Elsevier

European Journal of Cancer

Volume 37, Issue 16, November 2001, Pages 2082-2090
European Journal of Cancer

Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families

https://doi.org/10.1016/S0959-8049(01)00244-1Get rights and content

Abstract

In 517 Dutch families at a family cancer clinic, we screened for BRCA1/2 alterations using the Protein Truncation Test (PTT) covering approximately 60% of the coding sequences of both genes and direct testing for a number of previously identified Dutch recurrent mutations. In 119 (23%) of the 517 families, we detected a mutation in BRCA1 (n=98; 19%) or BRCA2 (n=21; 4%). BRCA1/2 mutations were found in 72 (52%) of 138 families with breast and ovarian cancer (HBOC), in 43 (13%) of the 339 families with breast cancer only (HBC), in 4 (36%) of 11 families with ovarian cancer only (HOC), and in nine of 29 families with one single young case (<40 years) of breast cancer. Between the different subgroups of families (subdivided by the number of patients, cancer phenotype and age of onset) the proportion of BRCA1/2 mutations detected, varied between 6 and 82%. Eight different mutations, each encountered in at least six distinct families, represented as much as 61% (73/119 families) of all mutations found. The original birthplaces of the ancestors of carriers of these eight recurrent mutations were traced. To estimate the relative contribution of two important regional recurrent mutations (BRCA1 founder mutation IVS12-1643del3835 and BRCA2 founder mutation 5579insA) to the overall occurrence of breast cancer, we performed a population-based study in two specific small regions. The two region-specific BRCA1 and BRCA2 founder mutations were detected in 2.8% (3/106) and 3.2% (3/93) of the unselected breast tumours, respectively. Of tumours diagnosed before the age of 50 years, 6.9% (3/43) and 6.6% (2/30) carried the region-specific founder mutation. Thus, large regional differences exist in the prevalence of certain specific BRCA1/BRCA2 founder mutations, even in very small areas concerning populations of approximately 200 000 inhabitants.

Introduction

Since the identification of the breast cancer susceptibility genes BRCA1[1] and BRCA2[2] in 1994 and 1995, respectively, a growing number of members from families with clustering of breast and/or ovarian cancer have sought genetic counselling [3]. In general, genetic testing of individuals at risk can only be offered when a specific mutation that segregates with the disease has been identified within the family. Both BRCA1 and BRCA2 are large genes and germline mutations in these genes are scattered throughout the coding sequences.

Both for practical and cost-effectiveness reasons, the probability that an individual with breast or ovarian cancer may have a mutation in BRCA1/BRCA2 is an important consideration in genetic testing. Therefore models have been developed, based on characteristics such as age at diagnosis of breast cancer and the number of breast and/or ovarian cancer patients in a family, to predict mutation carrier status before testing 4, 5, 6, 7.

The ethnic background of a patient can strongly influence these probability models. For example, Ashkenazi Jewish breast cancer patients have significantly higher probabilities for carrying a BRCA1 mutation [4]. This is explained by the fact that 3 BRCA1/2 founder mutations (BRCA1 185delAG, 5382insC and BRCA2 6174delT) are encountered at frequencies of 1, 0.1 and 1.5%, respectively, in the Ashkenazi Jewish population 8, 9. Similar effects were observed in breast cancer patients from the Icelandic population, in which the BRCA2 999del5 founder mutation is prevalent (population frequency of 0.6%) 10, 11.

In other countries, including The Netherlands, several recurrent mutations in the BRCA1 and BRCA2 genes have been described 12, 13, 14, 15, 16, 17, 18, 19, 20, 21. Thus far, haplotype analysis of Dutch recurrent mutations was consistent with a single origin of these mutations, indicating that they are founder mutations. In particular, the recurrent mutations IVS12-1643del3835 in BRCA1 and 5579insA in BRCA2, highlighted in the present study, were also shown to be founder mutations 15, 18.

By the end of 1998, 517 families with either clustering of breast and/or ovarian cancer or a single case of early onset breast cancer were registered at the Family Cancer Clinic of the Daniel den Hoed Cancer Center and/or the Department of Clinical Genetics of the Erasmus University Rotterdam. We determined family characteristics in terms of the age at onset of breast cancer, the presence of ovarian cancer and the number of affected individuals in the pedigree in relation to the percentage of mutations identified with a routinely applied set of mutation-detection methods.

