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01-02-2008 | Epidemiology

Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients

Authors: Irene Konstantopoulou, Theodore Rampias, Angela Ladopoulou, George Koutsodontis, Sophia Armaou, Theodore Anagnostopoulos, George Nikolopoulos, Smaragda Kamakari, George Nounesis, Antonis Stylianakis, Charisios Karanikiotis, Evangelia Razis, Helen Gogas, Antonios Keramopoulos, Vassiliki Gaki, Christos Markopoulos, Dimosthenis Skarlos, Nikos Pandis, Thalia Bei, Iordanis Arzimanoglou, George Fountzilas, Drakoulis Yannoukakos

Published in: Breast Cancer Research and Treatment | Issue 3/2008

Abstract

127 Greek breast/ovarian cancer families were screened for germline BRCA1/2 mutations by dHPLC followed by direct sequencing. Our results indicated 16 and 5 breast/ovarian cancer families bearing deleterious mutations in the BRCA1 and BRCA2 genes, respectively. Two novel BRCA2 germline mutations (G4X and 3783del10) are reported here for the first time. Subsequent compilation of our present findings with previously reported mutation data reveals that in a total of 287 Greek breast/ovarian cancer families, 46 and 13 carry a deleterious mutation in BRCA1 and BRCA2, respectively. It should be noted that two BRCA1 mutations, 5382insC and G1738R, both located in exon 20, account for 46% of the families found to carry a mutation. Based on our mutation analysis results, we propose here a hierarchical, cost-effective BRCA1/2 mutation screening protocol for individuals of Greek ethnic origin. The suggested protocol can impact on the clinical management of breast-ovarian cancer families on a national healthcare system level.

Walsh T, King MC (2007) Ten genes for inherited breast cancer. Cancer Cell 11:103–105PubMedCrossRef

Couch FJ (2004) Genetic epidemiology of BRCA1. Cancer Biol Ther 3:509–514PubMed

Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62:676–689PubMedCrossRef

Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–182PubMedCrossRef

Szabo CI, King MC (1997) Population genetics of BRCA1 and BRCA2. Am J Hum Genet 60:1013–1020PubMed

Neuhausen SL (1999) Ethnic differences in cancer risk resulting from genetic variation. Cancer 86:2575–2582PubMedCrossRef

Neuhausen SL, Mazoyer S, Friedman L, Stratton M, Offit K, Caligo A, Tomlinson G, Cannon-Albright L, Bishop T, Kelsell D, Solomon E, Weber B, Couch F, Struewing J, Tonin P, Durocher F, Narod S, Skolnick MH, Lenoir G, Serova O, Ponder B, Stoppa-Lyonnet D, Easton D, King MC, Goldgar DE (1996) Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet 58:271–280PubMed

Tonin P, Serova O, Lenoir G, Lynch H, Durocher F, Simard J, Morgan K, Narod S (1995) BRCA1 mutations in Ashkenazi Jewish women. Am J Hum Genet 57:189PubMed

Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV, Tulinius H, Ogmundsdottir HM, Eyfjord JE (1996) A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 13:117–119PubMedCrossRef

10.

Moller P, Heimdal K, Apold J, Fredriksen A, Borg A, Hovig E, Hagen A, Hagen B, Pedersen JC, Maehle L (2001) Genetic epidemiology of BRCA1 mutations in Norway. Eur J Cancer 37:2428–2434PubMedCrossRef

11.

Konstantopoulou I, Kroupis C, Ladopoulou A, Pantazidis A, Boumba D, Lianidou ES, Petersen MB, Florentin L, Chiotellis E, Nounesis G, Efstathiou E, Skarlos D, Tsionou C, Fountzilas G, Yannoukakos D (2000) BRCA1 mutation analysis in breast/ovarian cancer families from Greece. Hum Mutat 16:272–273PubMedCrossRef

12.

Armakolas A, Ladopoulou A, Konstantopoulou I, Pararas B, Gomatos IP, Kataki A, Konstadoulakis MM, Stathopoulos GP, Markopoulos C, Leandros E, Gogas I, Yannoukakos D, Androulakis G (2002) BRCA2 gene mutations in Greek patients with familial breast cancer. Hum Mutat 19:81–82PubMedCrossRef

13.

