Identification of low-penetrance alleles, genetic modifiers and mutation analysis in familial breast cancer cases

Catucci, Irene (2013). Identification of low-penetrance alleles, genetic modifiers and mutation analysis in familial breast cancer cases. PhD thesis The Open University.



To date, germline mutations in known high-penetrance genes, mainly BRCA1 and BRCA2, and in moderate- and low-penetrance genes are responsible for approximately 30- 35% of breast cancer familial clustering, leaving the majority of them unexplained. In addition, the variability of the risk conferred by BRCA1 and BRCA2 mutations suggests the presence of genetic modifiers of this risk. Therefore, the identification and characterization of as many as possible of genetic factors is crucial for risk prediction in members of breast cancer families.

In this context, the aim of this thesis was firstly to investigate the role of the two Fanconi Anemia (FA) genes PALB2 and SLX4 as breast cancer predisposing loci. In the PALB2 screening, I observed a frequency of deleterious mutation of 2.1 % in familial cases recruited in cancer centers in Milan. Interestingly, I also identified the recurrent mutation c.1027C>T, detected with 10-fold increased frequency in cases from Bergamo with respect to those ascertained in Milan, suggesting a founder effect. On the contrary. the SLX4 analysis failed to identify any clearly deleterious mutation, excluding a major role of this gene in breast cancer susceptibility in the Italian population. In addition, I genotyped the candidate low-risk rs895819 polymorphism, located in the gene coding for miR-27a, to evaluate its role in reducing breast cancer risk, previously reported in the German population. No such an association was observed in our sample set. Finally, I investigated the role of the CASP8 rs3834129 ins/del polymorphism as a genetic modifier in Italian BRCA1 and BRCA2 mutation carries and I observed an association of this SNP with increased breast cancer risk only in individuals carrying BRCA1 mutations.

In conclusion, our investigation contributed to assess the role of candidate predisposing loci and genetic modifiers of breast cancer risk, providing further knowledge on the susceptibility to this disease.

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