title: BRCA1 And BRCA2 analysis of Argentinean breast/ovarian cancer patients selected for age and family history highlights a role for novel mutations of putative south-American origin.
abstract: BACKGROUND
  The spectrum of BRCA1/2 genetic variation in breast-ovarian cancer patients has been scarcely investigated outside Europe and North America, with few reports for South America, where Amerindian founder effects and recent multiracial immigration are predicted to result in high genetic diversity. We describe here the results of BRCA1/BRCA2 germline analysis in an Argentinean series of breast/ovarian cancer patients selected for young age at diagnosis or breast/ovarian cancer family history.
  
  
  METHODS
  The study series (134 patients) included 37 cases diagnosed within 40 years of age and no family history (any ethnicity, fully-sequenced), and 97 cases with at least 2 affected relatives (any age), of which 57 were non-Ashkenazi (fully-sequenced) and 40 Ashkenazi (tested only for the founder mutations c.66_67delAG and c.5263insC in BRCA1 and c.5946delT in BRCA2).
  
  
  CONCLUSIONS
  We found 24 deleterious mutations (BRCA1:16; BRCA2: 8) in 38/134 (28.3%) patients, of which 6/37 (16.2%) within the young age group, 15/57 (26.3%) within the non-Ahkenazi positive for family history; and 17/40 (42.5%) within the Ashkenazi. Seven pathogenetic mutations were novel, five in BRCA1: c.1502_1505delAATT, c.2626_2627delAA c.2686delA, c.2728 C > T, c.3758_3759delCT, two in BRCA2: c.7105insA, c.793 + 1delG. We also detected 72 variants of which 54 previously reported and 17 novel, 33 detected in an individual patient. Four missense variants of unknown clinical significance, identified in 5 patients, are predicted to affect protein function. While global and European variants contributed near 45% of the detected BRCA1/2 variation, the significant fraction of new variants (25/96, 26%) suggests the presence of a South American genetic component. This study, the first conducted in Argentinean patients, highlights a significant impact of novel BRCA1/2 mutations and genetic variants, which may be regarded as putatively South American, and confirms the important role of founder BRCA1 and BRCA2 mutations in Argentinean Ashkenazi Jews.
authors: Laboratorio HRDC, INBIOMED-CONICET, Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155 Piso 5, (C1121ABG) Buenos Aires, Argentina ; Centro de Estudios Médicos e Investigaciones Clínicas, Galván 4102, (C1431FWO) Buenos Aires, Argentina.
authors: Angela Rosaria
authors: AR
authors: Solano
authors: Gitana Maria
authors: GM
authors: Aceto
authors: Dreanina
authors: D
authors: Delettieres
authors: Serena
authors: S
authors: Veschi
authors: Maria Isabel
authors: MI
authors: Neuman
authors: Eduardo
authors: E
authors: Alonso
authors: Sergio
authors: S
authors: Chialina
authors: Reinaldo Daniel
authors: RD
authors: Chacón
authors: Mariani-Costantini
authors: MC
authors: Renato
authors: Ernesto Jorge
authors: EJ
authors: Podestá
keywords: Argentina, early onset breast cancer; Ashkenazi; BRCA1/BRCA2; Ethnicity; Familial breast cancer; Genetic variants; Germline mutations
references: Breast Cancer Res Treat. 2007 Jul;103(3):349-53
references: 17063270
references: Nat Rev Clin Oncol. 2010 Nov;7(11):611
references: 21049572
references: J Clin Oncol. 2001 Sep 15;19(18 Suppl):118S-124S
references: 11560986
references: Eur J Hum Genet. 2002 Jun;10(6):395-7
references: 12080393
references: Clin Genet. 2011 Jul;80(1):89-92
references: 20950396
references: Nucleic Acids Res. 2006 Mar 06;34(5):1317-25
references: 16522644
