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Breast Cancer Res Treat (2007) 103:225–232 DOI 10.1007/s10549-006-9370-1

EPIDEMIOLOGY

High proportion of BRCA1/2 founder mutations in Hispanic breast/ovarian cancer families from Colombia Diana Torres Æ Muhammad Usman Rashid Æ Fabian Gil Æ Angela Umana Æ Giancarlo Ramelli Æ Jose Fernando Robledo Æ Mauricio Tawil Æ Lilian Torregrosa Æ Ignacio Briceno Æ Ute Hamann

Received: 7 August 2006 / Accepted: 7 August 2006 / Published online: 2 November 2006  Springer Science+Business Media B.V. 2006

Abstract In South America, a high proportion of the population is of Hispanic origin with an important representation in Colombia. Since nothing is known about the contribution of BRCA1 and BRCA2 germline mutations to hereditary breast/ovarian cancer in the Hispanic population from Colombia, we conducted the first study of 53 breast/ovarian cancer families from this country. Comprehensive BRCA mutation screening was performed using a range of techniques, including DHPLC, SSCP, and PTT, followed by DNA sequencing analysis. Thirteen deleterious germline mutations (24.5%) were identified in 53 families, comprising eight in BRCA1 and five in BRCA2. The two recurrent BRCA1 mutations, 3450 delCAAG and D. Torres Æ M. U. Rashid Æ U. Hamann (&) Division of Molecular Genome Analysis, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany e-mail: u.hamann@dkfz-heidelberg.de F. Gil Unidad de Epidemiologı´a Clı´nica y Bioestadı´stica, Pontificia Universidad Javeriana, Bogota´, Colombia A. Umana Æ G. Ramelli Æ I. Briceno Æ D. Torres Instituto de Gene´tica Humana, Pontificia Universidad Javeriana, Bogota´, Colombia M. U. Rashid Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan

A1708E, accounted for 100% of all BRCA1 mutations identified in this cohort and the recurrent 3034 delACAA BRCA2 mutation for 40% of all BRCA2 mutations. Haplotype analyses suggested that each of these mutations has arisen from a common ancestor. The prevalence of BRCA1 or BRCA2 mutations was 50% in multiple case breast cancer families, and was 33% for the breast-ovarian cancer families. Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer in Colombia. The spectrum of mutations differed completely to that previously reported in Hispanic families of predominantly Mexican origin from Southern California [1] suggesting that specific genetic risk assessment strategies for the different Hispanic populations in South America and in the United States need to be developed. Keywords BRCA1/2 Æ Germline mutations Æ Hereditary breast/ovarian cancer Æ Hispanics Æ Colombia Abbreviations SSCP Single strand conformational polymorphism PTT Protein truncation test DHPLC Denaturing high-pressure liquid chromatography

J. F. Robledo Departamento de Cirugı´a, Clı´nica del Country, Bogota´, Colombia

Introduction

M. Tawil Æ L. Torregrosa Facultad de Medicina, Departamento de Cirugı´a, Pontificia Universidad Javeriana, Bogota´, Colombia

The Hispanic population of the United States constitutes 14% of the total population in 2004 (excluding

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the 4 million residents of Puerto Rico) making Hispanic people the nation’s largest ethnic minority (US Consensus Bureau, 2005, http://www.census.gov). US Hispanics or Latinos trace their roots to Spain, Mexico and the Spanish speaking nations of Central and South America and the Caribbean. In South America, a high proportion of the population is of Hispanic origin with an important representation in Colombia. Breast cancer is the second most common cancer among women in Colombia and the third most common cause of cancer death with incidence and mortality age-standardized (world) annual rates (ASR) of 30.3 and 12.5, respectively (Globocan 2002, http//www-dep.iarc.fr/globocan/database.htm). These rates resemble those reported in parts of Africa, and Asia [2]. Approximately 5% of breast cancers and 10% of ovarian cancers are due to germline mutations in the BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) genes [3, 4]. Mutations in these genes are responsible for familial clustering in the majority of breast and ovarian cancer families and for about one-half of sitespecific breast cancer families [5–7]. It has been estimated that women carrying deleterious mutations in either of these genes confer a high lifetime risk, of up to 87% [8–10], of developing breast cancer and up to 68% of developing ovarian cancer [10–13]. In addition, women and men carrying BRCA2 mutations have heightened risks of pancreatic cancer, prostate cancer, and melanoma [14]. The frequency and spectrum of mutations within these genes shows considerable variation by ethnic group and by geographic region. To date, the majority of studies on the prevalence of the BRCA1 and BRCA2 mutations have been performed in white populations, but recently studies have also been conducted on Asian populations [15]. Little is known about the contribution of BRCA1 and BRCA2 to hereditary breast and/or ovarian cancer in Hispanic American populations. One previous study conducted in Southern California reported a prevalence of BRCA1 and BRCA2 mutations of 30.9% in 110 Hispanic breast and/or ovarian cancer families of predominantly Mexican origin [1]. Six recurrent mutations were identified accounting for 47% of all deleterious mutations and haplotype analyses suggested the presence of founder effects. However, since the Hispanic population is unevenly distributed across the United States and consists of a range of individuals from different countries of origin, these findings may not be applicable to the Hispanic population in Colombia. Therefore we conducted the first systematic study of familial breast/ovarian cancer in Colombia

