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Biological Research

Print version ISSN 0716-9760

Biol. Res. vol.35 no.1 Santiago  2002

http://dx.doi.org/10.4067/S0716-97602002000100011 

Analysis of 5382insC (BRCA1) and 6174delT (BRCA2) mutations in 382 healthy Chilean women with a family history of breast cancer

LILIAN JARA1, SANDRA AMPUERO2, LORENA SECCIA3, MARIO BUSTAMANTE1, RAFAEL BLANCO1 AND JOSÉ MANUEL OJEDA2

1Human Genetics Program, Institute of Biomedical Sciences, School of
Medicine, University of Chile
2Center for Cancer Prevention, School of Medicine, University of Chile
3Corporación Nacional del Cáncer (CONAC)

Corresponding Author: Dra. Lilian Jara Sosa. Av. Independencia 1027. P.O Box 70061. Telephone: (56-2) 678-6458 . Fax : (56-2) 737-3158. e-mail: ljara@machi.med.uchile.cl

Received: July 27, 2001. Accepted: February 14, 2002

ABSTRACT


Breast cancer is the most common malignancy among women. Chilean studies reveal that this cancer presents the third highest mortality rate. A family history of breast cancer is one of the major risk factors for the development of this disease. BRCA1 and BRCA2 are the two main hereditary breast cancer susceptibility genes, and mutations in these genes are related to inherited breast cancer. In specific populations only some mutations have been found to be associated with susceptibility. The purpose of this study was to establish the frequency of 5382insC (BRCA1) and 6174delT (BRCA2) germline mutations in 382 healthy Chilean women with at least two relatives affected with breast cancer and in probands and their relatives from 8 high risk families for breast cancer, using mismatch PCR assay. The results obtained showed that 5382insC and 6174delT mutations were not found in either of the groups studied. The ethnic origin of the contemporary Chilean population and the data reported in the literature suggest that these mutations may be absent or have a very low frequency in this population.. This genetic study is part of a breast cancer screening program that also includes annual mammography and clinical breast examination over a five-year period. Strategies to reduce morbidity and mortality associated with breast cancer lie in early detection in women with genetic risk.

Key terms: Breast Cancer, BRCA1 and BRCA2 genes, Mutations, Chilean Women

 

INTRODUCTION

Cancer is a disease in which malignant cells proliferate to produce malignant progeny. This mode of inheritance of the malignant phenotype provides strong evidence that this malignancy is encoded in the genes of the cancer cell. Much of the current cancer research is directed toward the identification, characterization and cloning of genes whose protein products are involved in transforming a normal cell into a malignant one. Studies have led to the identification of oncogenes and tumor suppressor genes (Hill and Tannock, 1998).

Breast cancer ranks third worldwide in cancer frequency, and more than six hundred thousand new cases are reported every year. In developing countries it represents the second most common cancer among women (Parkin, 1994). Current incidence in Chile has not been accurately established given that as yet there is no obligation to report occurrences of this disease. Recent studies in Chile establish that breast cancer constitutes the third highest mortality rate in women after gallbladder and gastric cancer, showing even higher mortality rates than uterine cervical cancer (Peralta et al., 1995). Female mortality rates due to breast cancer in Chile have increased steadily and as of 1995 had reached 11.7 per 100,000 (Peralta et al., 1995).

Epidemiological studies have shown that a woman with a first-degree relative who has experienced breast cancer may herself have a risk for breast cancer 1.7 to 4.0 times greater than that of the general population. Thus, a positive family history is itself a risk factor for breast disease. It has been estimated that 5% of breast cancer is inherited, but given its high incidence, this percentage is significant. In cases of women diagnosed before age 30, this figure rises markedly to 25% (Miki et al., 1994).

Among the genes whose alterations have been associated with a high risk of breast cancer are the tumor suppressor genes BRCA1 and BRCA2, both of which may account for at least 2/3 of all hereditary breast cancer (Hakansson et al., 1997). Mutations in other susceptibility genes such as p53, ATM, PTEN or MSH2, MLH1, PMS1, PMS2, MSH3 and MSH6 may indicate a predisposition to breast cancer (Kuschel et al., 2000; Tonin, 2000). Nevertheless, together they are responsible for only a small fraction of breast cancer not associated to BRCA1 or BRCA2 (Ellisen and Haber, 1998).

