High frequency of recurrent mutations inBRCA1 andBRCA2 genes in Polish families with breast and ovarian cancer

Grzybowska, Ewa; Zientek, Helena; Jasinska, Anna J.; Rusin, Marek; Kozlowski, Piotr; Sobczak, Krzysztof; Sikorska, A.; Kwiatkowska, Eliza; Gorniak, Laura; Kalinowska, Ewa; Utracka-Hutka, Beata; Włoch, Jan; Chmielik, Ewa; Krzyżosiak, Włodzimierz J.

doi:10.1002/1098-1004(200012)16:6<482::aid-humu5>3.0.co;2-o

Cited by 40 publications

(34 citation statements)

References 26 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

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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

Self Cite

179

148

View full text Add to dashboard Cite

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“…The 9631delC mutation was found in the region of oligonucleotide domain OB3 and led to formation of stop codon 3162. That mutation was described by Grzybowska et al [18] in three patients with breast and ovarian cancers and a family history of those tumours. We think that the mutation is characteristic of patients from the Polish population.…”

Section: Discussionmentioning

confidence: 72%

Novel germline mutations in BRCA2 gene among breast and breast-ovarian cancer families from Poland

et al. 2010

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Identification of mutations in the BRCA2 gene and estimation of their clinical consequences for women and men treated in the Maria Sklodowska-Curie Memorial Cancer Center Warsaw, Poland in the years 1998-2008. The probands (97 women and 8 men) had a family history of breast and ovarian cancer (median age 46). The presence of molecular changes was examined in DNA isolated from peripheral blood lymphocytes. Germline mutations in 27 exons of the BRCA2 gene were screened by 'touchdown' PCR amplification, DHPLC and sequencing. Missense mutations were classified by multiple-sequences alignments of orthologous BRCA2 protein sequences with T-Coffee software. 39 molecular changes (8 novel) were identified in the BRCA2 gene in 105 investigated patients. In 12 patients the following pathogenic mutations were identified: 5467insT, 6174delT, 6192delAT, 6675delTA, 8141del5, 9152delT, 9326insA, 9631delC, IVS23-2A > G and E394X. The presence of 10 missense type mutations was detected including the following: D1420O, T1915 M, N3124I. The determination of pathogenic status of molecular variants detected in BRCA2 gene, described in the BIC mutation database as 'UV' depends on many parameters. Important is the assessment of the evolutionary conservation of their protein sequences and studying of the frequency of molecular variants detected in breast cancer patients and in population. A high diversity was found of the pathogenic mutations detected in BRCA2 gene in the Polish population.

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“…Both alterations were detected in adult patients with multiple primaries who appeared to be members of LFS/LFL families [19,20]. It is in contrast to the relatively frequently detected germline BRCA1 mutations in breast/ovarian cancer families [20], a cancer phenotype to some extent overlapping with LF syndromes [4,7,10].…”

Section: Discussionmentioning

confidence: 99%

p53 tetramerization domain mutations: germline R342X and R342P, and somatic R337G identified in pediatric patients with Li–Fraumeni syndrome and a child with adrenocortical carcinoma

2009

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Germline p53 mutations are associated with Li-Fraumeni syndrome (LFS) and other familial cancer phenotypes not fulfilling the definition for LFS. The majority of germline p53 mutations cluster in exons 5-8, corresponding to a DNA binding domain. We report the identification of two germline mutations and a somatic mutation in a tetramerization domain (TD), a rare site for mutations. The germline mutation, R342X (16915C>T), and the novel mutation, R342P (16916G>C), were found in a child with adrenocortical carcinoma and in a LFS pediatric patient with multiple primaries. The novel somatic mutation, R337G (16900C>G), was discovered in myelodysplastic syndrome with transformation to acute myeloblastic leukemia, developing as the third primary in the LFS child. These findings add further information on p53 TD mutations and TD contribution to tumorigenesis.

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High frequency of recurrent mutations inBRCA1 andBRCA2 genes in Polish families with breast and ovarian cancer

Cited by 40 publications

References 26 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

Novel germline mutations in BRCA2 gene among breast and breast-ovarian cancer families from Poland

p53 tetramerization domain mutations: germline R342X and R342P, and somatic R337G identified in pediatric patients with Li–Fraumeni syndrome and a child with adrenocortical carcinoma

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