Ladopoulou A, Kroupis C, Konstantopoulou I, Ioannidou-Mouzaka L, Schofield AC, Pantazidis A, Armaou S, Tsiagas I, Lianidou E, Efstathiou E, Tsionou C, Panopoulos C, Mihalatos M, Nasioulas G, Skarlos D, Haites NE, Fountzilas G, Pandis N, Yannoukakos D (2002) Germ line BRCA1 & BRCA2 mutations in Greek breast/ovarian cancer families: 5382insC is the most frequent mutation observed. Cancer Lett 185:61–70PubMedCrossRef

14.

Belogianni I, Apessos A, Mihalatos M, Razi E, Labropoulos S, Petounis A, Gaki V, Keramopoulos A, Pandis N, Kyriacou K, Hadjisavvas A, Kosmidis P, Yannoukakos D, Nasioulas G (2004) Characterization of a novel large deletion and single point mutations in the BRCA1 gene in a Greek cohort of families with suspected hereditary breast cancer. BMC Cancer 4:61PubMedCrossRef

15.

Claes K, Poppe B, Coene I, Paepe AD, Messiaen L (2004) BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. Br J Cancer 90:1244–1251PubMedCrossRef

16.

Abkevich V, Zharkikh A, Deffenbaugh AM, Frank D, Chen Y, Shattuck D, Skolnick MH, Gutin A, Tavtigian SV (2004) Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet 41:492–507PubMedCrossRef

17.

Judkins T, Hendrickson BC, Deffenbaugh AM, Eliason K, Leclair B, Norton MJ, Ward BE, Pruss D, Scholl T (2005) Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. Cancer Res 65:10096–10103PubMedCrossRef

18.

Armaou S, Konstantopoulou I, Anagnostopoulos T, Razis E, Boukovinas I, Xenidis N, Fountzilas G, Yannoukakos D (2007) Novel genomic rearrangements in the BRCA1 gene detected in greek breast/ovarian cancer patients. Eur J Cancer 43:443–453PubMedCrossRef

19.

Ladopoulou A, Konstantopoulou I, Armaou S, Efstathiou E, Mihalatos M, Nasioulas G, Bardi G, Pandis N, Yannoukakos D, Athens (2002) A change in the last base of BRCA1 exon 23, 5586G → A, results in abnormal RNA splicing. Cancer Genet Cytogenet 134:175–177

20.

Kroupis C, Lianidou E, Goutas N, Ladopoulou A, Konstantopoulou I, Pantazidis A, Yannoukakos D, Efstathiou E, Vourlidis N, Tsionou C (2003) Atypical medullary breast carcinoma in a family carrying the 5382insC BRCA-1 mutation. Breast J 9:260–262PubMedCrossRef

21.

Rafnar T, Benediktsdottir KR, Eldon BJ, Gestsson T, Saemundsson H, Olafsson K, Salvarsdottir A, Steingrimsson E, Thorlacius S (2004) BRCA2, but not BRCA1, mutations account for familial ovarian cancer in Iceland: a population-based study. Eur J Cancer 40:2788–2793PubMedCrossRef

22.

Borg A, Dorum A, Heimdal K, Maehle L, Hovig E, Moller P (1999) BRCA1 1675delA and 1135insA account for one third of Norwegian familial breast-ovarian cancer and are associated with later disease onset than less frequent mutations. Dis Markers 15:79–84PubMed

23.

Gorski B, Jakubowska A, Huzarski T, Byrski T, Gronwald J, Grzybowska E, Mackiewicz A, Stawicka M, Bebenek M, Sorokin D, Fiszer-Maliszewska L, Haus O, Janiszewska H, Niepsuj S, Gozdz S, Zaremba L, Posmyk M, Pluzanska M, Kilar E, Czudowska D, Wasko B, Miturski R, Kowalczyk JR, Urbanski K, Szwiec M, Koc J, Debniak B, Rozmiarek A, Debniak T, Cybulski C, Kowalska E, Toloczko-Grabarek A, Zajaczek S, Menkiszak J, Medrek K, Masojc B, Mierzejewski M, Narod SA, Lubinski J (2004) A high proportion of founder BRCA1 mutations in Polish breast cancer families. Int J Cancer 110:683–686PubMedCrossRef

24.