references: Cancer Res. 2004 Jun 1;64(11):3790-7
references: 15172985
references: Br J Cancer. 2010 Mar 30;102(7):1091-8
references: 20234365
references: J Clin Oncol. 2010 Sep 20;28(27):4214-20
references: 20733129
references: Hum Mutat. 2002 Dec;20(6):474
references: 12442274
references: Cancer Res. 2010 Jun 15;70(12):4880-90
references: 20516115
references: BMC Cancer. 2008 May 20;8:140
references: 18489799
references: BMC Cancer. 2008 Jul 29;8:214
references: 18662409
references: Cancer Res. 2005 Nov 1;65(21):10096-103
references: 16267036
references: Breast Cancer Res. 2002;4(5):179-81
references: 12223120
references: Hum Mutat. 2001 Jun;17(6):520-1
references: 11385711
references: Fam Cancer. 2004;3(3-4):201-6
references: 15516842
references: Nature. 2010 Sep 2;467(7311):52-8
references: 20811451
references: J Clin Oncol. 2002 Mar 15;20(6):1480-90
references: 11896095
references: N Engl J Med. 2010 Mar 18;362(11):986-93
references: 20237344
references: Int J Cancer. 2003 Sep 10;106(4):588-93
references: 12845657
references: Thyroid. 2005 Jul;15(7):668-71
references: 16053382
references: Cancer Epidemiol Biomarkers Prev. 2005 Jul;14(7):1666-71
references: 16030099
references: Breast Cancer Res Treat. 2007 Jun;103(2):225-32
references: 17080309
references: Br J Cancer. 2004 Mar 22;90(6):1244-51
references: 15026808
references: Am J Hum Genet. 1997 May;60(5):1059-67
references: 9150153
references: J Med Genet. 2006 Apr;43(4):295-305
references: 16014699
references: Hum Mutat. 2002 Apr;19(4):460
references: 11933205
references: Nat Rev Clin Oncol. 2010 Dec;7(12):702-7
references: 20956982
references: Nat Med. 1996 Nov;2(11):1179-83
references: 8898735
references: Nature. 1995 Dec 21-28;378(6559):789-92
references: 8524414
references: Cancer Genet Cytogenet. 2006 Apr 1;166(1):36-45
references: 16616110
references: Electrophoresis. 1999 Jun;20(8):1733-9
references: 10435440
references: Nat Rev Clin Oncol. 2010 Dec;7(12):708-17
references: 21060331
references: J Natl Cancer Inst. 2003 Oct 15;95(20):1548-51
references: 14559878
references: Eur J Gynaecol Oncol. 2009;30(5):527-30
references: 19899408
references: Breast Cancer Res Treat. 2006 Jan;95(1):81-7
references: 16261400
references: Breast Cancer Res Treat. 2011 Jul;128(1):211-8
references: 21190077
references: PLoS Genet. 2008 Mar 21;4(3):e1000037
references: 18369456
references: Breast Cancer (Auckl). 2011;5:175-99
references: 21863131
references: Eur J Hum Genet. 2011 Mar;19(3):300-6
references: 21119707
references: Breast Cancer Res Treat. 2011 Apr;126(3):705-16
references: 20859677
references: Cancer. 1996 Jun 1;77(11):2318-24
references: 8635102
references: Genome Res. 2002 Mar;12(3):436-46
references: 11875032
references: Am J Hum Genet. 2004 Oct;75(4):535-44
references: 15290653
references: BMC Med Genet. 2006 Jan 20;7:5
references: 16426447
references: PLoS One. 2008 Apr 23;3(4):e2024
references: 18431501
references: Cancer Epidemiol Biomarkers Prev. 2007 Aug;16(8):1615-20
references: 17646271
references: Science. 1994 Oct 7;266(5182):66-71
references: 7545954
references: Curr Opin Obstet Gynecol. 2010 Feb;22(1):72-8
references: 19841585
references: Am J Hum Genet. 1997 Mar;60(3):505-14
references: 9042909
references: J Clin Oncol. 2008 Apr 1;26(10):1657-63
references: 18375895
references: N Engl J Med. 1996 Jan 18;334(3):137-42
references: 8531967
references: Hum Mutat. 2004 May;23(5):523-4
references: 15108288
references: Breast Cancer Res Treat. 2010 Aug;122(3):671-83
references: 19851859
references: Fam Cancer. 2012 Mar;11(1):57-67
references: 21918854