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and investigated 53 families for germline mutations in the BRCA1 and BRCA2 genes.

Material and methods Subjects Breast/ovarian cancer families were ascertained at the Instituto de Gene´tica Humana at the Pontificia Universidad Javeriana in Bogota´, Colombia from January 2001 to December 2003. The families came from different parts of Colombia, mainly from the central region, but also from the Caribbean and Pacific coasts. Fifty-seven probands from fifty-three Hispanic families diagnosed with in situ or invasive breast cancer were selected for genetic testing following genetic counseling. They were classified into six categories based on family history of cancer: Group A1: Families with one female breast cancer diagnosed at or before 35 years of age. Group A2: Families with two cases of breast cancer diagnosed at any age. Group A3: Families with three cases of breast cancer with at least one diagnosed at or before 50 years of age. Group A4: Families with at least four breast cancers with as a minimum one diagnosed at or before 50 years of age. Group A5: Families with at least one male breast cancer diagnosed at any age. Group B: Families with at least one female breast cancer and one or more ovarian cancers at any age. Information on ethnicity, personal and familial history of cancer was obtained from all probands by personal interview. From all probands, clinical and histopathological data was collected from medical records and pathology reports. Breast cancer, ovarian cancer and other malignancies in other family members were identified by detailed pedigree analysis. The study was approved by the Institutional Review Board of the Pontificia Universidad Javeriana and all study participants gave informed written consent prior to providing a blood sample.

DNA isolation Genomic DNA was extracted from 14 ml EDTA blood samples according to standard protocols. DNA samples from 57 probands were available for this study.


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Mutation screening The entire coding regions of the BRCA1 (Genbank accession number U14680) and BRCA2 (Genbank accession number U43746) genes were screened using single strand conformational polymorphism (SSCP) analysis, denaturing high pressure liquid chromatography (DHPLC) analysis and the protein truncation (PTT) assay. SSCP and PTT analysis was performed as previously described [16, 17]. DHPLC analysis was performed using the WAVE system (Transgenomics, Omaha, NE, USA). PCR-primer pairs, set-up of PCR reactions, cycling conditions and DHPLC running conditions were as previously described [18, 19]. When available, a mutation positive control was included in each set of SSCP and DHPLC analyses. BRCA1 exon 11 and BRCA2 exons 10 and 11, comprising about 60% of all coding sequences under investigation, were screened using the PTT assay in all 57 probands. For BRCA1, 6% of the remaining exons were screened by DHPLC and 34% by SSCP and for BRCA2, 29% by DHPLC and 11% by SSCP.

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intervals for binomial probabilities were computed using the method according to Wilson [22]. All statistical computations were undertaken using Stata 8.1 for Windows (StataCorp LP, College Station, USA).

Results Description of families The present study included 57 probands from 44 breast cancer families and nine breast-ovarian cancer families. Families have been recruited at the Instituto de Gene´tica Humana in Bogota´, Colombia. Seven patients were diagnosed with a ductal carcinoma in situ, 43 with an invasive breast cancer, three with both breast and ovarian cancers, and of the remaining seven the histological type was unknown. The median age of onset of disease was 42 years (range 28–77 years) for female breast cancer (n = 56), and 51 years (range 37–62 years) for ovarian cancer (n = 3). BRCA mutation spectra

