title: TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome.
abstract: 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.
authors.affiliation: Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ribi
authors.affiliation: Bone Tumor Reference Center at The Institute of Pathology, University Hospital Basel, CH-4003 Basel, Switzerland.|Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baumhoer
authors.affiliation: Department of Pediatrics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Lee
authors.affiliation: Duke-NUS Graduate Medical School Singapore, Singapore 169857, Singapore.
authors.lastname: Edison
authors.affiliation: Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Audrey S M
authors.initials: AS
authors.lastname: Teo
authors.affiliation: Duke-NUS Graduate Medical School Singapore, Singapore 169857, Singapore.
authors.forename: Babita
authors.initials: B
authors.lastname: Madan
authors.affiliation: Institute for Genomic Medicine, UC San Diego, La Jolla, CA 92830, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Huntsman Cancer Institute, University of Utah Health Care, Utah, UT 84112, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Kohlmann
authors.affiliation: Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Fei
authors.initials: F
authors.lastname: Yao
authors.affiliation: Computational & Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Wah Heng
authors.initials: WH
authors.lastname: Lee
authors.affiliation: Computational & Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Qiangze
authors.initials: Q
authors.lastname: Hoi
authors.affiliation: Computational & Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Shaojiang
authors.initials: S
authors.lastname: Cai
authors.affiliation: Personal Genomics Solutions, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Xing Yi
authors.initials: XY
authors.lastname: Woo
authors.affiliation: Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.|Duke-NUS Graduate Medical School Singapore, Singapore 169857, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Bone Tumor Reference Center at The Institute of Pathology, University Hospital Basel, CH-4003 Basel, Switzerland.
authors.forename: Gernot
authors.initials: G
authors.lastname: Jundt
authors.affiliation: Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany.|Department of Pediatrics and Wilhelm Sander Sarcoma Treatment Unit, Technische Universität München and Pediatric Oncology Center, 81675 Munich, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Smida
authors.affiliation: Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany.|Department of Pediatrics and Wilhelm Sander Sarcoma Treatment Unit, Technische Universität München and Pediatric Oncology Center, 81675 Munich, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nathrath
authors.affiliation: Computational & Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.|School of Computing, National University of Singapore, Singapore 117417, Singapore.
authors.forename: Wing-Kin
authors.initials: WK
authors.lastname: Sung
authors.affiliation: Department of Pediatrics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Schiffman
authors.affiliation: Duke-NUS Graduate Medical School Singapore, Singapore 169857, Singapore.
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
authors.affiliation: Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Axel M
authors.initials: AM
authors.lastname: Hillmer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001859:Bone Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015321:Gene Rearrangement; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007438:Introns; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D012516:Osteosarcoma / Q000235:genetics*; D010375:Pedigree; D055815:Young Adult
keywords: Li-Fraumeni syndrome; TP53; cancer genomics; osteosarcoma; structural variations