Founder BRCA1 mutations and two novel germline BRCA2 mutations in breast and/or ovarian cancer families from North-Eastern Poland

Looij, Marco van der; Wysocka, Barbara; Brożek, Izabela; Jassem, Jacek; Limon, Janusz; Olàh, Edith

doi:10.1002/(sici)1098-1004(200005)15:5<480::aid-humu13>3.0.co;2-g

Cited by 32 publications

(27 citation statements)

References 20 publications

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“…Smaller studies, cited in Table V, reported 50 mutations (39%) in 127 families with at least 3 affected relatives. [11][12][13][14][15][16][17]25,30 The proportion of families with BRCA1 mutations in our series is much higher (64%). It is possible that the average family size in the present study is larger than that in the smaller series.…”

Section: Discussionmentioning

confidence: 99%

“…11 Three BRCA1 mutations (5382insC, C61G and 4153delA) are common in Poland, 11 but several other BRCA1 and BRCA2 mutations have also been reported in one or a few families. [11][12][13][14][15][16][17] Our goal was to describe the frequency of BRCA1 and BRCA2 constitutional mutations in a series of 200 breast cancer and breast-ovarian cancer families representing all regions of Poland and to determine the relative contributions of founder and nonfounder mutations. Our study was conducted to advise on national genetic screening policies for the Polish population.…”

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confidence: 99%

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A high proportion of founder BRCA1 mutations in Polish breast cancer families

Górski

Jakubowska

Huzarski

et al. 2004

Intl Journal of Cancer

179

148

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Three mutations in BRCA1 (5382insC, C61G and 4153delA) are common in Poland and account for the majority of mutations identified to date in Polish breast and breast-ovarian cancer families. It is not known, however, to what extent these 3 founder mutations account for all of the BRCA mutations distributed throughout the country. This question has important implications for health policy and the design of epidemiologic studies. To establish the relative contributions of founder and nonfounder BRCA mutations, we established the entire spectrum of BRCA1 and BRCA2 mutations in a large set of breast-ovarian cancer families with origins in all regions of Poland. We sequenced the entire coding regions of the BRCA1 and BRCA2 genes in 100 Polish families with 3 or more cases of breast cancer and in 100 families with cases of both breast and ovarian cancer. A mutation in BRCA1 or BRCA2 was detected in 66% of breast cancer families and in 63% of breast-ovarian cancer families. Of 129 mutations, 122 (94.6%) were in BRCA1 and 7 (5.4%) were in BRCA2. Of the 122 families with BRCA1 mutations, 119 (97.5%) had a recurrent mutation (i.e., one that was seen in at least 2 families). In particular, 111 families (91.0%) carried one of the 3 common founder mutations. The mutation spectrum was not different between families with and without ovarian cancer. These findings suggest that a rapid and inexpensive assay directed at identifying the 3 common founder mutations will have a sensitivity of 86% compared to a much more costly and labor-intensive full-sequence analysis of both genes. This rapid test will facilitate large-scale national epidemiologic and clinical studies of hereditary breast cancer, potentially including studies of chemoprevention. Germline mutations in BRCA1 (MIM 113-705) and BRCA2 (MIM 600185) account for familial clustering in the majority of families with both breast and ovarian cancers and in approximately one-half of families with site-specific breast cancer. 1-3 Of the more than 1,000 BRCA mutations reported to the Breast Cancer Information Core (BIC) database, many are unique but there are also numerous examples of founder mutations. Founder mutations have been reported in genetic isolates such as Ashkenazi Jews 4,5 and the Icelandic, 6 Finnish, 7 Dutch 8,9 and French Canadian 10 populations. Founder mutations have also been noted in Slavic countries, including Poland. 11 Three BRCA1 mutations (5382insC, C61G and 4153delA) are common in Poland, 11 but several other BRCA1 and BRCA2 mutations have also been reported in one or a few families. 11-17 Our goal was to describe the frequency of BRCA1 and BRCA2 constitutional mutations in a series of 200 breast cancer and breast-ovarian cancer families representing all regions of