DNA sequence analysis Each sample revealing variants detected by either SSCP, DHPLC or PTT analysis was sequenced using an automated DNA CEQ 8000 sequencer (Beckman, Hilden, Germany) according to the manufacturers’ instructions. Bi-directional genomic DNA sequencing was performed to confirm the presence of a mutation. Haplotype analysis Individuals with identical BRCA1 and BRCA2 germline mutations from apparently unrelated families were scored for allele sharing indicative of a common ancestor. Haplotype analysis was performed at three intragenic microsatellite loci D17S855, D17S1322 and D17S1323 of the BRCA1 gene and at four loci D13S290, D13S260, D13S171 and D13S267 flanking the BRCA2 gene [20, 21]. Microsatellite alleles were determined by automated fluorescent-based fragment detection from amplified PCR products on a CEQ 8000 XL DNA Analysis System (Beckman, Hilden, Germany). Statistical analysis The comparison of the age of diagnosis between BRCA carriers and non-carriers was performed using the exact Wilcoxon rank-sum test. All statistical tests were two sided. Results were judged as statistically significant at a p-value of 0.05 or less. Confidence

The combination of SSCP, DHPLC, PTT followed by sequence analysis revealed 13 deleterious germline mutations in 53 families (13/53, 24.5%; 95% CI 13.76–38.28%). There was no difference in the age of breast cancer diagnosis of BRCA1 carriers (n = 9) and non-BRCA1/2 carriers (n = 42) with a median age of diagnosis of 41 years (range 32–55 years) and 42 years (range 28–77 years), respectively (p = 0.75, Exact Wilcoxon rank-sum test). There was also no difference in the age of breast cancer diagnosis of BRCA2 carriers (n = 6), median age of 45.5 years (range 35–50 years) from BRCA1 carriers (p = 0.37, Exact Wilcoxon rank-sum test). Eight mutations were detected in BRCA1 (8/13, 61.5%; 95% CI 31.58–86.14%) and five in BRCA2 (5/13, 38.5%; 95% CI 13.86–68.42%) (Table 1). Six mutations were distinct including four frame shift mutations, one nonsense mutation and one missense mutation. Whereas the former mutations were deemed causative as they were predicted to result in premature termination codons, the latter, A1708E, is most likely to result in an alteration of the BRCA1 BRCT domain structure or its interaction with other proteins, thereby eliminating normal protein function. One BRCA2 mutation (1/13, 7.7%, 95% CI 0.19–36.03%) is unique to the Colombian population. It was not found in 52 healthy controls suggesting that it is a causative change. The other mutations identified in the study population have been previously reported. The

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Table 1 Germline mutations in the BRCA1 and BRCA2 genes in Hispanic breast and/or ovarian cancer families from Colombia Family

Gene

Exon

Nucleotide Codon Base change

Deleterious mutations 3450 15, 17e, 25, 30, 47 BRCA1 11 5, 13, 53 BRCA1 18 5242 38 BRCA2 3 321 4, 23 BRCA2 11 3034 BRCA2 11 6076 16e 33 BRCA2 11 6503 Sequence variants of unknown significance 26, 27 BRCA1 3 233 50 BRCA1 Intron 20 – 9 41 33 25 6

BRCA2 BRCA2 BRCA2 BRCA2 BRCA2

15 7697 22 9078 27 10204 Intron 6 – Intron 13 –

1111 1708 31 936 1950 2092 38 – 2490 2950 3326 – –

Typea No. of BIC entriesb

Amino acid change

Designation

delCAAG C>A G>A delACAA delGTTA delTT

Stop 1115 Ala to Glu Trp to Stop Stop 958 Stop 1962 Stop 2099

3450 delCAAG A1708E W31X 3034 delACAA 6076 delGTTA 6503 delTT

FS MS NS FS FS FS

21 26 Novel 68 2 66

G>A insGTATTCCACTCC T>C G>T A>T C>T A>G

Lys to Lys –

233G > A IVS20 + 60ins12

SM UV

2 4

Ile to Thr Lys to Asn Lys to Stop – –

I2490T K2950N K3326X IVS6 + 14C > T IVS13 – 62A > G

MS MS NS UV UV

171 128 55 6 168 4 Novel 1 2 1

Totalc With Hispanic ancestryd 8 14 1 9 2 4 1 1

a

FS, frame shift mutation; MS, missense mutation; NS, nonsense mutation; SP, splice site mutation; SM, silent mutation; UV, unclassified variant

