Research Papers:

TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome

Sebastian Ribi _, Daniel Baumhoer, Kristy Lee, Edison ., Audrey S.M. Teo, Babita Madan, Kang Zhang, Wendy K. Kohlmann, Fei Yao, Wah Heng Lee, Qiangze Hoi, Shaojiang Cai, Xing Yi Woo, Patrick Tan, Gernot Jundt, Jan Smida, Michaela Nathrath, Wing-Kin Sung, Joshua D. Schiffman, David M. Virshup and Axel M. Hillmer

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Oncotarget. 2015; 6:7727-7740. https://doi.org/10.18632/oncotarget.3115

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Sebastian Ribi1,*, Daniel Baumhoer2,3,*, Kristy Lee4,*, Edison5, Audrey S.M. Teo1, Babita Madan5, Kang Zhang6, Wendy K. Kohlmann7, Fei Yao1, Wah Heng Lee8, Qiangze Hoi8, Shaojiang Cai8, Xing Yi Woo9, Patrick Tan1,5,10, Gernot Jundt2, Jan Smida3,11, Michaela Nathrath3,11, Wing-Kin Sung8,12, Joshua D. Schiffman4, David M. Virshup5, Axel M. Hillmer1

1Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore

2Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel, CH-4003 Basel, Switzerland

3Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany

4Department of Pediatrics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA

5Duke-NUS Graduate Medical School Singapore, Singapore 169857, Singapore

6Institute for Genomic Medicine, UC San Diego, La Jolla, CA 92830, USA

7Huntsman Cancer Institute, University of Utah Health Care, Utah, UT 84112, USA

8Computational & Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore

9Personal Genomics Solutions, Genome Institute of Singapore, Singapore 138672, Singapore

10Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore

11Department of Pediatrics and Wilhelm Sander Sarcoma Treatment Unit, Technische Universität München and Pediatric Oncology Center, 81675 Munich, Germany

12School of Computing, National University of Singapore, Singapore 117417, Singapore

*These authors have contributed equally to this work

Correspondence to:

David M. Virshup, e-mail: [email protected]

Axel M. Hillmer, e-mail: [email protected]

Keywords: TP53, Li-Fraumeni syndrome, osteosarcoma, cancer genomics, structural variations

Received: November 10, 2014     Accepted: January 08, 2015     Published: February 25, 2015


Somatic mutations of TP53 are among the most common in cancer and germline mutations of TP53 (usually missense) can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in osteosarcoma (OS), a highly malignant neoplasm of bone belonging to the spectrum of LFS tumors. Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription. Screening of 288 OS and 1,090 tumors of other types revealed evidence for TP53 rearrangements in 46 (16%) OS, while none were detected in other tumor types, indicating this rearrangement to be highly specific to OS. We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere. The inversion segregated with tumors in the LFS family. Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss. In conclusion, intron 1 rearrangements cause p53-driven malignancies by both germline and somatic mechanisms and provide an important mechanism of TP53 inactivation in LFS, which might in part explain the diagnostic gap of formerly classified “TP53 wild-type” LFS.

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