Analysis of BRCA1/BRCA2 genes' contribution to breast cancer susceptibility in high risk Jewish Ashkenazi women.
BACKGROUND
Three mutations in BRCA1 (185delAG 5382InsC) and BRCA2 (6174delT) can be detected in a substantial proportion of Jewish Ashkenazi breast/ovarian cancer families. Family-specific pathogenic mutations in both genes can be detected in up to 5% of high risk Ashkenazim. The contribution of major gene rearrangements and seemingly pathogenic missense mutations to inherited breast cancer predisposition has never been systematically evaluated in Ashkenazim.


METHODS
High risk, Jewish Ashkenazi women, non-carriers of the predominant Jewish BRCA1/BRCA2 mutations, were genotyped for major gene rearrangements in BRCA1/BRCA2 using Multiplex ligation-dependent probe amplification (MLPA), and for the occurrence rate of 6 seemingly pathogenic missense mutations in BRCA1 (R866C, R331S, R841W, Y179C, C61G, M1008I) using a modified restriction enzyme assay.


RESULTS
Overall, 105 Jewish Ashkenazi high risk women, participated in the study: 104 with breast cancer [age at diagnosis (mean +/- SD) 51.05 +/- 11.13 years], one was affected with ovarian cancer (61 years). Two were found to carry the M1008I mutation in BRCA1 and none harbored any of the other missense mutations. MLPA reveled four changes (amplifications of exons 5, 17, 19 and 21) in BRCA1 in five patients, and six patients exhibited 4 MLPA-detectable abnormalities in BRCA2 (amplifications in exons 1b, 2, and deletions in exons 11a and 25). None of these abnormalities could be confirmed using quantitative PCR (qPCR) analysis.


CONCLUSIONS
Major gene rearrangements involving BRCA1 BRCA2 contribute little to the burden of inherited predisposition of breast cancer in Ashkenazi Jews.
Distelman-Menachem
Tal
T
Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Shapira
Tal
T
Laitman
Yael
Y
Kaufman
Bella
B
Barak
Frida
F
Tavtigian
Sean
S
Friedman
Eitan
E
D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1 / Q000502:physiology*; D024522:Genes, BRCA2 / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007585:Jews / Q000235:genetics*; D008297:Male; D009363:Neoplasm Proteins; D010051:Ovarian Neoplasms / Q000235:genetics
D024682:BRCA2 Protein; D009363:Neoplasm Proteins
Clin Chem. 2006 Aug;52(8):1480-5
16793929
BMC Cancer. 2004 Sep 07;4:61
15353005
Nat Genet. 1997 Nov;17(3):341-5
9354803
Genes Chromosomes Cancer. 2001 May;31(1):75-84
11284038
Breast Cancer Res Treat. 2007 May;103(1):103-7
17063271
Cancer Genet Cytogenet. 2006 Jul 15;168(2):168-71
16843109
Breast Cancer Res Treat. 2008 Jun;109(3):581-3
17661172
Am J Hum Genet. 2003 May;72(5):1117-30
12677558
Genet Test. 2006 Summer;10(2):104-15
16792513
Hum Mol Genet. 1997 Sep;6(9):1513-7
9285788
Clin Genet. 2007 Apr;71(4):331-42
17470134
Am J Hum Genet. 2002 Apr;70(4):858-65
11880951
Nucleic Acids Res. 2002 Jun 15;30(12):e57
12060695
Cancer Res. 2005 Nov 1;65(21):10096-103
16267036
J Med Genet. 2005 May;42(5):e31
15863663
Cancer Res. 1999 Jan 15;59(2):455-61
9927062
Breast Cancer Res Treat. 2008 Feb;107(3):455-7
17458694
Cancer Res. 1997 Mar 1;57(5):828-31
9041180
Hum Mol Genet. 2003 May 1;12(9):1055-61
12700174
Br J Cancer. 2004 Sep 13;91(6):1155-9
15475941
Cancer Res. 2003 Apr 1;63(7):1449-53
12670888
J Med Genet. 2006 Apr;43(4):295-305
16014699
Genome Res. 1996 Nov;6(11):1029-49
8938427
Breast Cancer Res Treat. 2008 Nov;112(2):353-8
18176857
J Med Genet. 2002 Nov;39(11):817-21
12414821
Eur J Cancer. 2007 Jan;43(2):443-53
17174087
J Med Genet. 2005 Oct;42(10):e64
16199546
J Med Genet. 2002 Aug;39(8):611-4
12161607
Oncogene. 2002 Oct 3;21(44):6841-7
12360411
BMC Med Genet. 2007 Jun 11;8:32
17561994
Am J Hum Genet. 2004 Oct;75(4):535-44
15290653
J Pathol. 2007 Sep;213(1):46-55
17668415
Hum Mutat. 2007 Dec;28(12):1207-15
17688236
Cancer Detect Prev. 2006;30(6):530-4
17113724
Hum Mol Genet. 1996 Jun;5(6):835-42
8776600
Breast Cancer Res Treat. 2007 Dec;106(2):297-304
17972177
Hum Mutat. 2004 Dec;24(6):534
15532023
Oncol Rep. 2008 Jan;19(1):263-8
18097605
J Biol Chem. 1998 Apr 3;273(14):7795-9
9525870
Science. 2003 Oct 24;302(5645):643-6
14576434
J Clin Oncol. 2005 Jan 10;23(2):276-92
15637391
Cancer Res. 2004 Nov 15;64(22):8143-7
15548676
Genes Chromosomes Cancer. 2001 May;31(1):91-5
11284040
Hum Mutat. 2008 Apr;29(4):555-64
18330910