The existence of BRCA1 as a predisposing gene of breast and ovarian cancer was demonstrated by Hall et al. in 1990 through linkage analysis. The reports of Narod et al., 1991 and of Easton et al., 1993, confirmed the previous finding and calculated an Odds Score of <1026. In 1994, Miki et al. identified the BRCA1 gene by positional cloning in 17q12-21. The BRCA1 has 5592 nucleotides and 22 exons distributed in 89 kb of genomic DNA and encodes a protein of 1863 amino acids (Miki et al., 1994). This protein is present in normal breast and ovarian epithelium and is altered, reduced, or absent in some breast and ovarian tumors. The BRCA1 protein acts as a negative regulator of tumor growth (Miki et al., 1994). The BRCA2 gene was localized in 1994 in the 13q12-13 region (Wooster et al., 1994). It was sequenced in 1995 and has 10443 nucleotides and 26 exons distributed in 70 kb of genomic DNA. The gene encodes a protein of 3418 amino acids (Hakansson et al., 1997; Serova et al., 1997).

Studies carried out with families at high risk for breast and ovarian cancer have allowed the incorporation of 1070 different variants of BRCA1 and BRCA2 to the Breast Cancer Information Core (BIC), a data base established by the National Institutes of Research of the Human Genome (NHGRI, USA), as of May 2000. The great majority of these variants are associated with deleterious effects. The mutations in both genes are nearly ubiquitously distributed over the coding region, and more than 85% of them are frame-shift or nonsense mutations leading to the premature termination of protein translation (Peelen et al., 1997; Hakansson et al., 1997).

The mutations in BRCA1 and BRCA2 are associated with hereditary breast cancer, breast-ovarian cancer, male breast cancer, hereditary ovarian cancer and sporadic cases of breast and ovarian cancer. The BRCA1 and BRCA2 genes have also been associated with other types of cancer, such as prostate and colon (BRCA1) and larynx and pancreatic (BRCA2) (Hakansson et al., 1997, Oncolink). The literature describes BRCA1 as being responsible for approximately 50% of inherited breast cancer (Rebbeck et al., 1996; Serova et al., 1997; Stoppa-Lyonnet et al., 1997), 80 to 90% of hereditary breast-ovarian cancer (Serova et al., 1997; Whittemore et al., 1997; Gayther et al., 1997a), and the majority of hereditary ovarian cancer (Gayther et al., 1997b). BRCA2 mutations have been observed in 32-35% of families with more than 4 cases of hereditary female breast cancer (Rebbeck et al., 1996) and in 76% of male breast cancer (Serova et al., 1997; Ford et al., 1998), but they indicate a low risk for ovarian cancer (Serova et al., 1997). Approximately 15% of familial breast cancer could be attributable to other still unidentified genes (Rebbeck et al., 1996; Ford et al., 1998).

Whittemore et al., (1997) reported that inherited mutations of BRCA1 represent a risk for breast and ovarian cancer of approximately 73.5% at age 80. Ford et al., (1998) estimated a cumulative risk of breast cancer due to BRCA1 of 28% by age 50 and 84% by age 70. In the case of BRCA2, the cumulative risk for age 70 was also 84%. Although only 1% of breast cancer occurs in males, carriers of BRCA2 mutation have a lifetime cancer risk of 6% (Oncolink).

Several recent studies of the BRCA1 and BRCA2 genes have led to the description of a great number of mutations over the last four years. The BIC data base indicates that the mutations with the highest number of registrations associated with breast cancer are: a) deletion of adenine and guanine in the codon 185 of exon 2 (185delAG) with 359 registrations in the BRCA1 gene; b) the insertion of a cytosine in codon 5382 of exon 20 (5382insC) with 200 registrations in the BRCA1 gene; and c) deletion of thymidine in codon 6174 of exon 11e (6174) with 135 registrations of the BRCA2 gene.