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A high proportion of founder BRCA1 mutations in Polish breast cancer families

Górski

Jakubowska

Huzarski

et al. 2004

Intl Journal of Cancer

179

148

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“…In Polish families, with a strong aggregation of breast and ovarian cancers and no other cancer, the frequency of BRCA2 mutations is very low and does not exceed 5 -10% (van Der Looij et al, 2000;Gó rski unpublished data).…”

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confidence: 99%

BRCA2 gene mutations in families with aggregations of breast and stomach cancers

Jakubowska¹,

Nej

Huzarski³

et al. 2002

Br J Cancer

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Stomach cancer ranks second to lung cancer in the global cancer burden. It is estimated that 25% of families meeting the criteria for hereditary diffuse gastric carcinoma (HDCG) will have germline mutations in the E-cadherin gene. Evidence suggests that stomach cancer might also be a malignant manifestation of other inherited predispositions to disease. Recently, it has been reported that the incidence of stomach cancer is significantly increased in BRCA2 gene mutation carriers. We analysed by direct sequencing the BRCA2 gene in 29 breast cancer patients derived from 29 families with an aggregation of at least one female breast cancer diagnosed before the age of 50 years and one male stomach cancer diagnosed before the age of 55 years. In all but one of these families at least one additional relative was also affected by a malignant tumour. We identified three frameshift mutations and three sequence variants -potentially missense mutations, in six unrelated patients representing 20.7% (six out of 29) of the families investigated. Our results confirm that BRCA2 gene mutations are also associated with familial aggregations of not only breast but also of stomach cancer. In comparison to the number of cancers expected in the study population compared to the general population there is an over-representation of several cancers with significant confidence intervals to suggest that the associations are real and not a selection artefact.

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“…This mutation has been described in Poland (Jakubowska et al, 2001, van Der Looij et al, 2000a, Hungary (van Der Looij et al, 2000b), Germany (Spitzer et al, 2000), and in other regions of Europe (BIC), although it is not a recurrent mutation in the Spanish population. The affected family with the C61G mutation had no recent European ancestry, the maternal lineage having only Chilean ancestry dating back several generations.…”

Section: Discussionmentioning

confidence: 94%

Molecular analysis of the eighteen most frequent mutations in the BRCA1 gene in 63 Chilean breast cancer families

et al. 2004

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BRCA1 gene mutations account for nearly all families with multiple cases of both early onset breast and/or ovarian cancer and about 30% of hereditary breast cancer. Although to date more than 1,237 distinct mutations, polymorphisms, and variants have been described, several mutations have been found to be recurrent in this gene. We have analyzed 63 Chilean breast/ovarian cancer families for eighteen frequent BRCA1 mutations. The analysis of the five exons and two introns in which these mutations are located was made using mismatch PCR assay, ASO hybridization assay, restriction fragment analysis, allele specific PCR assay and direct sequentiation techniques. Two BRCA1 mutations (185delAG and C61G) and one variant of unknown significance (E1250K) were found in four of these families. Also, a new mutation (4185delCAAG) and one previously described polymorphism (E1038G) were found in two other families. The 185delAG was found in a 3.17 % of the families and the others were present only in one of the families of this cohort. Therefore these mutations are not prominent in the Chilean population. The variant of unknown significance and the polymorphism detected could represent a founder effect of Spanish origin.

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Founder BRCA1 mutations and two novel germline BRCA2 mutations in breast and/or ovarian cancer families from North-Eastern Poland

Cited by 32 publications

References 20 publications

A high proportion of founder BRCA1 mutations in Polish breast cancer families

A high proportion of founder BRCA1 mutations in Polish breast cancer families

BRCA2 gene mutations in families with aggregations of breast and stomach cancers

Molecular analysis of the eighteen most frequent mutations in the BRCA1 gene in 63 Chilean breast cancer families

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