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Br J Cancer. 2001 March; 84(5): 704–708.
PMCID: PMC2363799

A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families

Abstract

Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast and ovarian cancer. Our aim was to find associations between the clinical characteristics and positive mutation status in 148 breast cancer families in order to predict the probability of finding a BRCA mutation in a family. Several factors were associated with mutations in univariate analysis, whereas in multivariate analysis (logistic regression with backward selection) only the age of the youngest breast cancer patient and the number of ovarian cancer cases in a family were independent predictors of BRCA mutations. A logistic model was devised to estimate the probability for a family of harbouring a mutation in either BRCA1 or BRCA2. Altogether, 63 out of 148 families (43%) and 28 out of 29 (97%) mutation carrier families obtained probabilities over 10%. The mean probability was 55% for mutation-positive families and 11% for mutation-negative families. The models by Couch et al (1997) and Shattuck-Eidens et al (1997) previously designed for BRCA1 were also tested for their applicability to distinguish carrier families with mutations in either gene. The probability model should be a useful tool in genetic counselling and focusing the mutation analyses, and thus increasing also the cost-effectiveness of the genetic screening. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: breast cancer, ovarian cancer, BRCA1, BRCA 2, mutation, probability model

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Selected References

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  • Berry DA, Parmigiani G, Sanchez J, Schildkraut J, Winer E. Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst. 1997 Feb 5;89(3):227–238. [PubMed]
  • Chang-Claude J, Becher H, Caligo M, Eccles D, Evans G, Haites N, Hodgson S, Møller P, Weber BH, Stoppa-Lyonnet D. Risk estimation as a decision-making tool for genetic analysis of the breast cancer susceptibility genes. EC Demonstration Project on Familial Breast Cancer. Dis Markers. 1999 Oct;15(1-3):53–65. [PubMed]
  • Couch FJ, DeShano ML, Blackwood MA, Calzone K, Stopfer J, Campeau L, Ganguly A, Rebbeck T, Weber BL. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med. 1997 May 15;336(20):1409–1415. [PubMed]
  • Eerola H, Blomqvist C, Pukkala E, Pyrhönen S, Nevanlinna H. Familial breast cancer in southern Finland: how prevalent are breast cancer families and can we trust the family history reported by patients? Eur J Cancer. 2000 Jun;36(9):1143–1148. [PubMed]
  • Fodor FH, Weston A, Bleiweiss IJ, McCurdy LD, Walsh MM, Tartter PI, Brower ST, Eng CM. Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am J Hum Genet. 1998 Jul;63(1):45–51. [PubMed]
  • Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998 Mar;62(3):676–689. [PubMed]
  • Foulkes WD, Brunet JS, Warner E, Goodwin PJ, Meschino W, Narod SA, Goss PE, Glendon G. The importance of a family history of breast cancer in predicting the presence of a BRCA mutation. Am J Hum Genet. 1999 Dec;65(6):1776–1779. [PubMed]
  • Friedman LS, Szabo CI, Ostermeyer EA, Dowd P, Butler L, Park T, Lee MK, Goode EL, Rowell SE, King MC. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. Am J Hum Genet. 1995 Dec;57(6):1284–1297. [PubMed]
  • Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BA, Stratton MR, Easton D. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet. 1997 Jan;15(1):103–105. [PubMed]
  • Goelen G, Teugels E, Bonduelle M, Neyns B, De Grève J. High frequency of BRCA1/2 germline mutations in 42 Belgian families with a small number of symptomatic subjects. J Med Genet. 1999 Apr;36(4):304–308. [PMC free article] [PubMed]
  • Håkansson S, Johannsson O, Johansson U, Sellberg G, Loman N, Gerdes AM, Holmberg E, Dahl N, Pandis N, Kristoffersson U, et al. Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer. Am J Hum Genet. 1997 May;60(5):1068–1078. [PubMed]
  • Hodgson SV, Heap E, Cameron J, Ellis D, Mathew CG, Eeles RA, Solomon E, Lewis CM. Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer. J Med Genet. 1999 May;36(5):369–373. [PMC free article] [PubMed]
