Heterozygous mutations in the PALB2 hereditary breast cancer predisposition gene impact on the three‐dimensional nuclear organization of patient‐derived cell lines1. Issue 5 (23rd January 2013)

• Record Type: Journal Article
• Authors: Wark, Landon; Novak, David; Sabbaghian, Nelly; Amrein, Lilian; Jangamreddy, Jaganmohan R.; Cheang, Mary; Pouchet, Carly; Aloyz, Raquel; Foulkes, William D.; Mai, Sabine; Tischkowitz, Marc
• Is Part Of: Genes, chromosomes & cancer. Volume 52:Issue 5(2013:May)
• Page Start: 480
• Page End: 494
• Publication Date: 2013-01-23
• Subjects: Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22045
• Languages: English
• ISSNs: 1045-2257

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>PALB2/FANCN is a BRCA1‐ and BRCA2‐interacting Fanconi Anemia (FA) protein crucial for key BRCA2 genome caretaker functions. Heterozygous germline mutations in <italic>PALB2</italic> predispose to breast cancer and biallelic mutations cause FA. FA proteins play a critical role in the telomere maintenance pathway, with telomeric shortening observed in FA cells. Less is known about telomere maintenance in the heterozygous state. Here, we investigate the roles of <italic>PALB2</italic> heterozygous mutations in genomic instability, an important carcinogenesis precursor. Patient‐derived lymphoblastoid (LCL) and fibroblast (FCL) cell lines with monoallelic truncating <italic>PALB2</italic> mutations were investigated using a combination of molecular imaging techniques including centromeric FISH, telomeric Q‐FISH and spectral karyotyping (SKY). Mitomycin C and Cisplatin sensitivity was assayed via cellular metabolism of WST‐1. The <italic>PALB2</italic> c.229delT FCL showed increases in telomere counts associated with increased mean intensity compared with two wild‐type FCLs generated from first‐degree relatives (<italic>P</italic> =1.04E‐10 and <italic>P</italic> =9.68E‐15) and it showed evidence of chromosomal rearrangements. Significant differences in centromere distribution were observed in one of three <italic>PALB2</italic> heterozygous FCLs analyzed when compared with <italic>PALB2</italic> wild‐type, <italic>BRCA1</italic> and <italic>BRCA2</italic> heterozygous FCLs. No significant consistently increased sensitivity to Mitomycin C or Cisplatin was observed in LCLs. Our results are suggestive of an altered centromere distribution profile and a telomere instability phenotype. Together, these may indicate critical nuclear organization defects associated with the predisposition to transformation and early stage development of <italic>PALB2</italic>‐related cancers. © 2013 Wiley Periodicals, Inc.</p> </abstract>