7558
SL
Schreiber
Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
Peter S
PS
Hammerman
Department of Translational Hematology Oncology Research, Cleveland Clinic, 9500 Euclid Avenue/R40, Cleveland, Ohio 44195, USA.|Department of Radiation Oncology, Cleveland Clinic, 9500 Euclid Avenue/T2, Cleveland, Ohio 44195, USA.
Mohamed E
ME
Abazeed
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D056915:DNA Copy Number Variations / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000532:radiotherapy; D011836:Radiation Tolerance; D011839:Radiation, Ionizing