b

BIC, Breast Cancer Information Core database; August 2006

c

Including only those with ancestry data and those from this study that were not present in the BIC databases as of August 2006

d

Including those from Spain, Latin America/Carribean

e

Two mutations have previously been reported to the BIC database by I. Briceno

phenotypes of the families harboring BRCA1 and BRCA2 germline mutations are shown in Table 2. The A1708E missense mutation was identified in three multiple case breast cancer families. In Family 13, two sisters diagnosed with breast cancer at the ages of 32 and 41 years, respectively, carried the mutation. The other family members with malignancies in this family were another deceased sister diagnosed with breast cancer at the age of 30 years, a paternal female cousin diagnosed with breast cancer at the age of 38 years and the mother who suffered from stomach cancer and died at the age of 74 years. In Family 53, the female proband with breast cancer at the age of 42 years harbored the mutation which was probably transmitted from her deceased mother diagnosed with breast cancer at the age of 41 years. In Family 5, the female proband diagnosed with bilateral breast cancer at the ages of 32 and 38 years and her female cousin diagnosed with breast cancer at 37 years of age were found to harbor the mutation. The deceased mother of the proband was diagnosed with bilateral breast cancer at the ages of 45 and 67 years and the deceased father of the female cousin was found to have colon cancer at the age of 76 years. One other carrier was diagnosed with cervical cancer at the age of 44 years.

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In addition to the deleterious mutations already described, seven distinct BRCA1/2 sequence variants of unknown significance including one novel change were detected (Table 1). Among these were two missense mutations, one silent mutation, one previously classified nonsense variant [23], and three intronic variants. BRCA founder mutations Three mutations, 3450 delCAAG and A1708E in BRCA1 and 3034 delACAA in BRCA2 were found in multiple apparently unrelated patients. The 3450 delCAAG was identified in five patients, A1708E was found in three patients and 3034 delACAA in two patients. The two recurrent BRCA1 mutations accounted for 100% of all BRCA1 mutations identified in this cohort and the recurrent BRCA2 mutation for 40% of all BRCA2 mutations. Haplotype analyses of the two recurrent BRCA1 mutations was performed on all mutation carriers (and on a Spanish reference A1708E carrier) at three intragenic BRCA1 loci and for the recurrent BRCA2 mutation at four BRCA2 flanking loci (Fig. 1). Among the ten mutation carriers, eight were affected by breast


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Table 2 Characteristics of the families with BRCA1/2 mutations Family

No. of cancers

Age at onset (years)

Female Br (bilateral)

Br

Ov (Ov + Br)

Other cancer(s) (age at onset in years) Ov

Families carrying deleterious BRCA1 mutations 15 3 (1) 4 36/41, 45*, 50 17 3 (3) – 42/47, 42/50, 48/60*

45, 65, 67, 76 –

25

1

33, 37*

30 47 5 13 53 Families 38 4

1 1 55* 4 (1) – 39, 40/53, 41*, 64 7 (2) – 32/38*, 37, 40, 43, 45, 45/67, 55 4 – 30, 32*, 38, 41* 2 – 41, 42* carrying deleterious BRCA2 mutations 1 – 35* 5 – 42, 47, 47*, 60, 63

62* – – – –

23 16 33 Families 26 27 50 Families 9

3 – 41*, 45, 50* 7 – 29, 39, 39, 40, 48*, 49, 58 2 – 44, 44* carrying BRCA1 sequence variants 1 (1) – 32/41* 1 – 29* 2 – 39, 46* carrying BRCA2 sequence variants 2 – 42*,49*

– – –

Colon (58) Cervix (50), leukemia (8), prostate (59), stomach (60), tongue (58) – Prostate (75), stomach (62), uterus (49) 2 lung (45, 70), pancreas (80), skin (87)

– – –

– Larynx (60) Brain (56), 2 esophagus (50, 55), lung (50)

41 25

3 1

– 2

42*, 60, 66 37*

– 33, 37*

6

6

40*, 45*, 55, 55, 63, 67

Colon (76), liver (68), leukemia (77), lung (70), prostate (60) Cervix (50), liver (55) 2 cervix (50, 57), colon (55), leukemia (35), prostate (70), stomach (40) Thyroid (60)

