Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice

Rose Li, Yun; Halliwill, Kyle D.; Adams, Cassandra J.; Iyer, Vivek; Riva, Laura; Mamunur, Rashid; Jen, Kuang-Yu; del Rosario, Reyno; Fredlund, Erik; Hirst, Gillian; Alexandrov, Ludmil B.; Adams, David; Balmain, Allan

doi:10.1038/s41467-019-14261-4

Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice

Journal Article · Mon Jan 20 00:00:00 EST 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-14261-4· OSTI ID:1624241

Rose Li, Yun ^[1]; Halliwill, Kyle D. ^[2]; Adams, Cassandra J. ^[3]; Iyer, Vivek ^[4]; Riva, Laura ^[4]; Mamunur, Rashid ^[4]; Jen, Kuang-Yu ^[5]; del Rosario, Reyno ^[6]; Fredlund, Erik ^[7]; ^[6]; ^[8]; ^[4]; ^[9]

University of California San Francisco, California (United States). UCSF Helen Diller Family Comprehensive Cancer Center; University of California San Francisco, California (United States). Department of Radiation Oncology; DOE/OSTI
University of California San Francisco, California (United States). UCSF Helen Diller Family Comprehensive Cancer Center; Abbvie, Redwood City, California (United States)
University of California San Francisco, California (United States). UCSF Helen Diller Family Comprehensive Cancer Center; Univ. of Oxford (United Kingdom). Nuffield Department of Medicine
Wellcome Trust Sanger Institute, Hinxton, Cambridge (United Kingdom). Experimental Cancer Genetics
University of California San Francisco, California (United States). UCSF Helen Diller Family Comprehensive Cancer Center; University of California Davis Medical Center, Sacramento, California (United States). Department of Pathology
University of California San Francisco, California (United States). UCSF Helen Diller Family Comprehensive Cancer Center
University of California San Francisco, California (United States). UCSF Helen Diller Family Comprehensive Cancer Center; Doublestrand Bioinformatics, Stockholm (Sweden).
University of California, San Diego, La Jolla, California (United States). Department of Cellular and Molecular Medicine and Department of Bioengineering, Moores Cancer Center
University of California San Francisco, California (United States). UCSF Helen Diller Family Comprehensive Cancer Center; University of California San Francisco, San Francisco, California (United States). Department of Biochemistry and Biophysics

Lonising radiation (IR) is a recognised carcinogen responsible for cancer development in patients previously treated using radiotherapy, and in individuals exposed as a result of accidents at nuclear energy plants. However, the mutational signatures induced by distinct types and doses of radiation are unknown. Here, we analyse the genetic architecture of mammary tumours, lymphomas and sarcomas induced by high (⁵⁶Fe-ions) or low (gamma) energy radiation in mice carrying Trp53 loss of function alleles. In mammary tumours, high-energy radiation is associated with induction of focal structural variants, leading to genomic instability and Met amplification. Gamma-radiation is linked to large-scale structural variants and a point mutation signature associated with oxidative stress. The genomic architecture of carcinomas, sarcomas and lymphomas arising in the same animals are significantly different. Our study illustrates the complex interactions between radiation quality, germline Trp53 deficiency and tissue/cell of origin in shaping the genomic landscape of IR-induced tumours.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of California, San Francisco, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: SC0003679

