Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland

Sarantaus, Laura; Huusko, Pia; Eerola, Hannaleena; Launonen, Virpi; Vehmanen, Paula; Rapakko, Katrin; Gillanders, Elizabeth M.; Syrjäkoski, Kirsi; Kainu, Tommi; Vahteristo, Pia; Krahe, Ralf; Pääkkönen, Kati; Hartikainen, Jaana M.; Blomqvist, Carl; Löppönen, Tuija; Holli, Kaija; Bützow, Ralf; Borg, Åke; Arver, Brita; Holmberg, Eva; Mannermaa, Arto; Kere, Juha; Kallioniemi, Olli; Winqvist, Robert; Nevanlinna, Heli

doi:10.1038/sj.ejhg.5200529

Cited by 77 publications

(72 citation statements)

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“…Thus about 5% of the ovarian carcinoma patients were carriers of the recurrent BRCA1/2 founder mutations. The only unique mutation had been identified previously 21 in the same patient that also belonged to the present study cohort. Large genomic deletions that have been identified as major BRCA1 founder mutations in the Netherlands 27 do not seem to be significant in the Finnish population; no such mutations were found among the 11 ovarian carcinoma patients studied here or in another study of 80 Finnish breast and/or ovarian cancer families (R Winqvist, personal communication).…”

Section: Resultsmentioning

confidence: 63%

BRCA1 and BRCA2 mutations among 233 unselected Finnish ovarian carcinoma patients

et al. 2001

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Germline mutations of BRCA1 and BRCA2 predispose to hereditary breast-ovarian cancer syndrome. In Finland, 20 different BRCA1/2 mutations have been identified, and 13 of them are founder mutations that account for the vast majority of Finnish BRCA1/2 families. The purpose of our study was to determine the prevalence of BRCA1/2 mutations in unselected Finnish ovarian carcinoma patients and to evaluate the relationship between mutation carrier status and personal/family history of cancer. Two hundred and thirtythree patients were screened for all the 20 BRCA1/2 mutations known in the Finnish population. Additionally, a subgroup of patients with personal history of breast cancer and/or family history of breast and/or ovarian cancer was screened for novel BRCA1/2 mutations. Thirteen patients (5.6%) had mutations: eleven in BRCA1 and two in BRCA2. All the mutation-positive patients were carriers of the previously known Finnish BRCA1/2 mutations, and seven recurrent founder mutations accounted for 12 of the 13 mutations detected. A logistic regression analysis was used to determine the odds of mutation for ovarian carcinoma patients. The most significant predictor of a mutation was the presence of both breast and ovarian cancer in the same woman, but family history of breast cancer was also strongly related to mutation carrier status. Although BRCA1/2 mutation testing is not warranted in the general Finnish ovarian cancer patient population, patients who have also been diagnosed with breast cancer or have family history of breast or breast and ovarian cancer could benefit from referral to genetic counselling and mutation testing. European Journal of Human Genetics (2001) 9, 424 ± 430.

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Section: Resultsmentioning

confidence: 63%

BRCA1 and BRCA2 mutations among 233 unselected Finnish ovarian carcinoma patients

et al. 2001

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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%

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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“…Recurrent founder mutations in several cancer susceptibility genes, including the BRCA2, PALB2, and RAD51C FA genes, have been identified in the Finnish population (14)(15)(16). The PALB2 and RAD51C founder mutations have been detected at 2% frequency in Finnish breast or ovarian cancer families (15)(16)(17), whereas, in other populations, mutations in these genes are rare and often unique for each family.…”

Section: Significancementioning

confidence: 99%

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

Kiiski

Pelttari

Khan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26-2.75; P = 0.0018], with particular enrichment among patients with triplenegative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.breast cancer | DNA repair | FANCM | exome sequencing | triple-negative breast cancer B reast cancer is the most common cancer affecting women worldwide. It is also the principal cause of death from cancer among women globally, accounting for 14% of all cancer deaths (1). The etiology of breast cancer is multifactorial, and the risk depends on various factors like age, family history, and reproductive, hormonal, or dietary factors. The majority of breast cancers are sporadic, but approximately 15% of cases show familial aggregation (2, 3). Since the identification of the first breast and ovarian cancer susceptibility genes breast cancer 1 and 2 (BRCA1 and BRCA2, respectively) by linkage analysis and positional cloning, several breast cancer susceptibility genes and alleles with different levels of risk and prevalence in the population have been recognized. BRCA1 and BRCA2 mutation carriers have more than 10-fold increased risk of breast cancer compared with women in

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Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland

Cited by 77 publications

References 22 publications

BRCA1 and BRCA2 mutations among 233 unselected Finnish ovarian carcinoma patients

BRCA1 and BRCA2 mutations among 233 unselected Finnish ovarian carcinoma patients

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

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

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