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14.12.2018 | Brief Report

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

verfasst von: Laura Duran-Lozano, Gemma Montalban, Sandra Bonache, Alejandro Moles-Fernández, Anna Tenés, Marta Castroviejo-Bermejo, Estela Carrasco, Adrià López-Fernández, Sara Torres-Esquius, Neus Gadea, Neda Stjepanovic, Judith Balmaña, Sara Gutiérrez-Enríquez, Orland Diez

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 2/2019

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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 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.

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Titel: Alternative transcript imbalance underlying breast cancer susceptibility in a family carrying PALB2 c.3201+5G>T
verfasst von: Laura Duran-Lozano
Gemma Montalban
Sandra Bonache
Alejandro Moles-Fernández
Anna Tenés
Marta Castroviejo-Bermejo
Estela Carrasco
Adrià López-Fernández
Sara Torres-Esquius
Neus Gadea
Neda Stjepanovic
Judith Balmaña
Sara Gutiérrez-Enríquez
Orland Diez
Publikationsdatum: 14.12.2018
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 2/2019
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-05094-8

Springer Medizin

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