OSTI ID:: 1624241

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (77)

Radiation-induced sarcomas after radiotherapy for breast carcinoma: A large-scale single-institution review Kirova, Youlia M.; Vilcoq, Jacques R.; Asselain, Bernard Cancer, Vol. 104, Issue 4 https://doi.org/10.1002/cncr.21223	journal	January 2005
cgpCaVEManWrapper: Simple Execution of CaVEMan in Order to Detect Somatic Single Nucleotide Variants in NGS Data: cgpCaVEMan Wrapper to Detect Single Nucleotide Variants in NGS Data Jones, David; Raine, Keiran M.; Davies, Helen Current Protocols in Bioinformatics, Vol. 56, Issue 1 https://doi.org/10.1002/cpbi.20	journal	December 2016
Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas: Mutational signature associated with MUTYH deficiency in cancers Pilati, Camilla; Shinde, Jayendra; Alexandrov, Ludmil B. The Journal of Pathology, Vol. 242, Issue 1 https://doi.org/10.1002/path.4880	journal	March 2017
A mouse p53 mutant lacking the proline-rich domain rescues Mdm4 deficiency and provides insight into the Mdm2-Mdm4-p53 regulatory network Toledo, Franck; Krummel, Kurt A.; Lee, Crystal J. Cancer Cell, Vol. 9, Issue 4 https://doi.org/10.1016/j.ccr.2006.03.014	journal	April 2006
Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type Nguyen, David H.; Oketch-Rabah, Hellen A.; Illa-Bochaca, Irineu Cancer Cell, Vol. 19, Issue 5 https://doi.org/10.1016/j.ccr.2011.03.011	journal	May 2011
Chromothripsis in congenital disorders and cancer: similarities and differences Kloosterman, Wigard P.; Cuppen, Edwin Current Opinion in Cell Biology, Vol. 25, Issue 3 https://doi.org/10.1016/j.ceb.2013.02.008	journal	June 2013
Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations Rausch, Tobias; Jones, David T. W.; Zapatka, Marc Cell, Vol. 148, Issue 1-2 https://doi.org/10.1016/j.cell.2011.12.013	journal	January 2012
Deciphering Signatures of Mutational Processes Operative in Human Cancer Alexandrov, Ludmil B.; Nik-Zainal, Serena; Wedge, David C. Cell Reports, Vol. 3, Issue 1 https://doi.org/10.1016/j.celrep.2012.12.008	journal	January 2013
Mutational Analysis of Ionizing Radiation Induced Neoplasms Sherborne, Amy L.; Davidson, Philip R.; Yu, Katharine Cell Reports, Vol. 12, Issue 11 https://doi.org/10.1016/j.celrep.2015.08.015	journal	September 2015
Concepts and challenges in cancer risk prediction for the space radiation environment Barcellos-Hoff, Mary Helen; Blakely, Eleanor A.; Burma, Sandeep Life Sciences in Space Research, Vol. 6 https://doi.org/10.1016/j.lssr.2015.07.006	journal	July 2015
p53, guardian of the genome Lane, D. P. Nature, Vol. 358, Issue 6381 https://doi.org/10.1038/358015a0	journal	July 1992
Genomic profiling of Acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis Ratnaparkhe, M.; Hlevnjak, M.; Kolb, T. Leukemia, Vol. 31, Issue 10 https://doi.org/10.1038/leu.2017.55	journal	February 2017
The mutational landscapes of genetic and chemical models of Kras-driven lung cancer Westcott, Peter M. K.; Halliwill, Kyle D.; To, Minh D. Nature, Vol. 517, Issue 7535 https://doi.org/10.1038/nature13898	journal	November 2014
Chromothripsis from DNA damage in micronuclei Zhang, Cheng-Zhong; Spektor, Alexander; Cornils, Hauke Nature, Vol. 522, Issue 7555 https://doi.org/10.1038/nature14493	journal	May 2015
Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples Cibulskis, Kristian; Lawrence, Michael S.; Carter, Scott L. Nature Biotechnology, Vol. 31, Issue 3 https://doi.org/10.1038/nbt.2514	journal	February 2013
A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers Glodzik, Dominik; Morganella, Sandro; Davies, Helen Nature Genetics, Vol. 49, Issue 3 https://doi.org/10.1038/ng.3771	journal	January 2017
p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis Kemp, Christopher J.; Wheldon, Tom; Balmain, Allan Nature Genetics, Vol. 8, Issue 1 https://doi.org/10.1038/ng0994-66	journal	September 1994
Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancers McCreery, Melissa Q.; Halliwill, Kyle D.; Chin, Douglas Nature Medicine, Vol. 21, Issue 12 https://doi.org/10.1038/nm.3979	journal	November 2015
Heavy ion carcinogenesis and human space exploration Durante, Marco; Cucinotta, Francis A. Nature Reviews Cancer, Vol. 8, Issue 6, p. 465-472 https://doi.org/10.1038/nrc2391	journal	May 2008
New functions for the matrix metalloproteinases in cancer progression Egeblad, Mikala; Werb, Zena Nature Reviews Cancer, Vol. 2, Issue 3 https://doi.org/10.1038/nrc745	journal	March 2002
Targeted A-to-G base editing of chloroplast DNA in plants Mok, Young Geun; Hong, Sunghyun; Bae, Su-Ji Nature Plants, Vol. 8, Issue 12 https://doi.org/10.1038/s41477-022-01279-8	journal	December 2022
A pooled mutational analysis identifies ionizing radiation-associated mutational signatures conserved between mouse and human malignancies Davidson, Philip R.; Sherborne, Amy L.; Taylor, Barry Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-07888-0	journal	August 2017
Genomic instability in radiation-induced mouse lymphoma from p53 heterozygous mice Mao, Jiang-Hua; Li, Jiangzhen; Jiang, Tao Oncogene, Vol. 24, Issue 53 https://doi.org/10.1038/sj.onc.1208926	journal	August 2005
Germ-Line Mutations of the p53 Tumor-Suppressor Gene in Children and Young Adults with Second Malignant Neoplasms Malkin, David; Friend, Stephen H.; Li, Frederick P. New England Journal of Medicine, Vol. 336, Issue 10 https://doi.org/10.1056/nejm199703063361018	journal	March 1997
Activation of the c-myc oncogene by the immunoglobulin heavy-chain gene enhancer after multiple switch region-mediated chromosome rearrangements in a murine plasmacytoma. Fahrlander, P. D.; Sumegi, J.; Yang, J. Q. Proceedings of the National Academy of Sciences, Vol. 82, Issue 11 https://doi.org/10.1073/pnas.82.11.3746	journal	June 1985
Free Radicals in Biology: Oxidative Stress and the Effects of Ionizing Radiation Riley, P. A. International Journal of Radiation Biology, Vol. 65, Issue 1 https://doi.org/10.1080/09553009414550041	journal	January 1994
The UCSC genome browser and associated tools Kuhn, R. M.; Haussler, D.; Kent, W. J. Briefings in Bioinformatics, Vol. 14, Issue 2 https://doi.org/10.1093/bib/bbs038	journal	August 2012
Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads Ye, K.; Schulz, M. H.; Long, Q. Bioinformatics, Vol. 25, Issue 21 https://doi.org/10.1093/bioinformatics/btp394	journal	June 2009
Association between MDM2 SNP309, p53 Arg72Pro, and hepatocellular carcinoma risk: A MOOSE-compliant meta-analysis Duan, Xiaohua; Li, Jingquan Medicine, Vol. 96, Issue 36 https://doi.org/10.1097/md.0000000000007856	journal	January 2017
Mouse Mutants Reveal that Putative Protein Interaction Sites in the p53 Proline-Rich Domain Are Dispensable for Tumor Suppression Toledo, Franck; Lee, Crystal J.; Krummel, Kurt A. Molecular and Cellular Biology, Vol. 27, Issue 4 https://doi.org/10.1128/mcb.00999-06	journal	December 2006
