Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next?
Abstract
:1. Introduction
2. Results
2.1. NBN Sequence Variants
2.2. Clinical and Family History of Carriers of NBN Variants
2.3. In Silico Assessment of the Variants
2.4. Genotyping of the Independent Set of Cases and Controls
2.5. Expression of Variant Nibrin
2.6. Double-Strand Break Repair Assessment
2.7. NBN Haplotype Patterns
2.8. Whole Exome Sequencing Analysis
2.9. Review of the Literature
3. Discussion
4. Patients and Methods
4.1. Patient Recruitment
4.2. NBN Sequence Analysis
4.3. In Silico Variant Assessment
4.4. Genotyping of Independent Sets of Cases and Controls
4.5. Gene Expression Analyses
4.5.1. Real-Time PCR
4.5.2. Western Blotting
4.5.3. Double-Strand Break Repair Assessment
4.5.4. Haplotype Reconstruction and Evolutionary Analyses
4.5.5. Whole Exome Sequencing
4.5.6. Review of the Literature
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Reference | Country | Study Population | Testing Type | N Patients | N with NBN Variants (%) | Specific Variants (N) | Proband Cancer History | Variant Frequency in the Study | Population Frequency (gnomAD) § | p Value | Current Classification (ClinVar/LOVD) |
---|---|---|---|---|---|---|---|---|---|---|---|
[11] | France | Pts with suspected hereditary BC | NGS panel | 708 | 8 (1.13%) | c.1142delC (1) | ND | 0.14% | 0.005% 1 | 0.01 | C4/C5 |
c.156_157delTT (1) | 0.14% | 0.004% 1,2 | 0.01 | C4/C5 | |||||||
c.37+5G>A (3) | 0.42% | 0.56% 3 | 0.82 | C1/C2 | |||||||
c.38-10T>A (1) | 0.14% | 0.03% 3 | 0.50 | C3 | |||||||
c.657_661delACAAA (1) | 0.14% | 0.04% 1,2,4,5 | 0.69 | C5 | |||||||
c.788T>C (1) | 0.14% | 0.04% 1,2,6 | 0.68 | C3 | |||||||
[12] | USA | Pts previously tested for BRCA mut | NGS panel (42 genes) | 198 | 2 (1.01%) | c.643C>T (2) | (1) BC age 50; FH: BC, Mel (2) no cancer; FH: BC, CRC, OC | 1.01% | 0.49% 3 | 0.59 | C3 |
[13] | Poland | Pts with TNBC (158) or suspected hereditary, NTNBC (44) | Screening of 36 mutations in 8 genes | 202 | 7 (3.47%) | c.657_661delACAAA (1) | NTNBC age 63 | 0.49% | 0.04% | 0.14 | C5 |
c.511A>G (6 *) | 4: TNBC age 44–81 | ||||||||||
2: NTNBC age 49, 59 | 2.97% | 0.30% 3 | <0.0001 | C1 | |||||||
[14] | USA | Pts referred for BRCA and tested negative | Commercial NGS panels (25–29 genes) | 1046 | 2 (0.19%) only deleterious variants reported | c.657_661delACAAA (1) | BC age 54, PC; FH: BC, PrC, Mel, PC, LC, others BC age 49; FH: BC | 0.10% | 0.04% | 0.91 | C5 |
c.1142delC (1) | 0.10% | 0.005% | 0.07 | C4/C5 | |||||||
[15] | USA | Pts with early-onset BC (<40) BRCA-negative | NGS panel (22 genes) | 278 | 1 (0.36%) | c.664T>C | BC age 37, Leu 39; FH: PrC, Mel | 0.36% | 0.004% 1 | <0.0001 | C3 |
[16] | Australia | Familial BC pts | NGS panel (19 genes) | 684 | 1 (0.15%) | c.698_701delAACA (1) | BC age 42; FH: PrC | 0.15% | 0.004% 1,6 | 0.01 | C5 |
[17] | USA | BC pts | NGS panel (25 genes) | 488 | 1 (0.2%) | c.127C>T (1) | TNBC age 56; FH: LC, CNS, PC | 0.2% | 0.006% 1,4,6 | 0.01 | C5 |
