Pathogenicity Evaluation of BRCA1 and BRCA2 Unclassified Variants Identified in Portuguese Breast/Ovarian Cancer Families

被引:24
作者
Santos, Catarina [1 ]
Peixoto, Ana [1 ]
Rocha, Patricia [1 ]
Pinto, Pedro [1 ]
Bizarro, Susana [1 ]
Pinheiro, Manuela [1 ]
Pinto, Carla [1 ]
Henrique, Rui [2 ,3 ]
Teixeira, Manuel R. [1 ,3 ]
机构
[1] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal
[2] Portuguese Oncol Inst, Dept Pathol, Oporto, Portugal
[3] Univ Porto, Biomed Sci Inst ICBAS, P-4100 Oporto, Portugal
关键词
UNKNOWN CLINICAL-SIGNIFICANCE; EXONIC SPLICING ENHANCERS; DNA-SEQUENCE VARIANTS; BREAST-CANCER; MISSENSE SUBSTITUTIONS; ACTIVATION DOMAIN; FUNCTIONAL ASSAYS; HIGH PROPORTION; MUTATIONS; CLASSIFICATION;
D O I
10.1016/j.jmoldx.2014.01.005
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Hereditary breast/ovarian cancer syndrome is caused by germline deleterious mutations in BRCA1 and BRCA2. A major problem of genetic testing and counseling is the finding of variants of uncertain significance (VUS). We sought to ascertain the pathogenicity of 25 BRCA1 and BRCA2 VUS identified in Portuguese families during genetic testing. We performed cosegregation analysis of VUS with cancer in families, evaluated their frequency in unaffected controls, and looked for loss of heterozygosity in tumors. In addition, three different bioinformatic algorithms were used (Interactive Biosoftware, ESEfinder, and PolyPhen). Finally, six VUS Located in exon-intron boundaries were analyzed by RT-PCR. We found that seven variants segregated with the disease, six variants co-occurred with a pathogenic mutation in the same gene, and four variants co-occurred with a deleterious mutation in the other BRCA gene. By RT-PCR, we observed that four variants (BRCA1 c.4484G>T, BRCA2 c.682-2A>C, BRCA2 c.8488-1G>A, and BRCA2 c.8954-5A>G) disrupted splicing. After the combined analysis, we were able to classify 4 splicing variants as pathogenic mutations, 16 variants as neutral, and 3 variants as polymorphisms; only 2 variants remained classified as VUS. This work highlights the contribution of DNA, RNA, and in silico data to assess the pathogenicity of BRCA1/2 VUS, which, in turn, allows more accurate genetic counseling and clinical management of the families carrying them.
引用
收藏
页码:324 / 334
页数:11
相关论文
共 45 条
  • [11] Insights into the molecular basis of human hereditary breast cancer from studies of the BRCA1 BRCT domain
    Glover, JNM
    [J]. FAMILIAL CANCER, 2006, 5 (01) : 89 - 93
  • [12] Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population
    Hofmann, W
    Scherneck, S
    Horn, D
    Paepke, S
    Grumann, M
    Wappenschmidt, B
    Kempe, A
    Friedl, W
    von der Groeben, C
    Schmutzler, RK
    Betz, B
    Goecke, TO
    Bodden-Heidrich, R
    Beckmann, MW
    Niederacher, D
    Krueger, M
    Schaefer, D
    Jordan, J
    von Minckwitz, G
    Arnemann, J
    Botz, J
    Bartram, CR
    Voigtländer, T
    Bastert, G
    Henningsen, P
    Arnold, NK
    Gross, E
    Schlegelberger, B
    Gerber, WD
    Kiechle, M
    Thamm, B
    Kraus, H
    Langanke, D
    Voigt, T
    Froster, UG
    Brandau, O
    Golla, A
    Vodermeier, A
    Nestle-Krämling, C
    Meindl, A
    Preisler-Adams, S
    Dwornic-zak, B
    Jebali, P
    Jakisch, C
    Horst, J
    Eberhardt, E
    Volm, T
    Bochum, S
    Tamulionyte, L
    Grill, HJ
    [J]. INTERNATIONAL JOURNAL OF CANCER, 2002, 97 (04) : 472 - 480
  • [13] Tumor Characteristics as an Analytic Tool for Classifying Genetic Variants of Uncertain Clinical Significance
    Hofstra, Robert M. W.
    Spurdle, Amanda B.
    Eccles, Diana
    Foulkes, William D.
    de Wind, Niels
    Hoogerbrugge, Nicoline
    Hogervors, Frans B. L.
    [J]. HUMAN MUTATION, 2008, 29 (11) : 1292 - 1303
  • [14] Biallelic inactivation of BRCA2 in Fanconi anemia
    Howlett, NG
    Taniguchi, T
    Olson, S
    Cox, B
    Waisfisz, Q
    de Die-Smulders, C
    Persky, N
    Grompe, M
    Joenje, H
    Pals, G
    Ikeda, H
    Fox, EA
    D'Andrea, AD
    [J]. SCIENCE, 2002, 297 (5581) : 606 - 609
  • [15] Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells
    Kawai, H
    Li, HC
    Chun, P
    Avraham, S
    Avraham, HK
    [J]. ONCOGENE, 2002, 21 (50) : 7730 - 7739
  • [16] Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2
    King, MC
    Marks, JH
    Mandell, JB
    [J]. SCIENCE, 2003, 302 (5645) : 643 - 646
  • [17] BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients
    Kote-Jarai, Z.
    Leongamornlert, D.
    Saunders, E.
    Tymrakiewicz, M.
    Castro, E.
    Mahmud, N.
    Guy, M.
    Edwards, S.
    O'Brien, L.
    Sawyer, E.
    Hall, A.
    Wilkinson, R.
    Dadaev, T.
    Goh, C.
    Easton, D.
    Goldgar, D.
    Eeles, R.
    [J]. BRITISH JOURNAL OF CANCER, 2011, 105 (08) : 1230 - 1234
  • [18] Kwiatkowska E, 2001, HUM MUTAT, V17, DOI 10.1002/1098-1004(2001)17:1<73::AID-HUMU12>3.3.CO
  • [19] 2-F
  • [20] Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?
    Lovelock, Paul K.
    Spurdle, Amanda B.
    Mok, Myth T. S.
    Farrugia, Daniel J.
    Lakhani, Sunil R.
    Healey, Sue
    Arnold, Stephen
    Buchanan, Daniel
    Couch, Fergus J.
    Henderson, Beric R.
    Goldgar, David E.
    Tavtigian, Sean V.
    Chenevix-Trench, Georgia
    Brown, Melissa A.
    [J]. BREAST CANCER RESEARCH, 2007, 9 (06):