Analysis of 30 Putative BRCA1 Splicing Mutations in Hereditary Breast and Ovarian Cancer Families Identifies Exonic Splice Site Mutations That Escape In Silico Prediction

PLoS ONE

Volumn 7, Issue 12, 2012, Pages

  Wappenschmidt, Barbara ^a,b   Becker, Alexandra A ^a,b   Hauke, Jan ^a,b   Weber, Ute ^a,b   Engert, Stefanie ^c   Köhler, Juliane ^a,b   Kast, Karin ^d   Arnold, Norbert ^e   Rhiem, Kerstin ^a,b   Hahnen, Eric ^a,b   Meindl, Alfons ^c   Schmutzler, Rita K ^a,b  

^a UNIVERSITY HOSPITAL OF COLOGNE   (Germany)

^b UNIVERSITY OF COLOGNE   (Germany)

^c TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^d DRESDEN UNIVERSITY OF TECHNOLOGY   (Germany)

^e UNIVERSITY OF KIEL   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

MESSENGER RNA;

ACCURACY; ALGORITHM; AMINO ACID SUBSTITUTION; ARTICLE; BIOINFORMATICS; BREAST CANCER; COHORT ANALYSIS; COMPUTER MODEL; COMPUTER PREDICTION; CONTROLLED STUDY; EXON; EXONIC SPLICE SITE MUTATION; EXONIC VARIANT; FAMILIAL CANCER; FEMALE; GENE MUTATION; GENE SEQUENCE; GENETIC ANALYSIS; GENETIC VARIABILITY; HUMAN; HUMAN CELL; IN VITRO STUDY; INTRON; INTRONIC VARIANT; LEUKOCYTE; MISSENSE MUTATION; MUTATIONAL ANALYSIS; ONCOGENE; OVARY CANCER; PRE MRNA PROCESSING; RNA PROCESSING; RNA SPLICING;

ALTERNATIVE SPLICING; BRCA1 PROTEIN; BRCA2 PROTEIN; BREAST NEOPLASMS; COMPUTER SIMULATION; EXONS; FEMALE; HUMANS; INTRONS; MUTATION; OVARIAN NEOPLASMS; RNA PRECURSORS; RNA SPLICE SITES;

EID: 84871137013     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0050800     Document Type: Article

References (49)

1. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, et al. (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66-71.
2. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, et al. (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378: 789-792.
3. Schwartz GF, Hughes KS, Lynch HT, Fabian CJ, Fentiman IS, et al. (2008) Proceedings of the international consensus conference on breast cancer risk, genetics, & risk management, April, 2007. Cancer 113: 2627-2637.
4. Thery JC, Krieger S, Gaildrat P, Revillion F, Buisine MP, et al. (2011) Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes. Eur J Hum Genet 19: 1052-1058.
5. Raponi M, Kralovicova J, Copson E, Divina P, Eccles D, et al. (2011) Prediction of single-nucleotide substitutions that result in exon skipping: identification of a splicing silencer in BRCA1 exon 6. Hum Mutat 32: 436-444.
6. Gaildrat P, Krieger S, Thery JC, Killian A, Rousselin A, et al. (2010) The BRCA1 c.5434C->G (p.Pro1812Ala) variant induces a deleterious exon 23 skipping by affecting exonic splicing regulatory elements. J Med Genet 47: 398-403.
7. Bonnet C, Krieger S, Vezain M, Rousselin A, Tournier I, et al. (2008) Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene. J Med Genet 45: 438-446.
8. Anczukow O, Buisson M, Salles MJ, Triboulet S, Longy M, et al. (2008) Unclassified variants identified in BRCA1 exon 11: Consequences on splicing. Genes Chromosomes Cancer 47: 418-426.
9. Whiley PJ, Guidugli L, Walker LC, Healey S, Thompson BA, et al. (2011) Splicing and multifactorial analysis of intronic BRCA1 and BRCA2 sequence variants identifies clinically significant splicing aberrations up to 12 nucleotides from the intron/exon boundary. Hum Mutat 32: 678-687.
10. Thomassen M, Blanco A, Montagna M, Hansen TV, Pedersen IS, et al. (2012) Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members. Breast Cancer Res Treat 132: 1009-1023.
11. Krawczak M, Reiss J, Cooper DN, (1992) The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 90: 41-54.
12. Wang GS, Cooper TA, (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 8: 749-761.
13. Cartegni L, Chew SL, Krainer AR, (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3: 285-298.
14. Walker LC, Whiley PJ, Couch FJ, Farrugia DJ, Healey S, et al. (2010) Detection of splicing aberrations caused by BRCA1 and BRCA2 sequence variants encoding missense substitutions: implications for prediction of pathogenicity. Hum Mutat 31: E1484-1505.
15. Yeo G, Burge CB, (2004) Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11: 377-394.
16. Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, et al. (2009) Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37: e67.
17. Miller SA, Dykes DD, Polesky HF, (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16: 1215.
18. Gross E, Arnold N, Pfeifer K, Bandick K, Kiechle M, (2000) Identification of specific BRCA1 and BRCA2 variants by DHPLC. Hum Mutat 16: 345-353.
19. Houdayer C, Dehainault C, Mattler C, Michaux D, Caux-Moncoutier V, et al. (2008) Evaluation of in silico splice tools for decision-making in molecular diagnosis. Hum Mutat 29: 975-982.
20. Claes K, Vandesompele J, Poppe B, Dahan K, Coene I, et al. (2002) Pathological splice mutations outside the invariant AG/GT splice sites of BRCA1 exon 5 increase alternative transcript levels in the 5′ end of the BRCA1 gene. Oncogene 21: 4171-4175.
21. Meindl A, (2002) Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer 97: 472-480.
22. Friedman LS, Szabo CI, Ostermeyer EA, Dowd P, Butler L, et al. (1995) Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. Am J Hum Genet 57: 1284-1297.
23. Diez O, Osorio A, Duran M, Martinez-Ferrandis JI, de la Hoya M, et al. (2003) Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. Hum Mutat 22: 301-312.
24. Evans DG, Bulman M, Young K, Gokhale D, Lalloo F, (2003) Sensitivity of BRCA1/2 mutation testing in 466 breast/ovarian cancer families. J Med Genet 40: e107.
25. Dong J, Chang-Claude J, Wu Y, Schumacher V, Debatin I, et al. (1998) A high proportion of mutations in the BRCA1 gene in German breast/ovarian cancer families with clustering of mutations in the 3′ third of the gene. Hum Genet 103: 154-161.
26. Kiechle M, Gross E, Schwarz-Boeger U, Pfisterer J, Jonat W, et al. (2000) Ten novel BRCA1 and BRCA2 mutations in breast and/or ovarian cancer families from northern Germany. Hum Mutat 16: 529-530.
27. Shattuck-Eidens D, Oliphant A, McClure M, McBride C, Gupte J, et al. (1997) BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. Jama 278: 1242-1250.
28. Kroiss R, Winkler V, Bikas D, Fleischmann E, Mainau C, et al. (2005) Younger birth cohort correlates with higher breast and ovarian cancer risk in European BRCA1 mutation carriers. Hum Mutat 26: 583-589.
29. Adem C, Reynolds C, Soderberg CL, Slezak JM, McDonnell SK, et al. (2003) Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers. Cancer 97: 1-11.
30. Lu M, Conzen SD, Cole CN, Arrick BA, (1996) Characterization of functional messenger RNA splice variants of BRCA1 expressed in nonmalignant and tumor-derived breast cells. Cancer Res 56: 4578-4581.
31. Scholl T, Pyne MT, Russo D, Ward BE, (1999) BRCA1 IVS16+6T->C is a deleterious mutation that creates an aberrant transcript by activating a cryptic splice donor site. Am J Med Genet 85: 113-116.
32. Vreeswijk MP, Kraan JN, van der Klift HM, Vink GR, Cornelisse CJ, et al. (2009) Intronic variants in BRCA1 and BRCA2 that affect RNA splicing can be reliably selected by splice-site prediction programs. Hum Mutat 30: 107-114.
33. Coupier I, Baldeyron C, Rousseau A, Mosseri V, Pages-Berhouet S, et al. (2004) Fidelity of DNA double-strand break repair in heterozygous cell lines harbouring BRCA1 missense mutations. Oncogene 23: 914-919.
34. Mirkovic N, Marti-Renom MA, Weber BL, Sali A, Monteiro AN, (2004) Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition. Cancer Res 64: 3790-3797.
35. Bergthorsson JT, Ejlertsen B, Olsen JH, Borg A, Nielsen KV, et al. (2001) BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age. J Med Genet 38: 361-368.
36. McKean-Cowdin R, Spencer Feigelson H, Xia LY, Pearce CL, Thomas DC, et al. (2005) BRCA1 variants in a family study of African-American and Latina women. Hum Genet 116: 497-506.
37. Dosil V, Tosar A, Canadas C, Perez-Segura P, Diaz-Rubio E, et al. (2010) Alternative splicing and molecular characterization of splice site variants: BRCA1 c.591C>T as a case study. Clin Chem 56: 53-61.
38. Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, et al. (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31: 55-59.
39. Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, et al. (2010) Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42: 410-414.
40. Takahashi H, Behbakht K, McGovern PE, Chiu HC, Couch FJ, et al. (1995) Mutation analysis of the BRCA1 gene in ovarian cancers. Cancer Res 55: 2998-3002.
41. Spurdle AB, Couch FJ, Hogervorst FB, Radice P, Sinilnikova OM, (2008) Prediction and assessment of splicing alterations: implications for clinical testing. Hum Mutat 29: 1304-1313.
42. Plon SE, Eccles DM, Easton D, Foulkes WD, Genuardi M, et al. (2008) Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 29: 1282-1291.
43. Whiley PJ, Pettigrew CA, Brewster BL, Walker LC, Spurdle AB, et al. (2010) Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts. BMC Med Genet 11: 80.
44. Pettigrew CA, Wayte N, Wronski A, Lovelock PK, Spurdle AB, et al. (2008) Colocalisation of predicted exonic splicing enhancers in BRCA2 with reported sequence variants. Breast Cancer Res Treat 110: 227-234.
45. Lastella P, Surdo NC, Resta N, Guanti G, Stella A, (2006) In silico and in vivo splicing analysis of MLH1 and MSH2 missense mutations shows exon- and tissue-specific effects. BMC Genomics 7: 243.
46. Zatkova A, Messiaen L, Vandenbroucke I, Wieser R, Fonatsch C, et al. (2004) Disruption of exonic splicing enhancer elements is the principal cause of exon skipping associated with seven nonsense or missense alleles of NF1. Hum Mutat 24: 491-501.
47. Scott CL, Jenkins MA, Southey MC, Davis TA, Leary JA, et al. (2003) Average age-specific cumulative risk of breast cancer according to type and site of germline mutations in BRCA1 and BRCA2 estimated from multiple-case breast cancer families attending Australian family cancer clinics. Hum Genet 112: 542-551.
48. Tesoriero AA, Wong EM, Jenkins MA, Hopper JL, Brown MA, et al. (2005) Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families. Hum Mutat 26: 495.
49. Spearman AD, Sweet K, Zhou XP, McLennan J, Couch FJ, et al. (2008) Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol 26: 5393-5400.