Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next?

Abstract

The NBN gene has been included in breast cancer (BC) multigene panels based on early studies suggesting an increased BC risk for carriers, though not confirmed by recent research. To evaluate the impact of NBN analysis, we assessed the results of NBN sequencing in 116 BRCA-negative BC patients and reviewed the literature. Three patients (2.6%) carried potentially relevant variants: two, apparently unrelated, carried the frameshift variant c.156_157delTT and another one the c.628G>T variant. The latter was subsequently found in 4/1390 (0.3%) BC cases and 8/1580 (0.5%) controls in an independent sample, which, together with in silico predictions, provided evidence against its pathogenicity. Conversely, the rare c.156_157delTT variant was absent in the case-control set; moreover, a 50% reduction of NBN expression was demonstrated in one carrier. However, in one family it failed to co-segregate with BC, while the other carrier was found to harbor also a probably pathogenic TP53 variant that may explain her phenotype. Therefore, the c.156_157delTT, although functionally deleterious, was not supported as a cancer-predisposing defect. Pathogenic/likely pathogenic NBN variants were detected by multigene panels in 31/12314 (0.25%) patients included in 15 studies. The risk of misinterpretation of such findings is substantial and supports the exclusion of NBN from multigene panels.

Double heterozygous pathogenic variants prevalence in a cohort of patients with hereditary breast cancer

“…Most gene panels include high-penetrance genes, such as BRCA1 , BRCA2 , CDH1 , PALB2 , PTEN , STK11 , and TP53 , and moderate-penetrance genes, such as ATM , BRIP1 , CHEK2 , FANCD2 , RAD51C , NBN , and PMS2 , which also associates with lifetime BC risk ( 29 ). Although the clinical impact of NBN and PSM2 on BC susceptibility has remained uncertain, their introduction in clinical genetic testing for suspected hereditary BC has been recently supported ( 13 , 30 ). NBN was shown to increase about three-fold the risk in BC (odds ratio, 3.1; 95% CI, 1.4–6.6) and indicates that the 657del5 deletion [c.657_661del (p.Lys219fs)] and perhaps the R215W substitution contribute to inherited BC susceptibility ( 11 ).…”

“…ATM , CHEK2 , and BRIP1 , among others, are known to confer moderate risk ( 10 ). The clinical impact on BC susceptibility in NBN , PSM2 , and other genes has been described in certain populations, but its impact is still unclear ( 11 – 13 ). The majority of high- and moderate-penetrance genes have an autosomal dominant pattern, in which single heterozygous pathogenic variants lead to cancer risk.…”

Harnessing Epigenetics for Breast Cancer Therapy: The Role of DNA Methylation, Histone Modifications, and MicroRNA

“…Mutations and polymorphisms in them can lead to abnormal cell growth, which can lead to the development of cancer. Among the genes that are associated with the development and progression of breast cancer, the following are currently listed [ 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]: BRCA1 and BRCA2 genes, which have the best documented association with breast cancer; having a mutation in these genes is responsible for a 50–80% risk of breast cancer and a 45% risk of ovarian cancer before the age of 85—with a mutation in the BRCA1 gene and a 31–56% risk of breast cancer and 11–27% of ovarian cancer in BRCA2 mutation [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]; the PALB2 gene, which is responsible for the repair of damaged DNA; carriers of the defective gene have a 35% risk of developing breast cancer before the age of 70 [ 31 , 32 , 33 , 34 , 35 , 36 ]; the CHEK2 gene, which is responsible for the production of a protein that inhibits tumor growth; women with a mutation in this gene have a twice as high a risk of developing breast cancer compared to the general population [ 37 , 38 , 39 , 40 , 41 , 42 ]; the NBN gene, which encodes a protein regulating the DNA repair process and maintaining chromosome stability [ 43 , 44 , 45 , 46 , ...…”

“…the NBN gene, which encodes a protein regulating the DNA repair process and maintaining chromosome stability [ 43 , 44 , 45 , 46 , 47 ];…”

A Glance at Molecular Advances in Cancer Genetics: A Baffling Puzzle Still to Be Solved

“…The study from Zuntini et al [ 1 ] tackles the issue of the premature inclusion of candidate genes in multigene panel testing. For example, NBN is involved in homologous recombination deficiency (HRD), and it is allegedly associated with a higher risk of breast cancer.…”