The DNA Damage Response: Implications for Tumor Responses to Radiation and Chemotherapy Goldstein, Michael; Kastan, Michael B. Annual Review of Medicine, Vol. 66, Issue 1 https://doi.org/10.1146/annurev-med-081313-121208	journal	January 2015
Complex chromosomal rearrangements induced in vivo by heavy ions Durante, M.; Ando, K.; Furusawa, Y. Cytogenetic and Genome Research, Vol. 104, Issue 1-4 https://doi.org/10.1159/000077497	journal	January 2004
Sequential mutations in Notch1, Fbxw7, and Tp53 in radiation-induced mouse thymic lymphomas Jen, Kuang-Yu; Song, Ihn Young; Banta, Karl Luke Blood, Vol. 119, Issue 3 https://doi.org/10.1182/blood-2011-01-327619	journal	January 2012
BIC-seq: a fast algorithm for detection of copy number alterations based on high-throughput sequencing data Xi, Ruibin; Luquette, Joe; Hadjipanayis, Angela Genome Biology, Vol. 11, Issue Suppl 1 https://doi.org/10.1186/1465-6906-11-s1-o10	journal	January 2010
LUMPY: a probabilistic framework for structural variant discovery Layer, Ryan M.; Chiang, Colby; Quinlan, Aaron R. Genome Biology, Vol. 15, Issue 6 https://doi.org/10.1186/gb-2014-15-6-r84	journal	January 2014
Long-Term Solid Cancer Risk Among 5-Year Survivors of Hodgkin's Lymphoma Hodgson, David C.; Gilbert, Ethel S.; Dores, Graça M. Journal of Clinical Oncology, Vol. 25, Issue 12 https://doi.org/10.1200/jco.2006.09.0936	journal	April 2007
Involvement of Reactive Oxygen Species (ROS) in the Induction of Genetic Instability by Radiation Tominaga, Hideyuki; Kodama, Seiji; Matsuda, Naoki Journal of Radiation Research, Vol. 45, Issue 2 https://doi.org/10.1269/jrr.45.181	journal	January 2004
Heavy Ion Radiation Exposure Triggered Higher Intestinal Tumor Frequency and Greater β-Catenin Activation than γ Radiation in APCMin/+ Mice Datta, Kamal; Suman, Shubhankar; Kallakury, Bhaskar V. S. PLoS ONE, Vol. 8, Issue 3 https://doi.org/10.1371/journal.pone.0059295	journal	March 2013
Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice Chang, Hui-Hua; Moro, Aune; Takakura, Kazuki PLOS ONE, Vol. 12, Issue 9 https://doi.org/10.1371/journal.pone.0184455	journal	September 2017
A cell‐based model system links chromothripsis with hyperploidy Mardin, Balca R.; Drainas, Alexandros P.; Waszak, Sebastian M. Molecular Systems Biology, Vol. 11, Issue 9 https://doi.org/10.15252/msb.20156505	journal	September 2015
The Potential Impact of Bystander Effects on Radiation Risks in a Mars Mission Brenner, D. J.; Elliston, C. D. Radiation Research, Vol. 156, Issue 5 https://doi.org/10.1667/0033-7587(2001)156[0612:tpiobe]2.0.co;2	journal	November 2001
Relative Biological Effectiveness of High-Energy Iron Ions for Micronucleus Formation at Low Doses Groesser, Torsten; Chun, Eugene; Rydberg, Bjorn Radiation Research, Vol. 168, Issue 6 https://doi.org/10.1667/rr0967.1	journal	December 2007
MDM2 and P53 polymorphisms contribute together to the risk and survival of prostate cancer Xue, Li; Han, Xiujuan; Liu, Rongrong Oncotarget, Vol. 7, Issue 22 https://doi.org/10.18632/oncotarget.3923	journal	May 2015
Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations Sharma, Vyom; Collins, Leonard B.; Chen, Ting-huei Oncotarget, Vol. 7, Issue 18 https://doi.org/10.18632/oncotarget.8298	journal	March 2016
Personalized Cancer Risk Assessments for Space Radiation Exposures Locke, Paul A.; Weil, Michael M. Frontiers in Oncology, Vol. 6 https://doi.org/10.3389/fonc.2016.00038	journal	February 2016
