Abstract
Background Germline mutations in the BRCA1 and BRCA2 tumour-suppressor genes predispose to early-onset breast and ovarian cancer. Although both genes display a highly heterogeneous mutation spectrum, a number of alterations recur in some populations. Only a limited number of founder mutations have been identified in the Italian population so far. Objective To investigate the spectrum of BRCA1/BRCA2 mutations in a set of families originary from the Central–Eastern part of Tuscany and to ascertain the presence of founder effects. We also wanted to approximate the age of the most frequent BRCA1 founder mutation. Results Overall, four distinct BRCA1 mutations accounted for a large fraction (72.7%) of BRCA1-attributable hereditary breast/ovarian cancer in families originary from this area. We identified common haplotypes for two newly recognised recurrent BRCA1 mutations, c.3228_3229delAG and c.3285delA. The c.3228_3229delAG mutation was estimated to have originated about 129 generations ago. Interestingly, male breast cancer cases were present in 3 out of 11 families with the c.3228_3229delAG mutation. Conclusions The observation that a high proportion of families with BRCA1 alterations from Central–Eastern Tuscany harbours a limited number of founder mutations can have significant impact on clinical management of at risk subjects from this area. In addition, the identification of a large set of families carrying an identical mutation that predisposes to breast and ovarian cancer provides unique opportunities to study the effect of other genetic and environmental factors on penetrance and disease phenotype.
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Ferla R, Calò V, Cascio S et al (2007) Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol 18(Suppl 6):vi93–vi98. doi:10.1093/annonc/mdm234
Baudi F, Quaresima B, Grandinetti C et al (2001) Evidence of a founder mutation of BRCA1 in a highly homogeneous population from Southern Italy with breast/ovarian cancer. Hum Mutat 18:163–164. doi:10.1002/humu.1167
Marroni F, Cipollini G, Peissel B et al (2008) Reconstructing the genealogy of a BRCA1 founder mutation by phylogenetic analysis. Ann Hum Genet 72:310–318. doi:10.1111/j.1469-1809.2007.00420.x
Malacrida S, Agata S, Callegaro M et al (2008) BRCA1 p.Val1688del is a deleterious mutation that recurs in breast and ovarian cancer families from Northeast Italy. J Clin Oncol 26:26–31. doi:10.1200/JCO.2007.13.2118
Pisano M, Cossu A, Persico I et al (2000) Identification of a founder BRCA2 mutation in Sardinia. Br J Cancer 82:553–559. doi:10.1054/bjoc.1999.0963
Monne M, Piras G, Fancello P et al (2007) Identification of a founder BRCA2 mutation in Sardinian breast cancer families. Fam Cancer 6:73–79. doi:10.1007/s10689-006-9107-7
Berry DA, Iversen ES Jr, Gudbjartsson DF et al (2002) BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 20:2701–2712. doi:10.1200/JCO.2002.05.121
Ottini L, Rizzolo P, Zanna I et al (2008) BRCA1/BRCA2 mutation status and clinical-pathologic features of 108 male breast cancer cases from Tuscany: a population-based study in Central Italy. Breast Cancer Res Treat. doi:10.1007/s10549-008-0194-z
Reeve JP, Rannala B (2002) DMLE+: Bayesian linkage disequilibrium gene mapping. Bioinformatics 18:894–895. doi:10.1093/bioinformatics/18.6.894
Rannala B, Reeve JP (2001) High-resolution multipoint linkage-disequilibrium mapping in the context of a human genome sequence. Am J Hum Genet 69:159–178. doi:10.1086/321279
Bergman A, Einbeigi Z, Olofsson U et al (2001) The western Swedish BRCA1 founder mutation 3171ins5; a 3.7cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation. Eur J Hum Genet 9:787–793. doi:10.1038/sj.ejhg.5200704
Beloch KJ (1995) Storia della popolazione d’Italia. In: Del Panta L, Sonnino E (eds) Le Lettere, Firenze, pp xxxii, 695
Ford D, Easton DF, Peto J (1995) Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet 57:1457–1462
Whittemore AS, Gong G, Itnyre J (1997) Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: results from three US population-based case-control studies of ovarian cancer. Am J Hum Genet 60:496–504
Risch HA, McLaughlin JR, Cole DE et al (2006) Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98:1694–1706
Whittemore AS, Gong G, John EM et al (2004) Prevalence of BRCA1 mutation carriers among US non-Hispanic whites. Cancer Epidemiol Biomarkers Prev 13:2078–2083
Antoniou AC, Pharoah PD, McMullan G et al (2002) A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 86:76–83. doi:10.1038/sj.bjc.6600008
Bonatti F, Pepe C, Tancredi M et al (2006) RNA-based analysis of BRCA1 and BRCA2 gene alterations. Cancer Genet Cytogenet 170:93–101. doi:10.1016/j.cancergencyto.2006.05.005
Ottini L, Masala G, D’Amico C et al (2003) BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. Cancer Res 63:342–347
Slatkin M, Rannala B (2000) Estimating allele age. Annu Rev Genomics Hum Genet 1:225–249. doi:10.1146/annurev.genom.1.1.225
Easton DF, Steele L, Fields P et al (1997) Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12–13. Am J Hum Genet 61:120–128. doi:10.1086/513891
Tai YC, Domchek S, Parmigiani G et al (2007) Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 99:1811–1814. doi:10.1093/jnci/djm203
Friedman LS, Gayther SA, Kurosaki T et al (1997) Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population. Am J Hum Genet 60:313–319
Csokay B, Udvarhelyi N, Sulyok Z et al (1997) High frequency of germ-line BRCA2 mutations among Hungarian male breast cancer patients without family history. Cancer Res 59:995–998
Evans DG, Bulman M, Young K et al (2008) BRCA1/2 mutation analysis in male breast cancer families from North West England. Fam Cancer 7:113–117. doi:10.1007/s10689-007-9153-9
Brose MS, Rebbeck TR, Calzone KA et al (2002) Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 94:1365–1372
Anagnostopoulos T, Pertesi M, Konstantopoulou I et al (2008) G1738R is a BRCA1 founder mutation in Greek breast/ovarian cancer patients: evaluation of its pathogenicity and inferences on its genealogical history. Breast Cancer Res Treat 110:377–385. doi:10.1007/s10549-007-9729-y
Sarantaus L, Huusko P, Eerola H et al (2000) Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland. Eur J Hum Genet 8:757–763. doi:10.1038/sj.ejhg.5200529
Peelen T, van Vliet M, Petrij-Bosch A et al (1997) A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am J Hum Genet 60:1041–1049
Neuhausen SL, Mazoyer S, Friedman L et al (1996) Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet 58:271–280
Machado PM, Brandão RD, Cavaco BM et al (2007) Screening for a BRCA2 rearrangement in high-risk breast/ovarian cancer families: evidence for a founder effect and analysis of the associated phenotypes. J Clin Oncol 25:2027–2034. doi:10.1200/JCO.2006.06.9443
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The study was supported by Regione Toscana in the frame of the High-Risk Cancer Family Project and from a grant of Ente Cassa di Risparmio, Firenze, Italy.
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Papi, L., Putignano, A.L., Congregati, C. et al. Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy. Breast Cancer Res Treat 117, 497–504 (2009). https://doi.org/10.1007/s10549-008-0190-3
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DOI: https://doi.org/10.1007/s10549-008-0190-3