Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Functional characterization of novel germline TP53 variants in Swedish families

Kharaziha, Pedram ; Ceder, Sophia ; Axell, Olga ; Krall, Moritz ; Fotouhi, Omid ; Böhm, Stefanie ; Lain, Sonia ; Borg, Åke LU ; Larsson, Catharina and Wiman, Klas G. , et al. (2019) In Clinical Genetics 96(3). p.216-225
Abstract

Pathogenic germline TP53 variants predispose to a wide range of early onset cancers, often recognized as the Li-Fraumeni syndrome (LFS). They are also identified in 1% of families with hereditary breast cancer (HrBC) that do not fulfill the criteria for LFS. In this study, we present a total of 24 different TP53 variants identified in 31 Swedish families with LFS or HrBC. Ten of these variants, nine exonic and one splice, have previously not been described as germline pathogenic variants. The nine exonic variants were functionally characterized and demonstrated partial transactivation activity compared to wild-type p53. Some show nuclear localization similar to wild-type p53 while others possess cytoplasmic or perinuclear localization.... (More)

Pathogenic germline TP53 variants predispose to a wide range of early onset cancers, often recognized as the Li-Fraumeni syndrome (LFS). They are also identified in 1% of families with hereditary breast cancer (HrBC) that do not fulfill the criteria for LFS. In this study, we present a total of 24 different TP53 variants identified in 31 Swedish families with LFS or HrBC. Ten of these variants, nine exonic and one splice, have previously not been described as germline pathogenic variants. The nine exonic variants were functionally characterized and demonstrated partial transactivation activity compared to wild-type p53. Some show nuclear localization similar to wild-type p53 while others possess cytoplasmic or perinuclear localization. The four frameshift variants (W91Gfs*32, L111 Wfs*12, S227 Lfs*20 and S240Kfs*25) had negligible, while F134 L and T231del had low level of p53 activity. The L111 Wfs*12 and T231del variants are also deficient for induction of apoptosis. The missense variant R110C retain p53 effects and the nonsense E349* shows at least partial transcription factor activity but has reduced ability to trigger apoptosis. This is the first functional characterization of novel germline TP53 pathogenic or likely pathogenic variants in the Swedish cohort as an attempt to understand its association with LFS and HrBC, respectively.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
germline TP53 mutation, hereditary breast cancer, Li-Fraumeni syndrome, p53 activity
in
Clinical Genetics
volume
96
issue
3
pages
216 - 225
publisher
Wiley-Blackwell
external identifiers
  • pmid:31081129
  • scopus:85068464834
ISSN
0009-9163
DOI
10.1111/cge.13564
language
English
LU publication?
yes
id
66f9d811-3a3e-4997-a67d-aea49112ac61
date added to LUP
2019-07-19 11:33:36
date last changed
2024-05-01 17:19:36
@article{66f9d811-3a3e-4997-a67d-aea49112ac61,
  abstract     = {{<p>Pathogenic germline TP53 variants predispose to a wide range of early onset cancers, often recognized as the Li-Fraumeni syndrome (LFS). They are also identified in 1% of families with hereditary breast cancer (HrBC) that do not fulfill the criteria for LFS. In this study, we present a total of 24 different TP53 variants identified in 31 Swedish families with LFS or HrBC. Ten of these variants, nine exonic and one splice, have previously not been described as germline pathogenic variants. The nine exonic variants were functionally characterized and demonstrated partial transactivation activity compared to wild-type p53. Some show nuclear localization similar to wild-type p53 while others possess cytoplasmic or perinuclear localization. The four frameshift variants (W91Gfs*32, L111 Wfs*12, S227 Lfs*20 and S240Kfs*25) had negligible, while F134 L and T231del had low level of p53 activity. The L111 Wfs*12 and T231del variants are also deficient for induction of apoptosis. The missense variant R110C retain p53 effects and the nonsense E349* shows at least partial transcription factor activity but has reduced ability to trigger apoptosis. This is the first functional characterization of novel germline TP53 pathogenic or likely pathogenic variants in the Swedish cohort as an attempt to understand its association with LFS and HrBC, respectively.</p>}},
  author       = {{Kharaziha, Pedram and Ceder, Sophia and Axell, Olga and Krall, Moritz and Fotouhi, Omid and Böhm, Stefanie and Lain, Sonia and Borg, Åke and Larsson, Catharina and Wiman, Klas G. and Tham, Emma and Bajalica-Lagercrantz, Svetlana}},
  issn         = {{0009-9163}},
  keywords     = {{germline TP53 mutation; hereditary breast cancer; Li-Fraumeni syndrome; p53 activity}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{3}},
  pages        = {{216--225}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Clinical Genetics}},
  title        = {{Functional characterization of novel germline TP53 variants in Swedish families}},
  url          = {{http://dx.doi.org/10.1111/cge.13564}},
  doi          = {{10.1111/cge.13564}},
  volume       = {{96}},
  year         = {{2019}},
}