Towards a better understanding of genetic predisposition in breast cancer

Abstract

Breast cancer (BC) is the most frequently diagnosed cancer in women (12%) in Western industrialized countries. Heterozygous mutation carriers for the two major BC predisposing genes, BRCA1 and BRCA2, are at increased risk for developing breast and/or ovarian cancer. Germline mutations in BRCA1/2 are found in only 20% of the BC families. What the underlying genetic cause could be in the remaining 80% of the BC families still needs to be elucidated. In this PhD thesis, we try to further identify the genetic factors responsible for breast cancer predisposition. The ultimate aim would be to identify any person at risk for BC.
Firstly, we present the proof of principle for a Next Generation Sequencing based mutation screening procedure that allows the systematic detection of inherited Alu element insertions at any sequence position in the coding regions of BRCA1/2, and by extension in any gene. This approach was successfully implemented in the diagnostic procedure. Secondly, we try to discover new genetic factors (= pathogenic mutations in “new” genes) responsible for the occurrence of BC cases in families where no BRCA1/2 mutation was found. We investigated the role of BARD1 (a BRCA1 interacting protein) in BC predisposition by analysing a set of patients belonging to high risk non-BRCA1/2 BC families and a set of patients selected for a specific type of BC (Triple Negative BC or TNBC). Our data indicated a contribution of BARD1 to the development of BC, especially in TNBC patients.
In a third part, we investigate the nuclear BRCA1 expression pattern obtained in freshly collected leucocytes (normal cells) from BRCA1/2 mutation carriers. We show that the number of leucocytes presenting a BRCA1 nuclear staining is significantly decreased in BRCA1/2 mutation carriers when compared to leucocytes from sporadic BC cases and healthy controls. Therefore, we hypothesize that normal cells from heterozygous BRCA1/2 mutation carriers already present a slightly enhanced genomic instability.
Finally, we present an alternative cancer predisposition model built on the assumption that efficiencies of DNA maintenance mechanisms in normal cells are similar but not identical for each person. The relative level of genomic instability in a normal cell would correlate with the probability of the cell to transform into a cancer cell. When validated, this model may provide a more accurate estimation of individual cancer risks, even in persons without familial antecedents.

Date of Award	28 Jun 2016
Original language	English
Awarding Institution	Vrije Universiteit Brussel
Supervisor	Jacques De Grève (Promotor), Erik Teugels (Promotor), Kris Thielemans (Jury), Alexander Gheldof (Jury), Jan Lamote (Jury), Moustapha Hamdi (Jury), F. Hogervorst (Jury), Kathleen Claes (Jury) & Gert Matthijs (Jury)