  • Hogervorst FB, Cornelis RS, Bout M, van Vliet M, Oosterwijk JC, Olmer R, Bakker B, Klijn JG, Vasen HF, Meijers-Heijboer H, et al. Rapid detection of BRCA1 mutations by the protein truncation test. Nat Genet. 1995 Jun;10(2):208–212. [PubMed]
  • Hopper JL, Jenkins MA. Modeling the probability that Ashkenazi Jewish women carry a founder mutation in BRCA1 or BRCA2. Am J Hum Genet. 1999 Dec;65(6):1771–1776. [PubMed]
  • Hopper JL, Southey MC, Dite GS, Jolley DJ, Giles GG, McCredie MR, Easton DF, Venter DJ. Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol Biomarkers Prev. 1999 Sep;8(9):741–747. [PubMed]
  • Huusko P, Päkkönen K, Launonen V, Pöyhönen M, Blanco G, Kauppila A, Puistola U, Kiviniemi H, Kujala M, Leisti J, et al. Evidence of founder mutations in Finnish BRCA1 and BRCA2 families. Am J Hum Genet. 1998 Jun;62(6):1544–1548. [PubMed]
  • Kainu T, Juo SH, Desper R, Schaffer AA, Gillanders E, Rozenblum E, Freas-Lutz D, Weaver D, Stephan D, Bailey-Wilson J, et al. Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9603–9608. [PubMed]
  • Ligtenberg MJ, Hogervorst FB, Willems HW, Arts PJ, Brink G, Hageman S, Bosgoed EA, Van der Looij E, Rookus MA, Devilee P, et al. Characteristics of small breast and/or ovarian cancer families with germline mutations in BRCA1 and BRCA2. Br J Cancer. 1999 Mar;79(9-10):1475–1478. [PMC free article] [PubMed]
  • Malone KE, Daling JR, Thompson JD, O'Brien CA, Francisco LV, Ostrander EA. BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history. JAMA. 1998 Mar 25;279(12):922–929. [PubMed]
  • Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet. 1998 Jan;62(1):145–158. [PubMed]
  • Peelen T, van Vliet M, Petrij-Bosch A, Mieremet R, Szabo C, van den Ouweland AM, Hogervorst F, Brohet R, Ligtenberg MJ, Teugels E, et al. 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. 1997 May;60(5):1041–1049. [PubMed]
  • Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, Easton DF, Evans C, Deacon J, Stratton MR. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst. 1999 Jun 2;91(11):943–949. [PubMed]
  • Rebbeck TR, Couch FJ, Kant J, Calzone K, DeShano M, Peng Y, Chen K, Garber JE, Weber BL. Genetic heterogeneity in hereditary breast cancer: role of BRCA1 and BRCA2. Am J Hum Genet. 1996 Sep;59(3):547–553. [PubMed]
  • Sarantaus L, Huusko P, Eerola H, Launonen V, Vehmanen P, Rapakko K, Gillanders E, Syrjäkoski K, Kainu T, Vahteristo P, et al. Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland. Eur J Hum Genet. 2000 Oct;8(10):757–763. [PubMed]
  • Serova OM, Mazoyer S, Puget N, Dubois V, Tonin P, Shugart YY, Goldgar D, Narod SA, Lynch HT, Lenoir GM. Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes? Am J Hum Genet. 1997 Mar;60(3):486–495. [PubMed]
  • Shattuck-Eidens D, Oliphant A, McClure M, McBride C, Gupte J, Rubano T, Pruss D, Tavtigian SV, Teng DH, Adey N, et al. BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA. 1997 Oct 15;278(15):1242–1250. [PubMed]
  • Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997 May 15;336(20):1401–1408. [PubMed]
  • Syrjäkoski K, Vahteristo P, Eerola H, Tamminen A, Kivinummi K, Sarantaus L, Holli K, Blomqvist C, Kallioniemi OP, Kainu T, et al. Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients. J Natl Cancer Inst. 2000 Sep 20;92(18):1529–1531. [PubMed]
  • Szabo CI, King MC. Population genetics of BRCA1 and BRCA2. Am J Hum Genet. 1997 May;60(5):1013–1020. [PubMed]
  • Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Wacholder S, Tulinius H, Eyfjörd JE. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet. 1998 Oct 24;352(9137):1337–1339. [PubMed]
  • Vehmanen P, Friedman LS, Eerola H, Sarantaus L, Pyrhönen S, Ponder BA, Muhonen T, Nevanlinna H. A low proportion of BRCA2 mutations in Finnish breast cancer families. Am J Hum Genet. 1997 May;60(5):1050–1058. [PubMed]
  • Vehmanen P, Friedman LS, Eerola H, McClure M, Ward B, Sarantaus L, Kainu T, Syrjäkoski K, Pyrhönen S, Kallioniemi OP, et al. Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes. Hum Mol Genet. 1997 Dec;6(13):2309–2315. [PubMed]
  • Warner E, Foulkes W, Goodwin P, Meschino W, Blondal J, Paterson C, Ozcelik H, Goss P, Allingham-Hawkins D, Hamel N, et al. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst. 1999 Jul 21;91(14):1241–1247. [PubMed]

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