2

37*

– –

Stomach (68) Brain (76), 2 colon (75, 78), pancreas (93), prostate (74), uterus (52) 2 cervix (50, 57), colon (55), leukemia (35), prostate (70), stomach (40) Sarcoma (32), 2 stomach (60, 65) – Cervix (44), colon (76), lung (60) Stomach (74) Liver (65)

*: Proband; Br: breast cancer; Ov: ovarian cancer

A BRCA1 3450delCAAG 15

17

25

30

47

153

153 153

153

153

153

153

153

153

153

D17S1323

118

118 118

118

118

118

118

118

118

118

D17S1322

152

152 150

152

146

152

152

152

150

152

D17S855

cancer and two BRCA1 3450 delCAAG carriers by both breast and ovarian cancer. All carriers of each of these mutations shared the same haplotype indicating that each of these mutations is derived from a common ancestor.

B BRCA1 A1708E 5

13

53

SP

153

153 149

153 153

153

153

153

D17S1323

121

118 118

118 121

118

118

118

D17S1322

134

142 146

142 150

142

148

142

D17S855

C BRCA2 3034delACAA 4

23

178

178 180

178

D13S290

164

170 166

170

D13S260

225

229 239

229

D13S171

150

144 148

144

D13S267

Fig. 1 Haplotype analysis of mutation carriers at three intragenic BRCA1 loci (A, B) and four BRCA2 flanking loci (C). Family numbers are given above the haplotypes. Genotypes are given by apparent allele sizes in base pairs. Common haplotypes are indicated by a bold bar. SP: Spanish reference mutation carrier

BRCA mutation frequencies The frequencies of deleterious mutations in BRCA1 and BRCA2 were calculated for each of the different risk groups (Table 3). Seven families (13.2%) were classified into risk group A1, 17 (32.1%) in A2, 9 (17.0%) in A3, 10 (18.9%) in A4, one (1.8%) in A5, and 9 (17.0%) in B. The probability of detecting a mutation rose with the number of family members affected by breast cancer. For BRCA1, the highest mutations frequencies of 30% and 33.3% were found in patients from families with four or more cases of breast cancer and with breast and ovarian cancer, respectively.

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230 Table 3 BRCA1/2 mutation frequencies according to family structure

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Risk group

A1 A2 A3 A4 A5 B

Phenotype of families

All families Female breast cancer families 1 case £ 35 years 2 cases diagnosed at any age 3 cases with ‡1 diagnosed £50 years ‡4 cases with ‡1 diagnosed £50 years Male breast cancer families ‡1 case of male breast cancer Breast-ovarian cancer families ‡1 breast cancer and ‡1 ovarian cancer diagnosed at any age

Discussion In this study, we assessed the contribution of the BRCA1 and BRCA2 genes to hereditary breast/ovarian cancer in Hispanic families from Colombia. Although a few studies in Hispanic families from Chile [24, 25], Mexico [26] and Southern California [1] have previously been conducted, this is, to our knowledge, the first comprehensive study of the Hispanic population from Colombia. In our study, 13 deleterious BRCA1 and BRCA2 mutations were identified. The highest mutation frequencies were obtained in families with multiple breast cancer cases (50%) and with breast and ovarian cancer cases (33%). These frequencies were similar to those reported in other Caucasian and Asian populations including those of Belgium [27], Italy [28], Sweden [29], USA [30], Japan [31], Turkey [32] and similar to the prevalence observed in a Hispanic Mexican population from Southern California [1]. The substantial proportion of families without mutations supports the notion that apart from BRCA1 and BRCA2 other genetic and/or non-genetic factors may be important determinants of familial risk. Mutation screening was performed using the combined approach of SSCP, DHPLC, PTT, and sequencing analysis. Since no mutation detection method has 100% sensitivity, the mutation frequencies identified in this report should be considered as minimal estimations of their true frequency. Since only the coding regions have been analyzed, regulatory mutations outside the coding region, which affect transcription, would not have been detected. In addition, large genomic deletions and rearrangements accounting for about 10% of all BRCA1 mutations may have been missed. Among the identified 13

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No. of families

53 43 7 17 9 10

No. of families with mutations (%) in BRCA1

BRCA2

BRCA1 or BRCA2

8 5 0 1 1 3

5 5 1 1 1 2

13 10 1 2 2 5

(15.0) (11.6) (0) (5.9) (11.1) (30.0)

(9.5) (11.6) (14.3) (5.9) (11.1) (20.0)

(24.5) (23.2) (14.3) (11.8) (22.2) (50.0)

