Bogna Rusak1, Wojciech Kluźniak1, Dominika Wokołorczyk1, Klaudia Stempa1, Aniruddh Kashyap1, Helena Rudnicka1, Jacek Gronwald1, Tomasz Huzarski1,2, Tadeusz Dębniak1, Anna Jakubowska1,3, Marek Szwiec4,5, Mohammad R Akbari6,7, Steven A Narod8,9, Jan Lubiński1, Cezary Cybulski10. 1. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, 71-252, Poland. 2. Department of Clinical Genetics and Pathology, University of Zielona Góra, Zielona Góra, Poland. 3. Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland. 4. Department of Surgery and Oncology, University of Zielona Góra, Zielona Góra, Poland. 5. Department of Clinical Oncology, University of Zielona Góra, Zielona Góra, Poland. 6. Women's College Research Institute, Women's College Hospital, 76 Grenville St, 6th Floor, Toronto, ON, M5S 1B2, Canada. 7. Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. 8. Women's College Research Institute, Women's College Hospital, 76 Grenville St, 6th Floor, Toronto, ON, M5S 1B2, Canada. Steven.narod@wchospital.ca. 9. Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. Steven.narod@wchospital.ca. 10. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, 71-252, Poland. cezarycy@pum.edu.pl.
Abstract
BACKGROUND: 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). METHODS: 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). RESULTS: 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). CONCLUSION: 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.
BACKGROUND:NBN657del5 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). METHODS: 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). RESULTS: The NBN657del5 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). CONCLUSION: In Poland, the pathogenicity of the NBN657del5 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.
Authors: Chunling Hu; Steven N Hart; Rohan Gnanaolivu; Hongyan Huang; Kun Y Lee; Jie Na; Chi Gao; Jenna Lilyquist; Siddhartha Yadav; Nicholas J Boddicker; Raed Samara; Josh Klebba; Christine B Ambrosone; Hoda Anton-Culver; Paul Auer; Elisa V Bandera; Leslie Bernstein; Kimberly A Bertrand; Elizabeth S Burnside; Brian D Carter; Heather Eliassen; Susan M Gapstur; Mia Gaudet; Christopher Haiman; James M Hodge; David J Hunter; Eric J Jacobs; Esther M John; Charles Kooperberg; Allison W Kurian; Loic Le Marchand; Sara Lindstroem; Tricia Lindstrom; Huiyan Ma; Susan Neuhausen; Polly A Newcomb; Katie M O'Brien; Janet E Olson; Irene M Ong; Tuya Pal; Julie R Palmer; Alpa V Patel; Sonya Reid; Lynn Rosenberg; Dale P Sandler; Christopher Scott; Rulla Tamimi; Jack A Taylor; Amy Trentham-Dietz; Celine M Vachon; Clarice Weinberg; Song Yao; Argyrios Ziogas; Jeffrey N Weitzel; David E Goldgar; Susan M Domchek; Katherine L Nathanson; Peter Kraft; Eric C Polley; Fergus J Couch Journal: N Engl J Med Date: 2021-01-20 Impact factor: 91.245
Authors: Roberta Zuntini; Elena Bonora; Laura Maria Pradella; Laura Benedetta Amato; Michele Vidone; Sara De Fanti; Irene Catucci; Laura Cortesi; Veronica Medici; Simona Ferrari; Giuseppe Gasparre; Paolo Peterlongo; Marco Sazzini; Daniela Turchetti Journal: Int J Mol Sci Date: 2021-05-29 Impact factor: 5.923