Jobling MA, Tyler-Smith C (2003) The human Y chromosome: an evolutionary marker comes of age. Nat Rev Genet 4:598–612PubMedCrossRef

25.

Backe J, Hofferbert S, Skawran B, Dork T, Stuhrmann M, Karstens JH, Untch M, Meindl A, Burgemeister R, Chang-Claude J, Weber BH (1999) Frequency of BRCA1 mutation 5382insC in German breast cancer patients. Gynecol Oncol 72:402–406PubMedCrossRef

26.

Hamel N, Foretova L, Narod SA, Tihomirova L, Zajac V, Ciernikova S, Armaou S, Yannoukakos D, Greenwood C, Foulkes WD (2006) Investigating the origins of the BRCA1 mutation c.5385dupC. In: Abstracts of the 56th Annual Meeting of the American Society of Human Genetics, New Orleans, Louisiana, USA, October 10–13 2006, p 203

27.

Chenevix-Trench G, Healey S, Lakhani S, Waring P, Cummings M, Brinkworth R, Deffenbaugh AM, Burbidge LA, Pruss D, Judkins T, Scholl T, Bekessy A, Marsh A, Lovelock P, Wong M, Tesoriero A, Renard H, Southey M, Hopper JL, Yannoukakos K, Brown M, Easton D, Tavtigian SV, Goldgar D, Spurdle AB (2006) Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res 66:2019–2027PubMedCrossRef

28.

Glover JN (2006) Insights into the molecular basis of human hereditary breast cancer from studies of the BRCA1 BRCT domain. Fam Cancer 5:89–93PubMedCrossRef

29.

Mirkovic N, Marti-Renom MA, Weber BL, Sali A, Monteiro AN (2004) Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition. Cancer Res 64:3790–3797PubMedCrossRef

30.

Williams RS, Chasman DI, Hau DD, Hui B, Lau AY, Glover JN (2003) Detection of protein folding defects caused by BRCA1-BRCT truncation and missense mutations. J Biol Chem 278:53007–53016PubMedCrossRef

31.

Joo WS, Jeffrey PD, Cantor SB, Finnin MS, Livingston DM, Pavletich NP (2002) Structure of the 53BP1 BRCT region bound to p53 and its comparison to the BRCA1 BRCT structure. Genes Dev 16:583–593PubMedCrossRef

32.

Hayes F, Cayanan C, Barilla D, Monteiro AN (2000) Functional assay for BRCA1: mutagenesis of the COOH-terminal region reveals critical residues for transcription activation. Cancer Res 60:2411–2418PubMed

33.

Carvalho MA, Marsillac SM, Karchin R, Manoukian S, Grist S, Swaby RF, Urmenyi TP, Rondinelli E, Silva R, Gayol L, Baumbach L, Sutphen R, Pickard-Brzosowicz JL, Nathanson KL, Sali A, Goldgar D, Couch FJ, Radice P, Monteiro AN (2007) Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. Cancer Res 67:1494–1501PubMedCrossRef

34.

Karchin R, Monteiro AN, Tavtigian SV, Carvalho MA, Sali A (2007) Functional impact of missense variants in BRCA1 predicted by supervised learning. PLoS Comput Biol 3:e26PubMedCrossRef

35.

Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, Tang J, Li S, Zhang S, Shaw PA, Narod SA (2006) Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98:1694–1706PubMedCrossRef

Title: Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients
Authors: Irene Konstantopoulou
Theodore Rampias
Angela Ladopoulou
George Koutsodontis
Sophia Armaou
Theodore Anagnostopoulos
George Nikolopoulos
Smaragda Kamakari
George Nounesis
Antonis Stylianakis
Charisios Karanikiotis
Evangelia Razis
Helen Gogas
Antonios Keramopoulos
Vassiliki Gaki
Christos Markopoulos
Dimosthenis Skarlos
Nikos Pandis
Thalia Bei
Iordanis Arzimanoglou
George Fountzilas
Drakoulis Yannoukakos
Publication date: 01-02-2008
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2008
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-007-9571-2

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