The only molecular genetic study of BRCA1 and BRCA2 genes done in Chile was published by Trincado et al., 1999. These authors screened 185delAG mutation in 15 patients with familial breast cancer and in 40 patients with sporadic breast cancer without detecting this mutation in either group. In the present study we analyzed the mutations 5382insC (BRCA1) and 6174delT (BRCA2) in 382 healthy Chilean females with at least two relatives with breast cancer and in probands of families at high risk for breast cancer.

 

PATIENTS AND METHODS

Patients : Two groups of patients were included in the present study. Group A was comprised of 382 healthy Chilean females who had participated in the First Breast Cancer Prevention Campaign organized by Corporación Nacional del Cáncer (CONAC) (National Cancer Foundation of Chile). The criteria for inclusion in Group A was to have two relatives of the same lineage affected with breast cancer, which was certified by a physician or death certificate. The ages of this group ranged between 20 and 80 years of age . Group B consisted of probands and their relatives belonging to 8 families at high risk for breast cancer, selected from the files of the Breast Pathology Program of the Central Metropolitan Health Service. The families included were required to comply with at least one of the following criteria: 1) families with at least two first degree relatives with breast and/or ovarian cancer diagnosed at any age, 2) families with at least two first or second degree relatives with breast cancer diagnosed before age 50, 3) families with at least three first or second degree relatives with breast cancer, at least one of whom was diagnosed before age 40, 4) families with at least one member having a cancer diagnosed before age 50 and at least one member with ovarian cancer diagnosed at any age, 5) families with at least one case of male breast cancer diagnosed at any age and at least one case of female breast cancer diagnosed at any age, 6) families with three or more different cancers (female or male breast cancer, ovarian, prostate, pancreas and larynx in non-smoking individuals), 7) families with at least one breast cancer diagnosed before age 30, and 8) families with at least one case of bilateral breast cancer.

The probands were contacted by telephone and asked if they would be interested in participating in the study. All of the patients had a breast cancer diagnosis that had been confirmed through clinical examination, mammography, breast ecotomography and cytodiagnosis. The selected families were interviewed and asked to respond to a special questionnaire to obtain information about medical and reproductive history, ethnicity and general risk factors (alcoholism, smoking, exposure to drugs, use of hormones and others).

After obtaining the consent form from each individual, genomic DNA was extracted from peripherical blood lymphocytes. Samples were obtained according to the method described by Chomczynsky and Sacchi (1987). The PCR primer mismatch technique was performed for the mutation 5382insC (BRCA1) in group A only, according to the method described by Backe et al., 1999. Amplifications were in 50µl of reactions containing 200ng of genomic DNA, 1.5 mM of MgCl2, 0.2 mM of each dNTPS, 40 pmols of primers [BS10 (5'-CCA AAG CGA GCA AGA GAA TCT C-3') and BS9 (5'-GGG AAT CCA AAT TAC ACA GC-3')] and 1.5 U of Taq polymerase. The thermal cycles were initiated with 3 min at 94ºC, followed by 30 cycles of 30 sec at 94ºC, 30 sec at 61ºC and 30 sec at 72ºC and a final extension at 72ºC, for 5 min. The PCR products were digested with DdeI for 2 hours at 37ºC. Then 15µl of the digest was sized on a 3% agarose gel. Wild type PCR product was digested by DdeI into a 214bp and a 20bp fragment. In contrast the 5382insC mutation interferes with the creation of a DdeI restriction site resulting in an undigested aberrant allele of 234 bp. As a positive control, we used a mutated sample kindly donated by Dr. Sabine Pages of the Curie Institute, Paris, France.

The study of the 6174delT mutation was accomplished with mismatch PCR using the primers and amplification conditions described by Abeliovich et al., 1997. This mutation was studied in groups A and B. The PCR products were digested with the restriction endonuclease PmlI following the conditions described by suppliers (New England Biolabs). The digest products were sized on 2.5% agarose gels. The normal allele showed fragments of 127 bp and 21 bp. The mutant allele was not cut by PmlI giving a band of 147 bp. As a positive control we used a mutated sample, also provided by Dr. Sabine Pages.