The Role of Nuclear Fragmentation in Particle Therapy and Space Radiation Protection Zeitlin, Cary; La Tessa, Chiara Frontiers in Oncology, Vol. 6 https://doi.org/10.3389/fonc.2016.00065	journal	March 2016
Soft-Tissue Sarcomas, Breast Cancer, and Other Neoplasms: A Familial Syndrome? Li, Frederick P. Annals of Internal Medicine, Vol. 71, Issue 4 https://doi.org/10.7326/0003-4819-71-4-747	journal	October 1969
Prioritisation of structural variant calls in cancer genomes Ahdesmäki, Miika J.; Chapman, Brad A.; Cingolani, Pablo PeerJ, Vol. 5 https://doi.org/10.7717/peerj.3166	journal	January 2017
BreakDancer: Identification of Genomic Structural Variation from Paired‐End Read Mapping Fan, Xian; Abbott, Travis E.; Larson, David Current Protocols in Bioinformatics, Vol. 45, Issue 1 https://doi.org/10.1002/0471250953.bi1506s45	journal	March 2014
The Trp53 delta proline ( Trp53ΔP ) mouse exhibits increased genome instability and susceptibility to radiation-induced, but not spontaneous, tumor development: RADIATION INDUCED TUMORS IN Trp53△P MICE Adams, Cassandra J.; Yu, Jennifer S.; Mao, Jian-Hua Molecular Carcinogenesis, Vol. 55, Issue 9 https://doi.org/10.1002/mc.22377	journal	August 2015
ggplot2 Wickham, Hadley Use R! https://doi.org/10.1007/978-3-319-24277-4	book	January 2016
Detection of space radiation-induced double strand breaks as a track in cell nucleus Ohnishi, Takeo; Takahashi, Akihisa; Nagamatsu, Aiko Biochemical and Biophysical Research Communications, Vol. 390, Issue 3 https://doi.org/10.1016/j.bbrc.2009.09.114	journal	December 2009
Mutant p53 in Cancer: New Functions and Therapeutic Opportunities Muller, Patricia A. J.; Vousden, Karen H. Cancer Cell, Vol. 25, Issue 3 https://doi.org/10.1016/j.ccr.2014.01.021	journal	March 2014
Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development Stephens, Philip J.; Greenman, Chris D.; Fu, Beiyuan Cell, Vol. 144, Issue 1 https://doi.org/10.1016/j.cell.2010.11.055	journal	January 2011
A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer Viel, Alessandra; Bruselles, Alessandro; Meccia, Ettore EBioMedicine, Vol. 20 https://doi.org/10.1016/j.ebiom.2017.04.022	journal	June 2017
Mapping copy number variation by population-scale genome sequencing Mills, Ryan E.; Walter, Klaudia; Stewart, Chip Nature, Vol. 470, Issue 7332 https://doi.org/10.1038/nature09708	journal	February 2011
Signatures of mutational processes in human cancer Alexandrov, Ludmil B.; Nik-Zainal, Serena; Wedge, David C. Nature, Vol. 500, Issue 7463 https://doi.org/10.1038/nature12477	journal	August 2013
Mutational signatures of ionizing radiation in second malignancies Behjati, Sam; Gundem, Gunes; Wedge, David C. Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms12605	journal	September 2016
The repertoire of mutational signatures in human cancer Alexandrov, Ludmil B.; Kim, Jaegil; Haradhvala, Nicholas J. Nature, Vol. 578, Issue 7793 https://doi.org/10.1038/s41586-020-1943-3	journal	February 2020
Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing Cortés-Ciriano, Isidro; Lee, Jake June-Koo; Xi, Ruibin Nature Genetics, Vol. 52, Issue 3 https://doi.org/10.1038/s41588-019-0576-7	journal	February 2020
Germline Mutations of the p53 Tumor-Suppressor Gene in Children and Young Adults with Second Malignant Neoplasms Malkin, David; Jolly, Kent W.; Barbier, Noële New England Journal of Medicine, Vol. 326, Issue 20 https://doi.org/10.1056/NEJM199205143262002	journal	May 1992
