Abstract
A total of 264 unrelated breast/ovarian cancer patients and 45 healthy individuals with familial antecedents referred for genetic testing were scanned for germ-line mutations in BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis (CSGE) and heteroduplex analysis by capillary array electrophoresis (HA-CAE). We detected 101 distinct mutations (41 in BRCA1 and 60 in BRCA2); ten of them have not been previously reported. These mutations were c.2411_2429dup19, c.2802_2805delCAAA and c.5294A>G (p.E1725E) of BRCA1; and c.667C>T (p.Q147X), c.2683C>T (p.Q819X), c.5344_5347delAATA, c.5578_5579delAA;insT, c.8260_8261insGA, c.744+14C>T and c.8099A>G (p.Y2624C) of BRCA2. Twenty-four different mutations, including seven of the new mutations (five frameshift and two nonsense), were classified as pathogenic. These 24 alterations were found in 39 families (12.6% of all families). A remarkable proportion of deleterious mutations were found in BRCA2: 25 families carried a mutation in BRCA2 (BRCA2+; 64.1%) compared with 14 families BRCA1+ (35.9%). The highest incidences of deleterious mutations were found in families with three or more cases of site-specific breast cancer (BC) (27.4%) and families with BC and ovarian cancer (22.2%). Finally, four recurrent mutations, 3036_3039delACAA, c.5374_5377delTATG of BRCA2, as well as c.5272-1G>A and c.5242C>A (p.A1708E) of BRCA1, accounted for 44% of all of the deleterious mutations.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Cebrian A, Ruiz-Llorente S, Cascon A, Osorio A, Martinez-Delgado B, Benitez J, Robledo M (2002) A rapid and easy method for multiple endocrine neoplasia type 1 mutation detection using conformation-sensitive gel electrophoresis. J Hum Genet 47:190–195
Diez O, Domenech M, Alonso MC, Brunet J, Sanz J, Cortes J, del Rio E, Baiget M (1998) Identification of the 185delAG BRCA1 mutation in a Spanish Gypsy population. Hum Genet 103:707–708
Diez O, Osorio A, Duran M, Martinez-Ferrandis JI, de la Hoya M, Salazar R, Vega A, Campos B, Rodriguez-Lopez R, Velasco E, Chaves J, Diaz-Rubio E, Jesus Cruz J, Torres M, Esteban E, Cervantes A, Alonso C, San Roman JM, Gonzalez-Sarmiento R, Miner C, Carracedo A, Eugenia Armengod M, Caldes T, Benitez J, Baiget M (2003) Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. Hum Mutat 22:301–312
Duran M, Esteban-Cardenosa E, Velasco E, Infante M, Miner C (2003) Mutational analysis of BRCA2 in Spanish breast cancer patients from Castilla-Leon: identification of four novel truncating mutations. Hum Mutat 21:448
Esteban-Cardenosa E, Duran M, Infante M, Velasco E, Miner C (2004) High-throughput mutation detection method to scan BRCA1 and BRCA2 based on heteroduplex analysis by capillary array electrophoresis. Clin Chem 50:313–320
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, Breast Cancer Linkage Consortium (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62:676–689
Ganguly A, Rock MJ, Prockop DJ (1993) Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes. Proc Natl Acad Sci USA 90:10325–10329
Ikeda N, Miyoshi Y, Yoneda K, Shiba E, Sekihara Y, Kinoshita M, Noguchi S (2001) Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families. Int J Cancer 91:83–88
Katagiri T, Kasumi F, Yoshimoto M, Nomizu T, Asaishi K, Abe R, Tsuchiya A, Sugano M, Takai S, Yoneda M, Fukutomi T, Nanba K, Makita M, Okazaki H, Hirata K, Okazaki M, Furutsuma Y, Morishita Y, Iino Y, Karino T, Ayabe H, Hara S, Kajiwara T, Houga S, Shimizu T, Toda M, Yamazaki Y, Uchida T, Kunitomo K, Sonoo H, Kurebayashi J, Shimotsuma K, Nakamura Y, Miki Y (1998) High proportion of missense mutations of the BRCA1 and BRCA2 genes in Japanese breast cancer families. J Hum Genet 43:42–48
Martinez-Ferrandis JI, Vega A, Chirivella I, Marin-Garcia P, Insa A, Lluch A, Carracedo A, Chaves FJ, Garcia-Conde J, Cervantes A, Armengod ME (2003) Mutational analysis of BRCA1 and BRCA2 in Mediterranean Spanish women with early-onset breast cancer: identification of three novel pathogenic mutations. Hum Mutat 22:417–418
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al. (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71
Nathanson KL, Weber BL (2001) ‘Other’ breast cancer susceptibility genes: searching for more Holy Grail. Hum Mol Genet 10:715–720