 

RESULTS

Screenings for the mutation 5382insC in 382 healthy women with family backgrounds of breast cancer (Group A), were diagnosed as normal homozygotes. All of the women showed a band of 270 bp, which corresponds to the undigested PCR product, and a band of 214 bp, which corresponds to the PCR product digested with DdeI. No heterozygote individuals were detected. No mutant allele band (234 bp) was observed in group A. Results are shown in Figure 1.

The study of the 6174delT mutation by PCR mismatch technique showed that none of the 382 Group A women carried this mutation. All showed only a band of 127 bp after digestion with PmlI, which corresponds to the normal allele, and diagnosed as normal homozygotes. Therefore in this case no carrier individuals were detected. Figure 2 shows the results obtained.

Figure 3 shows the family histories analyzed, indicating the type of cancer present in each affected individual. The phenotypes of these families are presented in Table I. The average age of diagnosis for breast cancer was 49, and 75% of these families present three or more cases. Other cancer types are presented in Table I. The molecular study performed in the probands and in their healthy relatives indicated that 5382insC and 6174delT mutations were not present.

Figure 1: Electrophoresis in agarose gel (2.5%) of genomic DNA amplified by mismatch PCR to detect de 5382insC mutation. a) Undigested normal sample; b) Normal sample digested with Dde I; c) Marker's molecular weight (100 bp); d) Undigested positive control; e) Positive control digested with Dde I; f) Normal control digested with Dde I.

 

Figure 2: Electrophoresis in agarose gel (2%) of genomic DNA amplified by mismatch PCR to detect de 6174delT mutation. a) Undigested normal sample; b) Normal sample digested with Pm1I; c) Marker's molecular weight (100 bp); d) Normal control digested with Pm1I; e) Positive control digested with Pm1I.

 

DISCUSSION


The analysis of the BIC data base files indicates that as of May 2000, the 5382insC mutation is the second most frequent (200 records) of the total of the mutations associated with breast cancer. It represents approximately 10% of all known BRCA1 mutations (Couch and Weber, 1996) and was first identified in a Utah breast cancer family (Miki et al., 1994). The prevalence of the 5382insC mutation varies considerably among the different populations studied. Struewing et al., (1997) reported 0% in the general Ashkenazi Jewish population. In Russian familial breast/ovarian cancer patients it accounts for 47% of the mutations identified (Gayther et al., 1997b, Ramus et al., 1997). It is also present in 14% of 43 Hungarian breast and ovarian cancer families (Ramus et al., 1997). A high frequency of this mutation (13.3%) has been described in 30 Canadian breast/ovarian cancer families (Simard et al., 1994). It also constitutes a frequent mutation in the German high-risk breast cancer population (Backe et al., 1999). In contrast, Scandinavian studies show a surprisingly low frequency of this mutation. In a population of Southern Finland, the 5382insC was found in only one in 100 (1%) high-risk for breast/ovarian cancer families (Vehmanen et al., 1997). Likewise, the 5382insC mutation was not identified in any of the 47 families with familial breast/ovarian cancer studied in Southern Sweden (Johannsson et al., 1996), in 106 families in Sweden (Hakanson et al., 1997), or in 25 families in Norway (Andersen et al., 1996).

Based on the frequency and geographical distribution in Europe, it has been suggested that the 5382insC mutation originated in the Baltic area during the medieval period approximately 38 generations ago with a decreasing prevalence from the eastern to the western regions in Europe (Szabo and King 1997, Nuehausen et al., 1996).