Fast and accurate short read alignment with Burrows-Wheeler transform Li, H.; Durbin, R. Bioinformatics, Vol. 25, Issue 14 https://doi.org/10.1093/bioinformatics/btp324	journal	May 2009
Prediction of Frequency and Exposure Level of Solar Particle Events Kim, Myung-Hee Y.; Hayat, Matthew J.; Feiveson, Alan H. Health Physics, Vol. 97, Issue 1 https://doi.org/10.1097/01.HP.0000346799.65001.9c	journal	January 2009
Association between MDM2 SNP309, p53 Arg72Pro, and hepatocellular carcinoma risk: A MOOSE-compliant meta-analysis Duan, Xiaohua; Li, Jingquan Medicine, Vol. 96, Issue 36 https://doi.org/10.1097/MD.0000000000007856	journal	January 2017
Mouse Mutants Reveal that Putative Protein Interaction Sites in the p53 Proline-Rich Domain Are Dispensable for Tumor Suppression Toledo, Franck; Lee, Crystal J.; Krummel, Kurt A. Molecular and Cellular Biology, Vol. 27, Issue 4 https://doi.org/10.1128/MCB.00999-06	journal	December 2006
BIC-seq: a fast algorithm for detection of copy number alterations based on high-throughput sequencing data Xi, Ruibin; Luquette, Joe; Hadjipanayis, Angela Genome Biology, Vol. 11, Issue Suppl 1 https://doi.org/10.1186/1465-6906-11-S1-O10	journal	January 2010
Long-Term Solid Cancer Risk Among 5-Year Survivors of Hodgkin's Lymphoma Hodgson, David C.; Gilbert, Ethel S.; Dores, Graça M. Journal of Clinical Oncology, Vol. 25, Issue 12 https://doi.org/10.1200/JCO.2006.09.0936	journal	April 2007
New challenges in high-energy particle radiobiology Durante, M. The British Journal of Radiology, Vol. 87, Issue 1035 https://doi.org/10.1259/bjr.20130626	journal	March 2014
CNVkit: Genome-Wide Copy Number Detection and Visualization from Targeted DNA Sequencing Talevich, Eric; Shain, A. Hunter; Botton, Thomas PLOS Computational Biology, Vol. 12, Issue 4 https://doi.org/10.1371/journal.pcbi.1004873	journal	April 2016
The Potential Impact of Bystander Effects on Radiation Risks in a Mars Mission Brenner, D. J.; Elliston, C. D. Radiation Research, Vol. 156, Issue 5 https://doi.org/10.1667/0033-7587(2001)156[0612:TPIOBE]2.0.CO;2	journal	November 2001
Relative Biological Effectiveness of High-Energy Iron Ions for Micronucleus Formation at Low Doses Groesser, Torsten; Chun, Eugene; Rydberg, Bjorn Radiation Research, Vol. 168, Issue 6 https://doi.org/10.1667/RR0967.1	journal	December 2007
Signatures of mutational processes in human cancer. Alexandrov, Ludmil B.; Nik-Zainal Abidin, Serena; Wedge, David C. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.31889	text	January 2013
Deciphering signatures of mutational processes operative in human cancer. Alexandrov, Ludmil B.; Nik-Zainal Abidin, Serena; Wedge, David C. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.60112	text	January 2013
The repertoire of mutational signatures in human cancer Alexandrov, Ludmil B.; Kim, Jaegil; Haradhvala, Nicholas J. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.64271	text	January 2020
Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Cortés-Ciriano, Isidro; Lee, Jake June-Koo; Xi, Ruibin Springer Science and Business Media LLC https://doi.org/10.17863/cam.73656	journalarticle	January 2020
A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers Glodzik, D.; Morganella, S.; Davies, Helen Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.8300	text	January 2017
Mutational signatures of ionizing radiation in second malignancies Behjati, Sam; Gundem, G.; Wedge, Dc Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.8737	text	January 2016