Accurate classification of BRCA1 variants with saturation genome editing

Nature

Volumn 562, Issue 7726, 2018, Pages 217-222

  Findlay, Gregory M ^a   Daza, Riza M ^a   Martin, Beth ^a   Zhang, Melissa D ^a   Leith, Anh P ^a   Gasperini, Molly ^a   Janizek, Joseph D ^a   Huang, Xingfan ^a   Starita, Lea M ^a,b   Shendure, Jay ^a,b  

^a UNIVERSITY OF WASHINGTON   (United States)

^b BROTMAN BATY INSTITUTE FOR PRECISION MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOASSAY; CANCER; CANCRINITE; GENE; GENE EXPRESSION; GENETIC ANALYSIS; GENOME; PATHOGENICITY; TUMOR;

ARTICLE; CONTROLLED STUDY; EXON; GENE EDITING; GENE EXPRESSION; GENE TARGETING; GENETIC VARIABILITY; HUMAN; HUMAN CELL; LOSS OF FUNCTION MUTATION; MISSENSE MUTATION; PATHOGENICITY; PRIORITY JOURNAL; SEQUENCE ANALYSIS; SINGLE NUCLEOTIDE POLYMORPHISM; TUMOR SUPPRESSOR GENE; CELL LINE; CLASSIFICATION; ESSENTIAL GENE; FEMALE; GENETIC PREDISPOSITION; GENETIC VARIATION; GENETICS; HEREDITARY BREAST AND OVARIAN CANCER SYNDROME; HUMAN GENOME; METABOLISM; MOLECULAR MODEL; PROGNOSIS; RECOMBINATION REPAIR;

BRCA1 PROTEIN; BRCA1 PROTEIN, HUMAN; MESSENGER RNA;

BRCA1 PROTEIN; CELL LINE; EXONS; FEMALE; GENE EDITING; GENES, ESSENTIAL; GENETIC PREDISPOSITION TO DISEASE; GENETIC VARIATION; GENOME, HUMAN; HEREDITARY BREAST AND OVARIAN CANCER SYNDROME; HUMANS; LOSS OF FUNCTION MUTATION; MODELS, MOLECULAR; PROGNOSIS; RECOMBINATIONAL DNA REPAIR; RNA, MESSENGER;

EID: 85054375843     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/s41586-018-0461-z     Document Type: Article

References (49)