In Chile, no molecular genetic study has yet been carried out on the 5382insC mutation. In the present study, the 5382insC mutation was not detected in any of the 382 healthy Chilean women with at least two relatives with breast cancer. The contemporary Chilean population stems from the admixture of Amerindian populations and Spaniards (European-Caucasian) initiated in the 16th and 17th centuries. Later immigrations of Germans, Italians, Arabs and Croatians during the 19th century have had only minor impact on the population, generally restricted to specific locations of the country where they settled. The relationship between ethnicity Amerindian admixture, genetic markers and socioeconomic strata has been extensively studied in Chile (Valenzuela and Harb 1977, Valenzuela et al., 1987; Valenzuela 1988). Considering the aforementioned backgrounds of the country, it is possible to speculate that the prevalence of this mutation in the present Chilean admixed population, would be extremely low. The mammographic screening performed on the 382 women of Group A revealed breast cancer in three of them. None of these women presented the 5382insC mutation, which further supports the hypothesis that the frequency of this mutation in the Chilean population might be extremely low.

TABLE I
Phenotypes in families with high risk for
breast cancer

Family
Number of
Female Breast
Cancer
Average
Age (years)
 
Other Cancers

Family 1
3
60
 
Co, Sk, Lu, Ho, Br
Family 2
3
43
 
He
Family 3
2
39
 
Pa, Br
Family 4
3
55
 
Pr, St
Family 5
4
43
 
Co
Family 6
4
51
 
Usc, Bo
Family 7
2
50
 
Ut
Family 8
4
42
 
Ut, St, Usc

Co : Colon Cancer; Ut : Uterine Cancer; Sk : Skin Cancer; St : Stomach Cancer; Br : Brain Cancer; Pa : Pancreatic Cancer; Lu : Lung Cancer; Bo : Bone Cancer; He : Hepatic Cancer; Ho : Hodgkin's Disease; Usc : Unknown Site Cancer

 

Another mutation that has been extensively studied in populations of different ethnic origin is the 6174delT mutation, which is the outcome of a single base pair deletion in codon 1982 of exon 11e of the BRCA2 gene. This mutation creates a termination codon at 2003. The 6174delT mutation has 208 records in the BIC data base; the ethnicity or nationality is indicated in 102 records. The analysis of these latter data established that 89.21% (91/102) corresponds to Ashkenazi Jewish, 0.98% (1/102) to French-German, 3.92% (4/102) to Eastern Europe, 0.98% (1/102) to Canada, 1.85% (2/102) to Central and Eastern Europe, 1.85% (2/102) to Germany, and 0.98% (1/102) to Russia.

The 6174delT mutation presents a high frequency in Jewish women affected with breast cancer, a finding that has been reported in different publications. Neuhausen et al., (1996) reports a 7.5% frequency (6/80) for this mutation in Ashkenazi Jewish women with breast cancer diagnosed before age 42. This data shows that the frequency increases as the age of diagnosis decreases. In the same study, the mutation was not found in 93 Non-Jewish women with breast cancer diagnosed before age 42. Studies done by Oddoux et al., (1996) confirm the previous data, reporting a frequency of 6.5% (7/107) in Ashkenazi Jewish women with breast cancer. Furthermore, in the study carried out by Van Der Looij et al. (2000) with 500 Hungarian women with breast cancer, the 6174delT mutation was not found, nor was it found in Diez et al.'s 1999 study of 298 Spanish female breast cancer patients.

Our study of 382 healthy Chilean women (Group A) with family backgrounds of breast cancer did not detect the 6174delT mutation. Furthermore, the three affected women with familial breast cancer belonging to Group A also gave negative results for the 6174delT mutation. This mutation was also not detected in probands or their healthy relatives belonging to the 8 Chilean families (Group B) with familial breast cancer.

The ethnic origin of the contemporary Chilean population, the data reported in the literature, and the results obtained in this study suggest that this mutation may not be present in this population or have a very low frequency. This hypothesis could be confirmed by the analysis of a greater number of histories. This genetic study is part of a breast cancer screening program that also includes annual mammography and clinical breast examination over a five year period. Strategies to reduce morbidity and mortality associated with breast cancer lie in the early detection of women with genetic risk.

It is also worth mentioning that the PCR primer mismatch technique provides a rapid and reliable detection method for the 5382insC and 6174delT mutations and will be very useful for the analysis of large breast cancer populations.

 

ACKNOWLEDGEMENTS

This research was funded by the Avon Breast Cancer Crusade-CONAC and Fondecyt project number 1010800.

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