title: Chromosomal rearrangements and copy number abnormalities of TP63 correlate with p63 protein expression in lung adenocarcinoma.
abstract: The TP63 gene encodes a member of the p53 family of transcription factors. Although TP53 is a well-known tumor suppressor gene, the role of p63 in tumorigenesis is controversial. Our group recently identified novel chromosomal rearrangements involving TP63 in approximately 6% of peripheral T-cell lymphomas, which correlated with a p63+/p40- immunohistochemical profile. As a subset of lung adenocarcinomas are p63+/p40-, we undertook the current study to examine the presence of TP63 rearrangements and correlate with p63/p40 expression. Next-generation sequencing was used to identify genomic rearrangements of TP63 in 37 adenocarcinomas. Confirmatory fluorescence in-situ hybridization (FISH) using a break-apart probe to the TP63 gene region and immunohistochemistry for p63 and p40 were performed on adenocarcinomas with TP63 rearrangements identified by mate-pair sequencing. Immunohistochemistry for p63 and p40 was performed on 45 additional adenocarcinomas, and FISH was performed on all adenocarcinomas with p63 positivity. TP63 rearrangement was identified in two adenocarcinoma specimens from a single patient. The rearrangement resulted in a complex rearrangement of 3q that fused B3GALNT1 at the 3' intron to TP63. FISH confirmed the rearrangement in both tumors. Immunohistochemistry staining for p63 was diffuse (>80% cells+) and p40 was negative. Of the 44 additional adenocarcinomas, 13 (30%) showed p63 expression; p40 was negative in all cases. No case showed rearrangement of TP63 by a break-apart FISH. However, extra copies of the intact TP63 locus were seen in the p63-positive areas of all 12 cases, with copy numbers ranging from three to seven. We have identified a novel chromosomal rearrangement involving TP63 in a p63+/p40- lung adenocarcinoma. Break-apart FISH testing can be used to diagnose this finding. Immunohistochemistry for p63 was not specific for this rearrangement, as nearly 33% of adenocarcinomas expressed p63. Additional copies of the intact TP63 locus were also a common finding and correlated with immunohistochemistry positivity for p63.
authors.affiliation: Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Aubry
authors.affiliation: Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Anja
authors.initials: A
authors.lastname: Roden
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Murphy
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: George
authors.initials: G
authors.lastname: Vasmatzis
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Johnson
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Faye R
authors.initials: FR
authors.lastname: Harris
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Halling
authors.affiliation: Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Knudson
authors.affiliation: Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Rhett P
authors.initials: RP
authors.lastname: Ketterling
authors.affiliation: Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Feldman
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage; D015321:Gene Rearrangement; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D061346:Laser Capture Microdissection; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins