Allelic modification of breast cancer risk in women with an NBN mutation
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NBN 657del5 founder mutation predisposes to breast and prostate cancer. Recently, it has been reported that the pathogenicity of this mutation with regard to prostate cancer risk is modified by a missense variant of the same gene (E185Q).
To evaluate the interaction of the 657del5 and E185Q founder alleles of NBN on breast cancer risk in Poland, 4964 women with breast cancer and 6152 controls were genotyped for these two recurrent variants of NBN (657del5 truncating variant and E185Q missense variant).
The NBN 657del5 mutation was detected in 57 of 4964 unselected cases and in 35 of 6152 controls (OR = 2.0, p = 0.001). The E185Q GG genotype was detected in 2167 of 4964 unselected cases and in 2617 of 6152 controls (OR = 1.04, p = 0.3). In carriers of the 657del5 deletion, the elevated cancer risk was restricted to women with the GG genotype of the E185Q variant (OR = 3.6, 95% CI 1.9–6.6; p < 0.0001). Among women with other E185Q genotypes, the OR associated with 657del5 was 1.0 (95% CI 0.5–1.8; p = 0.9). The interaction between the two alleles was statistically significant (homogeneity p = 0.003).
In Poland, the pathogenicity of the NBN 657del5 mutation is restricted to women with a homozygous GG genotype of missense variant of the same gene (E185Q). This is the first clear example whereby a moderate penetrance breast cancer gene is impacted by a genetic modifier.
KeywordsNBN NBS1 Mutation Breast cancer
This study was funded by National Science Centre, Poland; Project Number: 2015/17/B/NZ5/02543. The study was approved by the Ethics Committee of the Pomeranian Medical University in Szczecin. Patient clinical data have been obtained in a manner conforming with the IRB ethical guidelines. We thank Daria Zanoza and Ewa Putresza for their help with managing databases.
This study was funded by National Science Centre (Narodowe Centrum Nauki), Poland; Project Number: 2015/17/B/NZ5/02543.
Compliance with ethical standards
Conflict of interest
All authors declare no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. The study was approved by the Ethics Committee of the Pomeranian Medical University in Szczecin.
Informed consent was obtained from all individual participants included in the study.
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