1. Rehm, H. L. et al. ClinGen–the Clinical Genome Resource. N. Engl. J. Med. 372, 2235–2242 (2015).
2. Kuchenbaecker, K. B. et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J. Am. Med. Assoc. 317, 2402–2416 (2017).
3. Hall, J. M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990).
4. Olopade, O. I. & Artioli, G. Efficacy of risk-reducing salpingo-oophorectomy in women with BRCA-1 and BRCA-2 mutations. Breast J. 10, S5–S9 (2004).
5. Rebbeck, T. R. et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J. Clin. Oncol. 22, 1055–1062 (2004).
6. Easton, D. F. et al. Gene-panel sequencing and the prediction of breast-cancer risk. N. Engl. J. Med. 372, 2243–2257 (2015).
7. Landrum, M. J. et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 44, D862–D868 (2016).
8. Millot, G. A. et al. A guide for functional analysis of BRCA1 variants of uncertain significance. Hum. Mutat. 33, 1526–1537 (2012).
9. Ransburgh, D. J. R., Chiba, N., Ishioka, C., Toland, A. E. & Parvin, J. D. Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination. Cancer Res. 70, 988–995 (2010).
10. Pierce, A. J., Hu, P., Han, M., Ellis, N. & Jasin, M. Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev. 15, 3237–3242 (2001).
11. Bouwman, P. et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov. 3, 1142–1155 (2013).
12. Woods, N. T. et al. Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. NPJ Genom. Med. 1, 16001 (2016).
13. Starita, L. M. et al. Massively parallel functional analysis of BRCA1 RING domain variants. Genetics 200, 413–422 (2015).
14. Steffensen, A. Y. et al. Functional characterization of BRCA1 gene variants by mini-gene splicing assay. Eur. J. Hum. Genet. 22, 1362–1368 (2014).
15. de la Hoya, M. et al. Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms. Hum. Mol. Genet. 25, 2256–2268 (2016).
16. Ghosh, R., Oak, N. & Plon, S. E. Evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines. Genome Biol. 18, 225 (2017).
17. Gibson, T. J., Seiler, M. & Veitia, R. A. The transience of transient overexpression. Nat. Methods 10, 715–721 (2013).
18. Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. BRCA1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999).
19. Drost, R. et al. BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. Cancer Cell 20, 797–809 (2011).
20. Shakya, R. et al. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 334, 525–528 (2011).
21. Vega, A. et al. The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript. Hum. Mutat. 17, 520–521 (2001).
22. Findlay, G. M., Boyle, E. A., Hause, R. J., Klein, J. C. & Shendure, J. Saturation editing of genomic regions by multiplex homology-directed repair. Nature 513, 120–123 (2014).
23. Blomen, V. A. et al. Gene essentiality and synthetic lethality in haploid human cells. Science 350, 1092–1096 (2015).
24. Ran, F. A. et al. Genome engineering using the CRISPR–Cas9 system. Nat. Protoc. 8, 2281–2308 (2013).
25. Beumer, K. J. et al. Efficient gene targeting in Drosophila by direct embryo injection with zinc-finger nucleases. Proc. Natl Acad. Sci. USA 105, 19821–19826 (2008).
26. Essletzbichler, P. et al. Megabase-scale deletion using CRISPR/Cas9 to generate a fully haploid human cell line. Genome Res. 24, 2059–2065 (2014).
27. Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
28. Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310–315 (2014).
29. Pollard, K. S., Hubisz, M. J., Rosenbloom, K. R. & Siepel, A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 20, 110–121 (2010).
30. Tavtigian, S. V., Byrnes, G. B., Goldgar, D. E. & Thomas, A. Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications. Hum. Mutat. 29, 1342–1354 (2008).
31. Towler, W. I. et al. Analysis of BRCA1 variants in double-strand break repair by homologous recombination and single-strand annealing. Hum. Mutat. 34, 439–445 (2013).
32. Starita, L. M. et al. A multiplexed homology-directed DNA repair assay reveals the impact of over 1,000 BRCA1 missense substitution variants on protein function. Am. J. Hum. Genet. 10.1016/j.ajhg.2018.07.016 (2018).
33. Brzovic, P. S., Rajagopal, P., Hoyt, D. W., King, M. C. & Klevit, R. E. Structure of a BRCA1–BARD1 heterodimeric RING–RING complex. Nat. Struct. Biol. 8, 833–837 (2001).
34. Shiozaki, E. N., Gu, L., Yan, N. & Shi, Y. Structure of the BRCT repeats of BRCA1 bound to a BACH1 phosphopeptide: implications for signaling. Mol. Cell 14, 405–412 (2004).
35. Wegrzyn, J. L., Drudge, T. M., Valafar, F. & Hook, V. Bioinformatic analyses of mammalian 5′-UTR sequence properties of mRNAs predicts alternative translation initiation sites. BMC Bioinformatics 9, 232 (2008).
36. Desmet, F.-O. et al. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 37, e67 (2009).
37. Gasperini, M., Starita, L. & Shendure, J. The power of multiplexed functional analysis of genetic variants. Nat. Protoc. 11, 1782–1787 (2016).
38. Starita, L. M. et al. Variant interpretation: functional assays to the rescue. Am. J. Hum. Genet. 101, 315–325 (2017).
39. Plon, S. E. et al. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum. Mutat. 29, 1282–1291 (2008).
40. Lovelock, P. K. et al. Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants? Breast Cancer Res. 9, R82 (2007).
41. Carette, J. E. et al. Ebola virus entry requires the cholesterol transporter Niemann–Pick C1. Nature 477, 340–343 (2011).
42. Walsh, T. et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc. Natl Acad. Sci. USA 107, 12629–12633 (2010).
43. Hsu, P. D. et al. DNA targeting specificity of RNA-guided Cas9 nucleases. Nat. Biotechnol. 31, 827–832 (2013).
44. Doench, J. G. et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR–Cas9. Nat. Biotechnol. 34, 184–191 (2016).
45. Colombo, M. et al. Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium. Hum. Mol. Genet. 23, 3666–3680 (2014).
46. Romero, A. et al. BRCA1 alternative splicing landscape in breast tissue samples. BMC Cancer 15, 219 (2015).
47. Tavtigian, S. V. et al. Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J. Med. Genet. 43, 295–305 (2006).
48. Kumar, P., Henikoff, S. & Ng, P. C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073–1081 (2009).
49. Adzhubei, I. & Jordan, D. M. Predicting functional effect of human missense mutations using PolyPhen-2. Curr. Protoc. Hum. Gen. 76, 7.20.1–7.20.41 (2013).