title: Association of germline or somatic TP53 missense mutation with oncogene amplification in tumors developed in patients with Li-Fraumeni or Li-Fraumeni-like syndrome.
abstract: Germline TP53 mutations are found in Li-Fraumeni syndrome (LFS) patients, predisposed to soft tissue sarcoma and other malignancies. The mutations and succeeding genetic events are thought to cause LFS-associated cancer, whose genetic alterations have rarely been investigated. Here, we study two LFS or Li-Fraumeni-like syndrome (LFLS) patients whose cancers showed aggressive phenotypes. Patient 1 with LFS and TP53(R273H) developed a rhabdomyosarcoma twice at the ages of 18 months and 21 years. A single-nucleotide polymorphism array-based analysis revealed two amplicons in the second tumor; one at 5q11.2 containing MAP3K1 and the other at 11q22.2 containing BIRC2/3 and YAP1. Increase of kinase signaling of MAP3K1 along with anti-apoptosis function of BIRC2/3 may have facilitated progression of this tumor. Patient 2 with LFLS and wild-typeTP53 suffered from acute myeloid leukemia. The leukemic cells had TP53(I195T) and two amplicons; one at 8q24.1 containing DEPDC6 and the other at 8q24.2 containing TRIB1, MYC, and PVT1. Quantitative PCR confirmed amplification of the genes and FISH revealed co-amplification of DEPDC6 and PVT1 in the same double minutes. Quantitative RT-PCR revealed increased expression levels of TRIB1, but no or little expression of DEPDC6, MYC, and PVT1. The results indicate that TRIB1 may be the target gene in the amplicon in the leukemia cells. Mutant TP53 can be engaged in pathways triggering gene amplification through impairment of DNA double-stranded break repair. The amplified candidate oncogenes identified in this study may have played a part in cancer development and lead to the poor outcome of LFS or LFLS-associated tumors.
authors.affiliation: Department of Cancer Diagnosis, Research Institute for Clinical Oncology, Saitama Cancer Center, Ina, Saitama, Japan.
authors.forename: Waka
authors.initials: W
authors.lastname: Sugawara
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Arai
authors.forename: Fumio
authors.initials: F
authors.lastname: Kasai
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Masayuki
authors.initials: M
authors.lastname: Haruta
authors.forename: Rie
authors.initials: R
authors.lastname: Hosaka
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nishida
authors.forename: Masashi
authors.initials: M
authors.lastname: Kurosumi
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Kiwamu
authors.initials: K
authors.lastname: Akagi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kaneko
mesh_terms: D000328:Adult; D005784:Gene Amplification; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D062085:RNA, Long Noncoding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C521123:PVT1 long-non-coding RNA, human; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D016159:Tumor Suppressor Protein p53; C556139:DEPTOR protein, human; D058570:TOR Serine-Threonine Kinases