University of Oulu

TOPBP1, CLSPN and PALB2 genes in familial breast cancer susceptibility

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Author: Erkko, Hannele1,2
Organizations: 1University of Oulu, Faculty of Medicine, Institute of Clinical Medicine, Department of Clinical Genetics
2University of Oulu, Biocenter Oulu
Format: ebook
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1 MB)
Persistent link:
Language: English
Published: 2008
Publish Date: 2008-12-09
Thesis type: Doctoral Dissertation
Defence Note: Academic dissertation to be presented, with the assent of the Faculty of Medicine of the University of Oulu, for public defence in Auditorium 5 of Oulu University Hospital, on December 19th, 2008, at 12 noon
Reviewer: Docent Minna Nyström
Professor Aarno Palotie


The currently known susceptibility genes account for approximately 25% of familial breast cancer predisposition. Additional factors contributing to the pathogenesis of breast cancer are, therefore, likely to be discovered. Most of the known genes affecting breast cancer predisposition function in the DNA damage response pathway. In this study three genes, TOPBP1, CLSPN and PALB2, involved in this complex process were investigated to reveal potentially pathogenic mutations associated with breast cancer susceptibility.

In the analysis of the TOPBP1 gene, one novel putative pathogenic alteration was observed. The Arg309Cys variant was found at an elevated frequency among familial cases (19/125) vs. controls (49/697) (p = 0.002; OR 2.4; 95% CI 1.3–4.2). In addition, altogether 18 other germline alterations were observed in this gene, but they all appeared to be harmless polymorphisms.

Investigation of CLSPN alterations among familial breast cancer families revealed altogether seven different changes. No clearly pathogenic alterations were observed. However, a potential modifier effect was discovered for the 1195delGlu change. The obtained results suggest that CLSPN alterations are unlikely to be significant breast cancer susceptibility alleles.

In the PALB2 gene, a pathogenic mutation c.1592delT was identified at an elevated frequency among breast cancer patients (0.9%) compared to controls (0.2%) (p = 0.003, OR 3.94, 95% CI 1.5–12.1). Among familial cases the frequency of c.1592delT was even higher (2.7%). This mutation was also functionally deficient. It had a markedly decreased BRCA2-binding affinity and was unable to support homologous recombination or to restore cross link repair in PALB2 knock-down cells. Additionally, this mutation was discovered in a familial prostate cancer family and was found to segregate with the disease, suggesting some association also with prostate cancer.

The penetrance and hazard ratio associated with PALB2 c.1592delT were determined in unselected breast cancer families. A substantially increased risk of breast cancer (HR 6.1; 95% CI 2.2–17.2; p = 0.01) was discovered resulting in an estimated 40% (95% CI 17–77) breast cancer risk by age 70 years, comparable to that for carriers of BRCA2 mutations. This markedly increased cancer risk suggests that genetic counselling for carriers is needed and screening for this mutation should be considered.

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Series: Acta Universitatis Ouluensis. D, Medica
ISSN-E: 1796-2234
ISBN: 978-951-42-8968-2
ISBN Print: 978-951-42-8967-5
Issue: 996
Copyright information: © University of Oulu, 2008. This publication is copyrighted. You may download, display and print it for your own personal use. Commercial use is prohibited.