Novel germline mutations in BRCA2 gene among 96 hereditary breast and breast–ovarian cancer families from Kerala, South India

Syamala, Vani; Sreeja, Leelakumari; Syamala, Volga S.; Vinodkumar, B.; Raveendran, Praveenkumar B.; Subramanian, Hariharan; Kuttappan, Ratheesan; Balakrishnan, Lekshmi; Ankathil, Ravindran

doi:10.1007/s00432-007-0229-6

Cited by 7 publications

(6 citation statements)

References 35 publications

(36 reference statements)

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“…found all exonic or intronic sequence variations were VUS. 26 Four unclassified variants of unknown clinical significance [942G > A (c.823G > A), 3238G > A (c.3119G > A), 5002T>C (c.4883T>C), and 5076G > A (c.4957G > A)] were observed in nine patients in BRCA1 , and nine missense mutations of unknown clinical significance in nine patients in BRCA2 , were found in a study by Juwle et al. 29 Similarly, Darooie et al.…”

Section: Resultsmentioning

confidence: 94%

“…In the same year, Syamala et al revealed 13 distinct germline BRCA2 sequence variants in 94 patients. 26 Vaidyanathan et al in 2009 found eight BRCA1 (20.5%) mutations with the majority (6/8; 75%) being frameshift mutations. They found only one BRCA2 mutation.…”

Section: Bangladeshmentioning

confidence: 98%

“…This study screened a total of 1768 female BC patients and 573 BC families for exploring the BRCA1 mutations, and 1347 female BC patients and 573 BC families for BRCA2 mutations (Supplementary File 2). 15,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]…”

Section: Brca1 and Brca2 Mutationsmentioning

confidence: 99%

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BRCA1/BRCA2 mutation spectrum analysis in South Asia: a systematic review

et al. 2022

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Objective Breast cancer (BC) is the most common form of cancer among Asian females. Mutations in the BRCA1/ BRCA2 genes are often observed in BC cases and largely increase the lifetime risk of having BC. Because of the paucity of high-quality data on the molecular spectrum of BRCA mutations in South Asian populations, we aimed to explore these mutations among South Asian countries. Methods A systematic literature search was performed for the BRCA1 and BRCA2 gene mutation spectrum using electronic databases such as PubMed, EMBASE, and Google Scholar. Twenty studies were selected based on specific inclusion and exclusion criteria. Results The 185delAG (c.68_69del) mutation in exon 2 of BRCA1 was the most common recurrent mutation and founder mutation found. Various intronic variants, variants of unknown significance, large genomic rearrangements, and polymorphisms were also described in some studies. Conclusions The South Asian population has a wide variety of genetic mutations of BRCA1 and BRCA2 that differ according to countries and ethnicities. A stronger knowledge of various population-specific mutations in these cancer susceptibility genes can help provide efficient strategies for genetic testing.

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Section: Resultsmentioning

confidence: 94%

Section: Bangladeshmentioning

confidence: 98%

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BRCA1/BRCA2 mutation spectrum analysis in South Asia: a systematic review

et al. 2022

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“… [13,[19][20][21][22][23][24][25][27][28][29][30][31][32][33][34][35][36][37] Bangladesh Only one study(Akter et.…”

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confidence: 99%

BRCA 1/2 Mutation Spectrum Analysis in South Asia: A Systematic Review

Kharel

Shrestha

Yadav

et al. 2021

Preprint

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Background: Breast cancer (BC) is the most common form of all cancers among Asian females. Mutations in BRCA1/BRCA2 gene are observed in BC cases and also largely increases the lifetime risk of having BC. Because of the paucity of high-quality data on the molecular spectrum of BRCA mutations in South Asian populations, we aimed to explore the spectrum of BRCA gene mutation among the South Asian Population.Methods: A systematic literature search of electronic databases like PubMed, EMBASE, and Google Scholar on BRCA1 and BRCA2 gene mutation spectrum was carried out for peer-reviewed articles providing information on the spectrum of either BRCA1 or BRCA2 gene mutation on South Asian women with any form of breast cancer.Results: Twenty studies were selected for review from four South Asian countries showing similar BRCA1/2 gene mutation patterns. 185delAG mutation in exon 2 in BRCA1 was the most common recurrent mutation and founder mutation found. Various intronic variants, variants of unknown significance, large genomic rearrangements (LGRs) and polymorphisms are also described in some studies. Conclusions: The prevalence of BRCA1 mutations is higher than BRCA2 mutations in the South Asian population with a wide variation among different countries and ethnicities. The knowledge of various population-specific mutations in these cancer susceptibility genes can help provide efficient strategies for genetic testing.