Neuhausen SL, Godwin AK, Gershoni-Baruch R, Schubert E, Garber J, Stoppa-Lyonnet D, Olah E, Csokay B, Serova O, Lalloo F, Osorio A, Stratton M, Offit K, Boyd J, Caligo MA, Scott RJ, Schofield A, Teugels E, Schwab M, Cannon-Albright L, Bishop T, Easton D, Benitez J, King MC, Ponder BAJ, Weber B, Devilee P, Borg A, Narod SA, Goldgar D (1998) Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study. Am J Hum Genet 62:1381–1388
Osorio A, Robledo M, Albertos J, Diez O, Alonso C, Baiget M, Benitez J (1998) Molecular analysis of the six most recurrent mutations in the BRCA1 gene in 87 Spanish breast/ovarian cancer families. Cancer Lett 123:153–158
Risch HA, McLaughlin JR, Cole DEC, Rosen B, Bradley L, Kwan E, Jack E, Vesprini DJ, Kuperstein G, Abrahamson JLA, Fan I, Wong B, Narod SA (2001) Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68:700–710
Salazar R, Cruz-Hernandez JJ, Sanchez-Valdivieso E, Rodriguez CA, Gomez-Bernal A, Barco E, Fonseca E, Portugal T, Gonzalez-Sarmiento R (2006) BRCA1-2 mutations in breast cancer: identification of nine new variants of BRCA1-2 genes in a population from central Western Spain. Cancer Lett 233(1):172–177
Tavtigian SV, Simard J, Rommens J, Couch F, Shattuck-Eidens D, Neuhausen S, Merajver S, Thorlacius S, Offit K, Stoppa-Lyonnet D, Belanger C, Bell R, Berry S, Bogden R, Chen Q, Davis T, Dumont M, Frye C, Hattier T, Jammulapati S, Janecki T, Jiang P, Kehrer R, Leblanc JF, Goldgar DE et al. (1996) The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 12:333–337
Tulinius H, Olafsdottir GH, Sigvaldason H, Arason A, Barkardottir RB, Egilsson V, Ogmundsdottir HM, Tryggvadottir L, Gudlaugsdottir S, Eyfjord JE (2002) The effect of a single BRCA2 mutation on cancer in Iceland. J Med Genet 39:457–462
Vallon-Christersson J, Cayanan C, Haraldsson K, Loman N, Bergthorsson JT, Brondum-Nielsen K, Gerdes AM, Moller P, Kristoffersson U, Olsson H, Borg A, Monteiro AN (2001) Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families. Hum Mol Genet 10:353–360
Vega A, Campos B, Bressac-de-Paillerets B, Bond PM, Janin N, Douglas FS, Domenech M, Baena M, Pericay C, Alonso C, Carracedo A, Baiget M, Diez O (2001) The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript. Hum Mutat 17:520–521
Velasco E, Infante M, Duran M, Esteban-Cardenosa E, Lastra E, Garcia-Giron C, Miner C (2005) Rapid mutation detection in complex genes by heteroduplex analysis with capillary array electrophoresis. Electrophoresis 26:2539–2552
Velasco-Sampedro E, Esteban-Cardenosa E, Infante-Sanz M, Durán-Dominguez M, Lastra-Aras E, Garcia-Giron C, Miner-Pino C (2002) Molecular study of the BRCA1 and BRCA2 genes in 153 breast cancer families from Castilla y Leon (Spain): new nine unclassified variants identified. Med Clin (Barc) 119:441–445
Wooster R, Weber BL (2003) Breast and ovarian cancer. N Engl J Med 348:2339–2347
Acknowledgements
This work has been supported by the Junta de Castilla y León through the regional Breast Cancer Prevention Program. M. Infante and E. Esteban-Cardeñosa were recipients of fellowships from the “Fundación Burgos para la Investigación en Salud.” We are also grateful to the patients and the clinicians, especially Dr. García Girón and Dr. Lastra (Hospital General Yagüe, Burgos, Spain), who collaborated in this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Infante, M., Durán, M., Esteban-Cardeñosa, E. et al. High proportion of novel mutations of BRCA1 and BRCA2 in breast/ovarian cancer patients from Castilla-León (central Spain). J Hum Genet 51, 611–617 (2006). https://doi.org/10.1007/s10038-006-0404-7
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s10038-006-0404-7
Keywords
This article is cited by
-
Contribution of BRCA1 and BRCA2 germline mutations to early onset breast cancer: a series from north of Morocco
BMC Cancer (2020)
-
Hereditary breast and ovarian cancer in Andalusian families: a genetic population study
BMC Cancer (2018)
-
Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical–pathological features in BRCA carriers and non-carriers
Familial Cancer (2017)
-
Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence
Familial Cancer (2013)
-
Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes
Breast Cancer Research (2012)
