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.
- 4.Cybulski C, Gliniewicz B, Sikorski A, Kładny J, Huzarski T, Gronwald J, Byrski T, Debniak T, Gorski B, Jakubowska A et al (2007) Epistatic relationship between the cancer susceptibility genes CHEK2 and p27. Cancer Epidemiol Biomark Prev 16:572–576. https://doi.org/10.1158/1055-9965.EPI-06-0566 CrossRefGoogle Scholar
- 5.Couch FJ, Wang X, McGuffog L, Lee A, Olswold C, Kuchenbaecker KB, Soucy P, Fredericksen Z, Barrowdale D, Dennis J et al (2013) Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet 9:e1003212. https://doi.org/10.1371/journal.pgen.1003212 CrossRefGoogle Scholar
- 8.Huzarski T, Cybulski C, Jakubowska A, Byrski T, Gronwald J, Domagała P, Szwiec M, Godlewski D, Kilar E, Marczyk E et al (2013) Clinical characteristics of breast cancer in patients with an NBS1 mutation. Breast Cancer Res Treat 141:471–476. https://doi.org/10.1007/s10549-013-2692-x CrossRefGoogle Scholar
- 11.Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR, Hays L, Morgan WF, Petrini JH (1998) The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93:477–486. https://doi.org/10.1016/s0092-8674(00)81175-7 CrossRefGoogle Scholar
- 12.Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanová E, Cooper PR, Nowak NJ et al (1998) Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93:467–476. https://doi.org/10.1016/S0092-8674(00)81174-5 CrossRefGoogle Scholar
- 15.Mijuskovic M, Saunders EJ, Leongamornlert DA, Wakerell S, Whitmore I, Dadaev T, Cieza-Borrella C, Govindasami K, Brook MN, Haiman CA et al (2018) Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease. Br J Cancer 119:96–104. https://doi.org/10.1038/s41416-018-0141-7 CrossRefGoogle Scholar
- 16.Hebbring SJ, Fredriksson H, White KA, Maier C, Ewing C, McDonnell SK, Jacobsen SJ, Cerhan J, Schaid DJ, Ikonen T et al (2006) Role of the Nijmegen breakage syndrome 1 gene in familial and sporadic prostate cancer. Cancer Epidemiol Biomark Prev 15:935–938. https://doi.org/10.1158/1055-9965.EPI-05-0910 CrossRefGoogle Scholar
- 17.Zuhlke KA, Johnson AM, Okoth LA, Stoffel EM, Robbins CM, Tembe WA, Salinas CA, Zheng SL, Xu J, Carpten JD et al (2012) Identification of a novel NBN truncating mutation in a family with hereditary prostate cancer. Fam Cancer 11:595–600. https://doi.org/10.1007/s10689-012-9555-1 CrossRefGoogle Scholar
- 18.Leongamornlert DA, Saunders EJ, Wakerell S, Whitmore I, Dadaev T, Cieza-Borrella C, Benafif S, Brook MN, Donovan JL, Hamdy FC et al (2019) Germline DNA repair gene mutations in young-onset prostate cancer cases in the UK: evidence for a more extensive genetic panel. Eur Urol. https://doi.org/10.1016/j.eururo.2019.01.050 Google Scholar