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“…In contrast, there are also some silent mutations that do not result in a change of codons therefore such mutations do not affect BRCA1 functionality [94]. Tumours from patients with a germline mutation of BRCA1 have a distinct pathology.…”

Section: Brca1 and Breast Cancermentioning

confidence: 99%

Identifying long-range control elements of the BRCA1 promoter

Lee¹

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BRCA1 is a tumour suppressor protein involved in many important pathways such as DNA repair, cell cycle regulation, apoptosis, spindle formation and telomere regulation. BRCA1 germline mutations confer the highest risk to breast cancer. Furthermore, reduced levels of BRCA1 are also observed in many sporadic breast cancers. Despite the obvious importance of BRCA1, genetic screening is usually restricted to BRCA1 exons and intronexon boundaries. The possibility that mutations exist outside these regions has not been fully investigated and may be responsible for breast cancer predisposition in a subset of . However, identifying regulatory elements outside BRCA1 and determining whether mutations in these elements contribute to BRCA1 deregulation is still relatively unexplored. This project aims to expand the repertoire of BRCA1 long-range regulatory elements using gene conformation techniques such as chromosome conformation capture (3C) and its derivatives. The project hypothesis is that defects in long-range regulatory elements of BRCA1 transcription contribute to breast cancer predisposition.Using a candidate 3C approach, we identified a potential cis-regulatory element, called PRE1, located approximately 157 kb downstream of the BRCA1 promoter. The frequency of this interaction increased with estrogen stimulation, suggesting that chromatin looping is associated with BRCA1 transcription. Bioinformatic analysis showed that this element is flanked by DNase hypersensitivity and histone marks, which suggests it is an enhancer of BRCA1. This was confirmed by luciferase reporter assays which demonstrated that PRE1 acts as a weak enhancer, resulting in a 10% increase in BRCA1 promoter activity. Using ChIP we showed that the TF c-Myc binds to both PRE1 and the BRCA1 promoter, however depletion of c-Myc RNA levels did not alter PRE1s enhancer activity. Using a genome-wide circular-3C (4C) approach, we identified a potential trans-regulatory silencer element located 5kb upstream of G2E3 on chromosome 14. This trans-interaction was 2 validated by 3C in MCF7 cells, which suggests that the interaction is potentially functional.Consistent with this, bioinformatic analysis showed that this element, called PRE2, is flanked by DNase hypersensitivity and strong histone marks indicative of a silencer.Notably, luciferase assays showed that a modified version of PRE2 could repress BRCA1 promoter activity, resulting in a 3-fold decrease in activity. This research project has provided the first important steps to fully understanding the molecular pathways underlying BRCA1 regulation. The identification and characterisation of novel long-range control elements of breast cancer genes will immediately improve genetic screening procedures, and permit the development of more specific therapeutic approaches.3

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Novel germline mutations in BRCA2 gene among 96 hereditary breast and breast–ovarian cancer families from Kerala, South India

Abstract: The results of this study suggest that germline mutations of BRCA2 gene account for rather small proportion of Hereditary Breast/Ovarian cancer in Kerala, South India.

Cited by 7 publications

References 35 publications

BRCA1/BRCA2 mutation spectrum analysis in South Asia: a systematic review

BRCA1/BRCA2 mutation spectrum analysis in South Asia: a systematic review

BRCA 1/2 Mutation Spectrum Analysis in South Asia: A Systematic Review

Identifying long-range control elements of the BRCA1 promoter

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