Frequencies of BRCA1 and BRCA2 founder mutations detected in the Southwestern part of The Netherlands differed from those reported elsewhere in The Netherlands [16] (see the BIC database). Therefore, we looked more closely into the geographical origin of the families with an identified mutation and investigated the prevalence of certain founder mutations in population-based series of breast cancer patients from specific regions within the South-western part of The Netherlands.

Section snippets

Families and geographical distribution of families with a mutation

A series of families with clustering of breast and/or ovarian cancer was referred for onco-genetic and medical counselling to our departments between 1 January 1994 and 1 January 1999; this closing date was chosen because the routinely applied mutation-detection methods at that time took 6 to 12 months. Eligible for the present study were all families out of these series in which BRCA1/BRCA2 mutation analysis was performed (n=517), according to a protocol approved by the Medical Ethical

Family characteristics and mutation spectrum

Overall, in the 517 families 119 (23%) mutations in total were detected in BRCA1 (n=98; 19%) and in BRCA2 (n=21; 4%). Table 3 lists the general clinical characteristics of the families in which genetic analysis was performed and the number of mutations found per gene. In 52% (n=72) of 138 families with both breast and ovarian cancer (HBOC), a mutation was identified: in BRCA1 in 46% (n=64) and in BRCA2 in 6% (n=8). In families with breast cancer only (HBC), in 13% (n=43) of the 339 families a

Discussion

In this report, we describe the results of a BRCA1/BRCA2 germline mutation analysis in a large series of 517 families visiting our Family Cancer Clinic. Overall, we detected a BRCA1 mutation in 19% of the families, while in 4% a BRCA2 mutation was identified. In accordance with others, we found that the presence of ovarian cancer, early onset of breast cancer (<40 years), and increasing numbers of young affected women in a family, greatly enhanced the probability of finding a mutation 4, 5, 6, 7

Electronic-Database Information

Accession numbers and URLs for data in this article are as follows: BIC: http://www.nhgri.nih.gov/Intramural_research/Lab_transfer/Bic/ (for BRCA1 and BRCA2 mutations); Dutch database: http://ruly70.medfac.leidenuniv.nl/∼devilee/Lab/b1nl5.htm; http://ruly70.medfac.leidenuniv.nl/∼devilee/Lab/b2nl5.htm; (for BRCA1 and BRCA2 mutations in The Netherlands); Online Mendelian Inheritance in Man (OMIM): http://www.ncbi.nlm.nih.gov./Omim/ (for BRCA1 [MIM 113705] and BRCA2 [MIM 600185]).

Acknowledgements

The authors thank Robert van der Helm, Mieke Kraan-van der Est, Lisbet van Sörnsen de Koste-Kok, Renske Olmer and Petra Bos for excellent technical assistance, and Ellen Crepin for collecting data. We thank Conny van der Meer, Rogier Olderburg and Margreethe van Vliet for genetic counselling. This study was supported by grant DDHK 95-953 from the Dutch Cancer Society.

References (32)

  • C. Shattuck-Eidens et al.

    BRCA1 sequence analysis in women at high risk for susceptibility mutations; risk factor analysis and implications for genetic testing

    JAMA

    (1997)
  • T.S. Frank et al.

    Sequence analysis of BRCA1 and BRCA2Correlation of mutations with family history and ovarian cancer risk

    J. Clin. Oncol.

    (1998)
  • J.P. Struewing et al.

    The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals

    Nat. Genet.

    (1995)
  • B.B. Roa et al.

    Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2

    Nat. Genet.

    (1996)
  • S. Thorlacius et al.

    A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes

    Nat. Genet.

    (1996)
  • S. Thorlacius et al.

    Study of a single BRCA2 mutation with high carrier frequency in a small population

    Am. J. Hum. Genet.

    (1997)
  • Cited by (0)

    1

    All authors are from the Family Cancer Clinic and Daniel den Hoed Cancer Center at the University Hospital Rotterdam, Rotterdam, The Netherlands

    View full text