[18] | USA | BC pts with Ashkenazi ancestry | NGS panel (23 genes) | 1007 | 1 (0.1%) | c.1903A>T (1) | BC age 42 | 0.1% | 0.15% 7 | 0.96 | C5 |
[19] | Germany | BC/OC pts | NGS panel (14 genes) | 581 | 6 (1.03%) | c.1397+1delG (1) | NTNBC age 35; FH: BC NTNBC age 43; FH: BC NTNBC age 52; FH: BC (1)BC age 53; FH: BC (2) BC age 49; FH: BC (3)TNBC/OC age 56/66; FH: BC, LC, Leu | 0.17% | 0.0008% 2 | <0.0001 | C5 |
c.2028delT(1) | 0.17% | ND | - | ND (C4) | |||||||
c.2097dupT (1) | 0.17% | ND | - | ND (C4) | |||||||
c.657_661delACAAA (3) | 0.52% | 0.04% | <0.0001 | C5 | |||||||
c | |||||||||||
[20] | China | Women with personal or familial history of BC | NGS panel (27 genes) | 240 | 1 (0.42%) | c.2140C>T (1) | BC age 33 | 0.42% | 0.005% 1,7 | <0.0001 | C5 |
[21] | Germany | BC pts tested negative for BRCA | NGS panels (8 genes selected) | 5589 | 12 (0.21%) only truncating variants reported | c.123delC (1) | ND | 0.02% | 0.0008% 1 | 0.15 | C5 |
c.211_212insGA (1) | 0.02% | 0.0008% 1 | 0.15 | C5 | |||||||
c.657_661delACAAA (7) | 0.13% | 0.04% | 0.008 | C5 | |||||||
c.1141del (1) | 0.02% | ND | - | ND (C4) | |||||||
c.1396del (1) | 0.02% | ND | - | ND (C4) | |||||||
c.1651dup (1) | 0.02% | 0.002% 6 | 0.29 | C5 | |||||||
[22] | Germany | BC pts tested negative for BRCA | NGS panel (94 genes) | 237 | 1 (0.4%) VUS excluded | c.657_661delACAAA | BC age 32 | 0.4% | 0.04% | 0.19 | C5 |
[23] | US | BC/OC pts | NGS panels (11 genes selected) | 5436 | ND (0.35%) path ND (2.5%) VUS | ND | |||||
[24] | Israel | BC pts tested negative for founder BRCA variants | Commercial NGS panels (30–83 genes) | 144 | 1 (0.7%) VUS excluded | c.966C>G | ND (BRCAPRO prob: 0.6%) | 0.7% | ND | - | ND (C4) |
[25] | Italy | Male BC pts | NGS panel (24 genes) | 81 | 1 (1.2%) | c.547G>A | Male BC age 49; FH: BC | 1.2% | 0.003% 1,7 | <0.0001 | C3 |
[26] | China | BC pts | Virtual panel from WES | 831 | 1 (0.1%) | c.127C>T | ND | 0.1% | 0.006% 1,4,6 | 0.07 | C5 |
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Zuntini, R.; Bonora, E.; Pradella, L.M.; Amato, L.B.; Vidone, M.; De Fanti, S.; Catucci, I.; Cortesi, L.; Medici, V.; Ferrari, S.; et al. Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next? Int. J. Mol. Sci. 2021, 22, 5832. https://doi.org/10.3390/ijms22115832
Zuntini R, Bonora E, Pradella LM, Amato LB, Vidone M, De Fanti S, Catucci I, Cortesi L, Medici V, Ferrari S, et al. Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next? International Journal of Molecular Sciences. 2021; 22(11):5832. https://doi.org/10.3390/ijms22115832
Chicago/Turabian StyleZuntini, Roberta, Elena Bonora, Laura Maria Pradella, Laura Benedetta Amato, Michele Vidone, Sara De Fanti, Irene Catucci, Laura Cortesi, Veronica Medici, Simona Ferrari, and et al. 2021. "Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next?" International Journal of Molecular Sciences 22, no. 11: 5832. https://doi.org/10.3390/ijms22115832