Advanced

Alternative transcript imbalance underlying breast cancer susceptibility in a family carrying PALB2 c.3201+5G>T

Duran-Lozano, Laura LU ; Montalban, Gemma ; Bonache, Sandra ; Moles-Fernández, Alejandro ; Tenés, Anna ; Castroviejo-Bermejo, Marta ; Carrasco, Estela ; López-Fernández, Adrià ; Torres-Esquius, Sara and Gadea, Neus , et al. (2019) In Breast Cancer Research and Treatment 174(2). p.543-550
Abstract

PURPOSE: Disruption of splicing motifs by genetic variants can affect the correct generation of mature mRNA molecules leading to aberrant transcripts. In some cases, variants may alter the physiological transcription profile composed of several transcripts, and an accurate in vitro evaluation is crucial to establish their pathogenicity. In this study, we have characterized a novel PALB2 variant c.3201+5G>T identified in a breast cancer family.

METHODS: Peripheral blood RNA was analyzed in two carriers and ten controls by RT-PCR and Sanger sequencing. The splicing profile was also characterized by semi-quantitative capillary electrophoresis and quantitative PCR. RAD51 foci formation and PALB2 LOH status were evaluated in primary... (More)

PURPOSE: Disruption of splicing motifs by genetic variants can affect the correct generation of mature mRNA molecules leading to aberrant transcripts. In some cases, variants may alter the physiological transcription profile composed of several transcripts, and an accurate in vitro evaluation is crucial to establish their pathogenicity. In this study, we have characterized a novel PALB2 variant c.3201+5G>T identified in a breast cancer family.

METHODS: Peripheral blood RNA was analyzed in two carriers and ten controls by RT-PCR and Sanger sequencing. The splicing profile was also characterized by semi-quantitative capillary electrophoresis and quantitative PCR. RAD51 foci formation and PALB2 LOH status were evaluated in primary breast tumor samples from the carriers.

RESULTS: PALB2 c.3201+5G>T disrupts intron 11 donor splice site and modifies the abundance of several alternative transcripts (∆11, ∆12, and ∆11,12), also present in control samples. All transcripts are predicted to encode for non-functional proteins. Semi-quantitative and quantitative analysis of PALB2 full-length transcript indicated haploinsufficiency in carriers. One tumor exhibited PALB2 LOH and RAD51 assay indicated homologous recombination deficiency in both tumors.

CONCLUSIONS: Our results support a pathogenic classification for PALB2 c.3201+5G>T, highlighting the impact of variants causing an imbalanced expression of natural RNA isoforms in cancer susceptibility.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
publishing date
type
Contribution to journal
publication status
published
subject
in
Breast Cancer Research and Treatment
volume
174
issue
2
pages
543 - 550
publisher
Springer
external identifiers
  • pmid:30552643
  • scopus:85056948951
ISSN
1573-7217
DOI
10.1007/s10549-018-05094-8
language
English
LU publication?
no
id
4033d25a-4bd4-4dc6-8d88-4ffc56e33157
date added to LUP
2019-05-09 10:02:18
date last changed
2019-05-12 05:00:00
@article{4033d25a-4bd4-4dc6-8d88-4ffc56e33157,
  abstract     = {<p>PURPOSE: Disruption of splicing motifs by genetic variants can affect the correct generation of mature mRNA molecules leading to aberrant transcripts. In some cases, variants may alter the physiological transcription profile composed of several transcripts, and an accurate in vitro evaluation is crucial to establish their pathogenicity. In this study, we have characterized a novel PALB2 variant c.3201+5G&gt;T identified in a breast cancer family.</p><p>METHODS: Peripheral blood RNA was analyzed in two carriers and ten controls by RT-PCR and Sanger sequencing. The splicing profile was also characterized by semi-quantitative capillary electrophoresis and quantitative PCR. RAD51 foci formation and PALB2 LOH status were evaluated in primary breast tumor samples from the carriers.</p><p>RESULTS: PALB2 c.3201+5G&gt;T disrupts intron 11 donor splice site and modifies the abundance of several alternative transcripts (∆11, ∆12, and ∆11,12), also present in control samples. All transcripts are predicted to encode for non-functional proteins. Semi-quantitative and quantitative analysis of PALB2 full-length transcript indicated haploinsufficiency in carriers. One tumor exhibited PALB2 LOH and RAD51 assay indicated homologous recombination deficiency in both tumors.</p><p>CONCLUSIONS: Our results support a pathogenic classification for PALB2 c.3201+5G&gt;T, highlighting the impact of variants causing an imbalanced expression of natural RNA isoforms in cancer susceptibility.</p>},
  author       = {Duran-Lozano, Laura and Montalban, Gemma and Bonache, Sandra and Moles-Fernández, Alejandro and Tenés, Anna and Castroviejo-Bermejo, Marta and Carrasco, Estela and López-Fernández, Adrià and Torres-Esquius, Sara and Gadea, Neus and Stjepanovic, Neda and Balmaña, Judith and Gutiérrez-Enríquez, Sara and Diez, Orland},
  issn         = {1573-7217},
  language     = {eng},
  number       = {2},
  pages        = {543--550},
  publisher    = {Springer},
  series       = {Breast Cancer Research and Treatment},
  title        = {Alternative transcript imbalance underlying breast cancer susceptibility in a family carrying PALB2 c.3201+5G>T},
  url          = {http://dx.doi.org/10.1007/s10549-018-05094-8},
  doi          = {10.1007/s10549-018-05094-8},
  volume       = {174},
  year         = {2019},
}