Germ line BRCA1 and BRCA2 gene mutations in Turkish breast cancer patients

Özdağ, Hilal; Tez, Mesut; Sayek, İskender; Müslümanoğlu, Mahmut; Tarcan, Onurcan; İçlı, Fikri; Öztürk, Mehmet; Özçelık, Tayfun

doi:10.1016/s0959-8049(00)00277-x

Cited by 23 publications

(15 citation statements)

References 8 publications

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“…However, the molecular genetic basis of inherited predisposition to breast cancer in non-BRCA1, non-BRCA2, non-LiFraumeni individuals is not known (Nathanson et al, 2001). We therefore sought germ-line mutations in Chk2 in a panel of breast cancers previously characterized for BRCA1 status (Ozdag et al, 2000). Other than three individuals heterozygous for a previously described non-coding polymorphism, no deviations from the published coding sequence of Chk2 were detected in the germ-line of these individuals.…”

Section: Discussionmentioning

confidence: 99%

“…Normal tissue was available for two of the cases with mutations and sequencing of DNA from this revealed that the mutations were somatically acquired rather than germ- Absence of germ-line mutations in hereditary, familial, early onset and male breast cancer Germ-line mutations in Chk2 have been described in individuals with the Li-Fraumeni syndrome (Bell et al, 1999) and in a very small number of non-BRCA1, non-BRCA2 hereditary breast cancers (Allinen et al, 2001;Vahteristo et al, 2001). We therefore analysed the germ-line structure of Chk2 in 45 individuals with various forms of breast cancer, in whom the BRCA1 and BRCA2 status has been previously described (Ozdag et al, 2000). In these cases, direct sequencing of genomic DNA isolated from peripheral blood lymphocytes detected the codon 84 polymorphism in three of the 45 cases, but no germ-line mutations in any of the cases.…”

Section: Novel Somatic Chk2 Mutations Are Detected In Breast Cancermentioning

confidence: 99%

“…For analysis of germ-line Chk2 mutations, genomic DNA samples were analysed from 45 individuals, comprising hereditary (seven cases), familial (six cases), early onset (23 cases) and male breast cancer (nine cases) groups. The BRCA1 and BRCA2 status of these cases has been described previously (Ozdag et al, 2000). Each patient gave fully informed consent for participation in the study.…”

Section: Tumoursmentioning

confidence: 99%

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Concomitant inactivation of p53 and Chk2 in breast cancer

Sullivan

Yuille²,

Repellin

et al. 2002

Oncogene

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The structure and expression of the human Rad53 homologue Chk2 was analysed in breast cancer. The previously described silent polymorphism at nucleotide 252 in codon 84 (GAA4GAG) was observed in 5/141 cases. Somatic Chk2 coding mutations were detected in 7/141 cases, these occurring in 4/18 BRCA1-associated breast cancers, 1/78 sporadic breast cancers and 2/25 typical medullary carcinomas. Each of the BRCA1-associated cancers with Chk2 mutations also contained mutations in p53, whereas the single sporadic cancer with Chk2 mutation was wild-type for p53. Expression of Chk2 was ubiquitously detected in normal ductal epithelium of the breast, but there was loss of expression in a signi®cant proportion of breast carcinomas, and this occurred in cancers both with and without p53 mutation. A CpG island was identi®ed 5' of the Chk2 transcriptional start site, but there was no evidence of cytosine methylation in any of the cancers with down-regulated Chk2 expression. Analysis of the germ-line of 45 individuals with hereditary or early onset breast cancer revealed wild-type Chk2 sequence in all cases. Thus, despite the rarity of somatic mutations in Chk2 in sporadic breast carcinomas, our results nevertheless reveal that concomitant loss of function in Chk2 (via down-regulation of expression) and p53 (via mutation) occurs in a proportion of sporadic cases. However, consistent with other studies, we show that germ-line mutations in Chk2 are unlikely to account for a signi®cant proportion of non BRCA1-, non BRCA2-associated hereditary breast cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Novel Somatic Chk2 Mutations Are Detected In Breast Cancermentioning

confidence: 99%

Section: Tumoursmentioning

confidence: 99%

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Concomitant inactivation of p53 and Chk2 in breast cancer

Sullivan

Yuille²,

Repellin

et al. 2002

Oncogene

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“…Genomic DNAs were isolated as described previously (Unsal et al, 1994;Yakicier et al, 1999). The exon 3 sequence of b-catenin was studied for base substitutions and small insertion/deletions by SSCP as described previously (Ozdag et al, 2000), as well as by direct DNA sequencing. In addition, the b-catenin gene region encompassing exons 2 to 4 was studied for larger deletions, essentially as described by Koch et al (1999).…”

Section: B-catenin Mutation Analysismentioning

confidence: 99%

p53 mutation as a source of aberrant β-catenin accumulation in cancer cells

Çağatay

Öztürk

2002

Oncogene

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b-catenin is involved in both cell -cell interactions and wnt pathway -dependent cell fate determination through its interactions with E-cadherin and TCF/LEF transcription factors, respectively. Cytoplasmic/nuclear levels of b-catenin are important in regulated transcriptional activation of TCF/LEF target genes. Normally, these levels are kept low by proteosomal degradation of bcatenin through Axin1-and APC-dependent phosphorylation by CKI and GSK-3b. Deregulation of b-catenin degradation results in its aberrant accumulation, often leading to cancer. Accordingly, aberrant accumulation of b-catenin is observed at high frequency in many cancers. This accumulation correlates with either mutational activation of CTNNB1 (b-catenin) or mutational inactivation of APC and Axin1 genes in some tumors. However, there are many tumors that display b-catenin accumulation in the absence of a mutation in these genes. Thus, there must be additional sources for aberrant bcatenin accumulation in cancer cells. Here, we provide experimental evidence that wild-type b-catenin accumulates in hepatocellular carcinoma (HCC) cells in association with mutational inactivation of p53 gene. We also show that worldwide p53 and b-catenin mutation rates are inversely correlated in HCC. These data suggest that inactivation of p53 is an important cause of aberrant accumulation of b-catenin in cancer cells.

