Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, 71-252, Poland.
Department of Clinical Genetics and Pathology, University of Zielona Góra, Zielona Góra, Poland.
Breast Cancer Res Treat. 2019 Nov;178(2):427-431. doi: 10.1007/s10549-019-05391-w. Epub 2019 Aug 13.
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.
NBN 657del5 突变是乳腺癌和前列腺癌的致病突变。最近，据报道，该突变对前列腺癌风险的致病性可由同一基因的错义变体（E185Q）修饰。
为了评估 NBN 的 657del5 和 E185Q 突变在波兰乳腺癌风险中的相互作用，对 4964 名乳腺癌患者和 6152 名对照者进行了这两种 NBN 常见变异（657del5 截断变异和 E185Q 错义变异）的基因分型。
在 4964 名未选择的病例中，检测到 57 例 NBN 657del5 突变，在 6152 例对照中，检测到 35 例（OR=2.0，p=0.001）。在 4964 名未选择的病例中，检测到 E185Q GG 基因型 2167 例，在 6152 例对照中，检测到 2617 例（OR=1.04，p=0.3）。在携带 657del5 缺失的患者中，升高的癌症风险仅限于 E185Q 变体 GG 基因型的女性（OR=3.6，95%CI 1.9-6.6；p<0.0001）。在其他 E185Q 基因型的女性中，与 657del5 相关的 OR 为 1.0（95%CI 0.5-1.8；p=0.9）。两个等位基因之间的相互作用具有统计学意义（同质性 p=0.003）。
在波兰，NBN 657del5 突变的致病性仅限于同一基因的错义变体（E185Q）纯合 GG 基因型的女性。这是第一个明确的例子，说明中度外显率的乳腺癌基因受到遗传修饰物的影响。