1

0 (0)

0 (0)

0 (0)

9

3 (33.3)

0 (0)

3 (33.3)

mutations, one was novel. Since it was not detected in 52 healthy controls it is likely to be disease-causative. Three mutations were recurrent and probably have European origins. The most commonly observed mutation was the BRCA1 3450 delCAAG frame shift mutation found in five families. According to data from the BIC database [http://www.nhgri.nih.gov/Intramural_research/Lab_transfer/Bic/], this mutation has been identified in 21 families mainly from Europe, but only in one family of Latin American/Caribbean ancestry. The second most commonly observed mutation was the BRCA1 A1708E mutation identified in three families. Of the 26 observations in the BIC database, the majority was of European ancestry and only nine were of Latin American/Caribbean descent. This mutation has also previously been found in eleven Spanish families [33–35] and in a family from El Salvador [1]. The third recurrent mutation, 3034 delACAA in BRCA2 was found in two families. Of the 68 observations reported to the BIC database, the majority were of Western European ancestry and only six were of Latin American descent. The BRCA1 mutation carriers identified in our study shared the same haplotype implying that each of the two recurrent BRCA1 mutations may have arisen from a common founder. The two BRCA2 3034 delACAA mutation carriers also shared the same haplotype again suggesting a founder effect. However, a previous study among 3034 delACAA carriers from families from various Western European and North American countries had found a considerable amount of haplotype diversity among eleven families examined, although the statistical evidence of multiple independent origins for this mutation was not significant [21]. Since the number of mutation carriers in our study was small and only


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few markers have been analyzed, this may have occurred by chance. Thus, the origin(s) of this mutation needs to be determined in future studies with a larger number of mutation carriers. The three recurrent BRCA mutations accounted for almost 80% of the deleterious mutations identified in our Hispanic American cohort. Additionally, one deleterious mutation seen only once in our study was reported in another Hispanic family in the BIC database. This suggests the possibility that a fast and cost-effective multiplex assay for these four BRCA mutations could be developed for the initial screening of the Hispanic population of Colombia that would detect 85% of all mutations. Interestingly, the spectrum of recurrent mutations identified in Hispanic families from Colombia differed completely from that of Hispanic families of predominantly Mexican origin from Southern California [1]. None of the six recurrent mutations identified in Hispanic families of predominantly Mexican origin in the US were found in Hispanic families from Colombia implying that the mutation spectra among the Hispanic populations in other parts of Southern America and the US may also differ. In most Western countries breast and ovarian cancers occurring in BRCA1 mutation carriers were diagnosed about 5–10 years earlier than those among women not found to have mutations. In contrast to this situation, BRCA1 mutation carriers and non-carriers were diagnosed with breast cancer at a similar age most likely reflecting the very young age of the Colombian patients included in our study. The same findings have recently been reported for BRCA1 carriers and noncarriers from Pakistan [36, 37]. The similarity in age of breast cancer diagnosis between BRCA1 carriers and non-carriers may be useful for genetic counseling and management of Colombian women at risk. Altogether, our findings contribute to the body of knowledge about the prevalence of BRCA germline mutations in the rapidly growing Hispanic population. The high percentage of recurrent mutations accounting for 85% of all mutations identified in this cohort may facilitate carrier detection in the Hispanic population from Colombia. Further, our findings may point to the necessity of developing specific genetic tests for the screening of the different Hispanic populations all over America. Acknowledgements We are grateful to all family members for their participation in this study. We thank Jaime Bernal for his support in the recruitment of families. We thank Alberto Go´mez for critical discussions and reading of the manuscript, Bernd Arnold and Dieter Niederacher for DNA samples of BRCA1/2 mutation controls and advice for DHPLC analysis, Ana Osorio

231 for providing a DNA sample of a Spanish A1708E mutation carrier, and Antje Seidel-Renkert and Michael Gilbert for expert technical assistance. This work was supported by the Deutsches Krebsforschungszentrum, Heidelberg and the Pontificia Universidad Javeriana, Bogota´. Diana Torres was a guest researcher from the Instituto de Gene´tica Humana, Pontificia Universidad Javeriana, Bogota´, Colombia in the DKFZ, Heidelberg, supported by a fellowship from the DAAD, Germany, and by a special funding of the Vicerrectorı´a Acade´mica, Pontificia Universidad Javeriana, Bogota´, Colombia.

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