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“…Different patient selection criteria and different mutation detection methods were applied, no predominant mutation was observed in Turkish population 15,[17][18][19][20][21][22][23][24][30][31][32][33][34] .…”

Section: Discussionmentioning

confidence: 99%

Meme Kanserli̇ Hastalarda Brca1 Ve Brca2 Gen Mutasyonlarinin Değerlendi̇ri̇lmesi̇

Karakuş¹,

Kara²,

Yiğit³

et al. 2017

Cumhuriyet Medical Journal

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SUMMARYObjective: Worldwide, breast cancer is the most common malignancy among women. In Turkey, breast cancer is also the most common cancer among women with the frequency of 25% of all female cancers. Germline mutations in tumor suppressor genes (BRCA1 and BRCA2) cause genetic susceptibility to malignancies and are responsible for 5-10% of all breast and ovarian cancers. Women carrying mutations in BRCA1 or BRCA2 genes are at high risk to develop breast cancer, especially before the age of 45. The aim of this study was to determine the frequencies of the most common BRCA1 and BRCA2 gene mutations (185delAG and 5382insC in BRCA1 gene and 6174delT in BRCA2) in patients with early-onset breast cancer in a Turkish population. Method: 50 female early-onset (≤45) breast cancer patient were included in this study. The common BRCA1 and BRCA2 gene mutations were determined using conventional DNA sequencing. Results: The patient's ages ranged from 28 to 45 years with a mean age of 40.08±4.275 years. The 185delAG (rs386833395) and 5382insC (rs397507246) mutations of BRCA1 gene and 6174delT (rs80359550) mutation of BRCA2 gene were analyzed in 50 breast cancer patients. These three mutations were not observed any of the breast cancer patients including in our study. Conclusions: Our results showed that BRCA1 gene 185delAG and 5382insC mutations and BRCA2 gene 6174delT mutation are not common in Turkish breast cancer patients. It is believed that there might be other mutations of BRCA1/2 genes or other genes rather than BRCA1/2 that might be responsible for breast cancer in Turkish population. Keywords : Breast cancer; BRCA1; BRCA2; mutation; sequencing ÖZET Amaç: Dünya çapında, meme kanseri kadınlarda en sık görülen kanserdir. Türkiye'de de meme kanseri tüm kadın kanserlerinin %25'i gibi bir sıklıkta kadınlarda en sık görülen kanserdir. Tümör baskılayıcı genlerdeki (BRCA1 ve BRCA2) germline mutasyonlar kanser için genetik yatkınlığa neden olur ve tüm meme ve yumurtalık kanserlerinin %5-10'undan sorumludur. BRCA1 veya BRCA2 genlerinde mutasyon taşıyan kadınlar, özellikle 45 yaşından önce meme kanserine yakalanmak için yüksek riske sahiptir. Bu çalışmanın amacı, en yaygın olan BRCA1 ve BRCA2 gen mutasyonlarının, Türk populasyonunda erken yaş meme kanserli hastalardaki sıklığını belirlemektir. Yöntem: Bu çalışmaya, erken yaş (≤45) meme kanserli 50 kadın hasta dahil edilmiştir. Yaygın BRCA1 ve BRCA2 gen mutasyonları, geleneksel DNA dizileme tekniği kullanılarak belirlenmiştir. Bulgular: Yaşları 28 ila 45 yıl arasında değişen hastaların yaş ortalaması 40.08 ± 4.275 olarak belirlenmiştir. 50 meme kanserli hastada, BRCA1 geni 185delAG (rs386833395) ve 5382insC (rs397507246) mutasyonları ile BRCA2 geni 6174delT (rs80359550) mutasyonu analiz edilmiştir. Bu çalışmaya dahil edilen meme kanserli hastaların hiçbirinde bu üç mutasyona da rastlanmamıştır. Sonuç: Sonuçlarımız, BRCA1 geni 185delAG ve 5382insC mutasyonları ile BRCA2 geni 6174delT mutasyonunun, Türk meme kanserli hastalarda yaygın olmadığını göstermiştir. Türk populasyonunda...

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Germ line BRCA1 and BRCA2 gene mutations in Turkish breast cancer patients

Cited by 23 publications

References 8 publications

Concomitant inactivation of p53 and Chk2 in breast cancer

Concomitant inactivation of p53 and Chk2 in breast cancer

p53 mutation as a source of aberrant β-catenin accumulation in cancer cells

Meme Kanserli̇ Hastalarda Brca1 Ve Brca2 Gen Mutasyonlarinin Değerlendi̇ri̇lmesi̇

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