Evidence of Founder Mutations in Finnish BRCA1 and BRCA2 Families

Huusko, Pia; Pääkkönen, Kati; Launonen, Virpi; Pöyhönen, Minna; Blanco, Guillermo; Kauppila, Antti; Puistola, Ulla; Kiviniemi, Heikki; Kujala, Marika; Leisti, J; Winqvist, Robert

doi:10.1086/301880

Cited by 77 publications

(77 citation statements)

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“…Both Oulu and Helsinki families were previously tested negative for BRCA1 and BRCA2 mutations by heteroduplex analysis (ie DGGE, SSCP or CSGE), protein truncation test and linkage analysis (data not shown). 5,7,8 In addition, the Oulu families were excluded having large rearrangements by Southern blot analysis. 16 All families were screened for CHEK2 mutation 1100delC, which is present in 1.1 -1.4% of the normal population and has recently been identified as a lowpenetrance allele with a two-fold increased breast cancer risk.…”

Section: Familiesmentioning

confidence: 99%

“…For example, a large fraction of breast cancer in Ashkenazi Jewish families can be explained by prevalent founder mutations in the BRCA1 and BRCA2 genes, 6 whereas in the Finnish population mutations in these genes seem to be less frequent. 5,7,8 Many efforts have been made to discover additional, previously unknown susceptibility genes by linkage or association analyses. Positive linkage has been observed at chromosome region 8p12 -p22 in two German families.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide scanning for linkage in Finnish breast cancer families

et al. 2003

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Only a proportion of breast cancer families has germline mutations in the BRCA1 or BRCA2 genes, suggesting the presence of additional susceptibility genes. Finding such genes by linkage analysis has turned out to be difficult due to the genetic heterogeneity of the disease, phenocopies and incomplete penetrance of the mutations. Isolated populations may be helpful in reducing the level of genetic heterogeneity and in providing useful starting points for further genetic analyses. Here, we report results from a genome-wide linkage analysis of 14 high-risk breast cancer families from Finland. These families tested negative for BRCA1 and BRCA2 germline mutations and showed no linkage to the 13q21 region, recently proposed as an additional susceptibility locus. Suggestive linkage was seen at marker D2S364 (2q32) with a parametric two-point LOD score of 1.61 (h ¼ 0), and an LOD score of 2.49 in nonparametric analyses. Additional genotyping of a 40 cM chromosomal region surrounding the region of interest yielded a maximum parametric two-point LOD score of 1.80 (h ¼ 0) at D2S2262 and a nonparametric LOD score of 3.11 at an adjacent novel marker 11291M1 in BAC RP11-67G7. A nonparametric multipoint LOD score of 3.20 was seen at 11291M1 under the assumption of dominant inheritance. While not providing proof of linkage considering the small number of families and large number of laboratory and statistical analyses performed, these results warrant further studies of the 2q32 chromosomal region as a candidate breast cancer susceptibility locus. Both linkage and association studies are likely to be useful, particularly in other isolated populations.

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Section: Familiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genome-wide scanning for linkage in Finnish breast cancer families

et al. 2003

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“…For 53 other families, all previously reported 18 Finnish BRCA1 and BRCA2 mutations (Vehmanen et al, 1997a,b;Huusko et al, 1998;Sarantaus et al, 2000), and one recently discovered new BRCA1 mutation (3264 delT) were analysed by allele-specific oligonucleotide (ASO) (Friedman et al, 1995) hybridization or restriction fragment length polymorphism (RFLP). The RFLP analyses were designed such that incomplete A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families Summary Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast and ovarian cancer.…”

Section: Methodsmentioning

confidence: 99%

“…In previous studies, 11 recurrent founder mutations have been found to account for vast majority (84%) of all Finnish BRCA1 and BRCA2 families (Vehmanen et al, 1997a,b;Huusko et al, 1998). Therefore, screening of the known mutations was used to evaluate the feasibility of screening of the BRCA1 and BRCA2 genes in these families.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, Goelen et al (1999) reported that BRCA1/2 mutation testing can be done with reasonable efficiency in the Belgian population when there are 2 symptomatic family members. Prevalent founder mutations account for a large fraction of breast cancer families in Belgium (Peelen et al, 1997;Goelen et al, 1999), while BRCA1 and BRCA2 mutations are more rare in the Finnish population (Vehmanen et al, 1997a,b;Huusko et al, 1998). Also in studies of patients with early onset breast cancer, only a small proportion of familial risk of breast cancer has been attributed to these two genes, and the majority appears to be due to other genes (Peto et al, 1999).…”

Section: Mutation Frequencies In Families With Defined Family Historymentioning

confidence: 99%

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A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families

et al. 2001

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Mutations in the two breast-ovarian cancer susceptibility genes, BRCA1 and BRCA2, account for a varying fraction of breast cancer families in different populations (Szabo and King, 1997). Both BRCA1 and BRCA2 mutations are scattered throughout the large coding regions of the genes (Breast Cancer Information Core). In admixed populations, most mutations appear uniquely in single families only, making the mutation screening laborious and expensive. Furthermore, there is also evidence of other predisposing genes (Ford et al, 1998;Kainu et al, 2000). It is, therefore, important to find the clinical risk factors that could best predict the presence of BRCA1 and BRCA2 mutations, so that the screening could be directed to potential mutation carrier families. Several probability models for mutation detection have been developed. These are, however, based only on BRCA1 (Berry et al, 1997;Couch et al, 1997;Shattuck-Eidens et al, 1997), focus on specific founder mutations in the Ashkenazi population (Foulkers et al, 1999;Hodgson et al, 1999;Hopper and Jenkins, 1999), or require information such as penetrance estimations not available in all populations (Berry et al, 1997;Parmigiani et al, 1998; ChangClaude et al, 1999).Here we have developed a model for predicting the presence of a BRCA1 or BRCA2 mutation in families with 3 or more relatives affected with breast or ovarian cancer. We also compared this model with those of Shattuck-Eidens et al (1997) and Couch et al (1997) originally designed for BRCA1 only. Additionally, the frequency of BRCA1/2 mutations was studied in 295 families with two affected family members to evaluate the feasibility of genetic screening in families with moderate family history. PATIENTS AND METHODSThe cohort studied consisted of 148 families with 3 or more 1st or 2nd degree relatives affected with breast or ovarian cancer. The families were identified by patient interviews, and full pedigrees were constructed with the confirmation of all genealogy data through the Finnish population registration as well as diagnostic data through hospital records and/or Finnish Cancer Registry as previously described (Vehmanen et al, 1997a,b;Eerola et al, 2000). Additionally, 295 breast cancer cases with one 1st degree relative affected with breast or ovarian cancer and identified in the patient cohorts described in Eerola et al (2000) were also studied. In the following, these are called small families. The family history of these cases was based on information reported by the index patient. All patients participating in the study signed an informed consent before the blood sample for the genetic analysis was taken. This study has been approved by the Ethical Committees of Departments of Obstetrics and Gynaecology, and Oncology, HUCH, and appropriate permissions were obtained from the Ministry of Social Affairs and Health in Finland.The mutations identified by a complete mutation analysis of the whole coding sequences and exon/intron boundaries of the genes in 95 of these families have been previously reported...

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Ethnic differences in cancer risk resulting from genetic variation

Neuhausen¹

1999

Cancer

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Evidence of Founder Mutations in Finnish BRCA1 and BRCA2 Families

Cited by 77 publications

References 13 publications

Genome-wide scanning for linkage in Finnish breast cancer families

Genome-wide scanning for linkage in Finnish breast cancer families

A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families

Ethnic differences in cancer risk resulting from genetic variation

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