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Novel sequence variants and a high frequency of recurrent polymorphisms in BRCA1 gene in Sri Lankan breast cancer patients and at risk individuals.

De Silva W, Karunanayake EH, Tennekoon KH, Allen M, Amarasinghe I, Angunawala P, Ziard MH - BMC Cancer (2008)

Bottom Line: Nineteen sequence variants were found in BRCA1 gene.After screening of 66 patients with family history and 64 sporadic breast cancer patients, 2 deleterious mutations (c.3086delT and c.5404delG) in two families were identified and two more possibly pathogenic mutations (c.856T>G and IVS17-2A>T) in two families were identified.BRCA1--Gene Bank: Accession # U14680 Version # 14680.1.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Biochemistry Molecular Biology and Biotechnology, University of Colombo, 90, Cumaratunga Munidasa Mawatha, Colombo 03, Sri Lanka. Wasanthi_e@yahoo.co.uk

ABSTRACT

Background: Breast Cancer is the most commonly diagnosed cancer among Sri Lankan women. Germline mutations in the susceptibility genes BRCA1 and BRCA2 in hereditary breast/ovarian cancer, though low in prevalence, are highly penetrant and show geographical variations. There have been only a few reports from Asia on mutations in BRCA1/2 genes and none from Sri Lanka.

Methods: A total of 130 patients with (N = 66) and without (N = 64) a family history of breast cancer, 70 unaffected individuals with a family history of breast cancer and 40 control subjects were analysed for BRCA1 mutations. All but exon 11 were screened by single strand conformation analysis (SSCP) and heteroduplex analysis. PCR products which showed abnormal patterns in SSCP were sequenced. Exon 11 was directly sequenced.

Results: Nineteen sequence variants were found in BRCA1 gene. Two novel deleterious frame-shift mutations; c.3086delT/exon11 (in one patient) and c.5404delG/exon21 (in one patient and two of her family members) were identified. A possibly pathogenic novel missense mutation (c.856T>G/exon 11) and three novel intronic variants (IVS7+36C>T, IVS7+41C>T, IVS7+49del15) were characterised. Ten previously reported common polymorphisms and three previously reported intronic variants were also observed.

Conclusion: After screening of 66 patients with family history and 64 sporadic breast cancer patients, 2 deleterious mutations (c.3086delT and c.5404delG) in two families were identified and two more possibly pathogenic mutations (c.856T>G and IVS17-2A>T) in two families were identified.

Data base: BRCA1--Gene Bank: Accession # U14680 Version # 14680.1.

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Related in: MedlinePlus

Pedigree of family F-01. Age of onset of the disease for members affected with breast cancer, other cancers and benign breast disease indicated.
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Figure 2: Pedigree of family F-01. Age of onset of the disease for members affected with breast cancer, other cancers and benign breast disease indicated.

Mentions: SSCP analysis showed abnormal migration patterns in polyacrylamide gels for exons 7, 8, 13, 16, 18 and 21. Abnormal migration patterns in SSCP analysis of exon 21 were seen only in three study participants (III.12, III.16, III.19) of a single sib ship (Figure 1). The pedigree of this family (F-01) is shown in Figure 2. Direct sequencing showed the presence of a novel frame shift mutation: c.5404delG (codon 1762) resulting in a stop codon at 1764 of BRCA1 protein in all three of them. This family was Sinhalese in ethnicity and had five individuals of three different generations affected by breast, uterine and salivary gland cancer. Out of the three with the mutation, one (III.16) developed breast cancer at 33 years of age and the other two were her first and second-degree female relatives. However these two family members do not have clinical or radiological evidence of breast cancer to date. The patient and her sister carrying the same mutation were the daughters of a breast cancer patient diagnosed with the disease at 38 years of age. The second-degree female relative who carries the same mutation was the daughter of our breast cancer patient's maternal aunt who was diagnosed with uterine cancer at the age of 42 years. These breast and uterine cancer patients in the FII generations had deceased and no archival specimens were available for genetic studies. We screened 19 first and second degree living relatives of our index case (III.16) including her three sisters and two brothers for BRCA1 mutations.


Novel sequence variants and a high frequency of recurrent polymorphisms in BRCA1 gene in Sri Lankan breast cancer patients and at risk individuals.

De Silva W, Karunanayake EH, Tennekoon KH, Allen M, Amarasinghe I, Angunawala P, Ziard MH - BMC Cancer (2008)

Pedigree of family F-01. Age of onset of the disease for members affected with breast cancer, other cancers and benign breast disease indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2519088&req=5

Figure 2: Pedigree of family F-01. Age of onset of the disease for members affected with breast cancer, other cancers and benign breast disease indicated.
Mentions: SSCP analysis showed abnormal migration patterns in polyacrylamide gels for exons 7, 8, 13, 16, 18 and 21. Abnormal migration patterns in SSCP analysis of exon 21 were seen only in three study participants (III.12, III.16, III.19) of a single sib ship (Figure 1). The pedigree of this family (F-01) is shown in Figure 2. Direct sequencing showed the presence of a novel frame shift mutation: c.5404delG (codon 1762) resulting in a stop codon at 1764 of BRCA1 protein in all three of them. This family was Sinhalese in ethnicity and had five individuals of three different generations affected by breast, uterine and salivary gland cancer. Out of the three with the mutation, one (III.16) developed breast cancer at 33 years of age and the other two were her first and second-degree female relatives. However these two family members do not have clinical or radiological evidence of breast cancer to date. The patient and her sister carrying the same mutation were the daughters of a breast cancer patient diagnosed with the disease at 38 years of age. The second-degree female relative who carries the same mutation was the daughter of our breast cancer patient's maternal aunt who was diagnosed with uterine cancer at the age of 42 years. These breast and uterine cancer patients in the FII generations had deceased and no archival specimens were available for genetic studies. We screened 19 first and second degree living relatives of our index case (III.16) including her three sisters and two brothers for BRCA1 mutations.

Bottom Line: Nineteen sequence variants were found in BRCA1 gene.After screening of 66 patients with family history and 64 sporadic breast cancer patients, 2 deleterious mutations (c.3086delT and c.5404delG) in two families were identified and two more possibly pathogenic mutations (c.856T>G and IVS17-2A>T) in two families were identified.BRCA1--Gene Bank: Accession # U14680 Version # 14680.1.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Biochemistry Molecular Biology and Biotechnology, University of Colombo, 90, Cumaratunga Munidasa Mawatha, Colombo 03, Sri Lanka. Wasanthi_e@yahoo.co.uk

ABSTRACT

Background: Breast Cancer is the most commonly diagnosed cancer among Sri Lankan women. Germline mutations in the susceptibility genes BRCA1 and BRCA2 in hereditary breast/ovarian cancer, though low in prevalence, are highly penetrant and show geographical variations. There have been only a few reports from Asia on mutations in BRCA1/2 genes and none from Sri Lanka.

Methods: A total of 130 patients with (N = 66) and without (N = 64) a family history of breast cancer, 70 unaffected individuals with a family history of breast cancer and 40 control subjects were analysed for BRCA1 mutations. All but exon 11 were screened by single strand conformation analysis (SSCP) and heteroduplex analysis. PCR products which showed abnormal patterns in SSCP were sequenced. Exon 11 was directly sequenced.

Results: Nineteen sequence variants were found in BRCA1 gene. Two novel deleterious frame-shift mutations; c.3086delT/exon11 (in one patient) and c.5404delG/exon21 (in one patient and two of her family members) were identified. A possibly pathogenic novel missense mutation (c.856T>G/exon 11) and three novel intronic variants (IVS7+36C>T, IVS7+41C>T, IVS7+49del15) were characterised. Ten previously reported common polymorphisms and three previously reported intronic variants were also observed.

Conclusion: After screening of 66 patients with family history and 64 sporadic breast cancer patients, 2 deleterious mutations (c.3086delT and c.5404delG) in two families were identified and two more possibly pathogenic mutations (c.856T>G and IVS17-2A>T) in two families were identified.

Data base: BRCA1--Gene Bank: Accession # U14680 Version # 14680.1.

Show MeSH
Related in: MedlinePlus