Survivin, encoded by BIRC5 gene (baculoviral IAP repeat containing 5), belongs to the family of inhibitors of apoptosis proteins (IAPs). In mammalian cells it participates in the control of mitosis, ...apoptosis regulation, and cellular stress response. Its expression is increased in almost all types of cancers. The aim of this study was to investigate the role of BIRC5 polymorphisms in breast cancer (BC) and to connect survivin expression with various clinicopathological characteristics of BC patients. Blood and archival tumour tissue samples were collected from 26 BC patients from Croatia. Survivin expression was determined immunohistochemically. BIRC5 promoter, coding region, and 3’UTR were genotyped. DNA from 74 healthy women was used as control. BIRC5 polymorphisms and survivin expression were tested against age of onset, histological grade, tumour type and size, lymph node status, oestrogen, progesterone, Her2, and Ki67 status. Numbers of samples with weak, moderate, and strong survivin expression were 9 (33.3%), 11 (40.7%), and 7 (25.9%), respectively. Most patients had nuclear survivin staining (92.6%). High survivin expression was significantly associated with negative oestrogen receptor status (p=0.007) and positive Ki67 expression (p=0.032). Ki67 expression was also positively correlated with histological grade (p=0.0009). Fourteen polymorphisms were found in BC samples, located mostly in promoter and 3’UTR of BIRC5. There was no significant difference in the distribution of polymorphisms between BC and control samples. Among clinicopathological characteristics of BC patients, alleles of five BIRC5 polymorphisms were associated with younger age of onset: c.-644T>C (55.8 years y vs. 48.1 y; p=0.006), c.-241C>T (54.2 y vs. 45.0; p=0.029), c.9809T>C (55.8 y vs. 48.1 y; p=0.006), c.-1547C>T (58.3 y vs. 50.9 y; p=0.011), and c.9386T>C (50.8 y vs. 59.5 y; p=0.004). To assess the significance of BIRC5 polymorphisms and survivin expression as predictive and prognostic biomarkers for BC further research with a larger sample size is needed.
Rak dojke je jedan od najčešćih tumora u žena, koji u sebi nosi i značajnu komponentu obiteljske sklonosti bolesti u kojoj geni BRCA1 i BRCA2 imaju veliku ulogu. Žene s mutacijom u genu BRCA1 ili ...BRCA2 imaju vjerojatnost 45–85% za nastanak raka dojke i 11–62% vjerojatnost za nastanak raka jajnika do 70. godine života. Tumori koji se razviju kod nositelja mutacija imaju nefunkcionalne gene BRCA1 ili BRCA2 koji u normalnim stanicama sudjeluju u procesima popravka oštećenja DNA. Takvi tumori pokazuju izuzetnu osjetljivost na agense koji uzrokuju oštećenje DNA i na inhibitore PARP (inhibitori enzima poli(adenozin difosfat riboza) polimeraze 1). Te se spoznaje već primjenjuju u novim ciljanim terapijama kod nositelja mutacija. Uspješan postupak izlječenja najbolje će se postići suradnjom patologa, onkologa i genetičkog laboratorija koji obavlja testiranje na mutacije u genima BRCA1 i BRCA2.
BRCA1 and BRCA2 genes from 167 candidates (145 families) were scanned for mutations. We identified 14 pathogenic point mutations in 17 candidates, 9 in BRCA1 and 5 in BRCA2. Of those, 11 have been ...previously described and 3 were novel (c.5335C>T in BRCA1 and c.4139_4140dupTT and c.8175G>A in BRCA2). No large deletions or duplications involving BRCA1 and BRCA2 genes were identified. No founder mutations were detected for the Croatian population. Croatia shares most of the mutations with neighboring Slovenia and also with Germany, Austria and Poland.
Two common sequence variants in BRCA1, c.2077G>A and c.4956G>A, were found more frequently in mutation carriers compared to healthy controls. No difference in BRCA2 variants was detected between the groups.
Haplotype inference showed no difference in haplotype distributions between deleterious mutation carriers and non-carriers in neither BRCA1 nor BRCA2. In silico analyses identified one BRCA1 sequence variant (c.4039A>G) and two BRCA2 variants (c.5986G>A and c.6884G>C) as harmful with high probability, and inconclusive results were obtained for our novel BRCA2 variant c.3864_3866delTAA.
Combination of QMPSF and HRMA methods provides high detection rate and complete coverage of BRCA1/2 genes. Benefit of BRCA1/2 mutation testing is clear, since we detected mutations in young unaffected women, who will be closely monitored for breast and ovarian cancer.
► QMPSF and HRMA provide high detection rate and complete coverage of BRCA1/2 genes. ► 14 pathogenic point mutations in 17 candidates, 9 in BRCA1 and 5 in BRCA2. ► Three novel mutations: BRCA1 c.5335C>T; BRCA2 c.4139_4140dupTT and c.8175G>A. ► BRCA1 c.2077G>A and c.4956G>A variants are more frequent among mutation carriers. ► In silico analysis confirmed BRCA2 mutation c.9371A>T pathogenic character.
Background: Mutations in BRCA1 and BRCA2 genes are associated with family predisposition to breast and ovarian cancer. Novel screening methods are required for efficient and rapid detection of ...sequence variants in cancer patients and their family members. Methods: The screening for variants in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 in Croatia was performed by a high-resolution melting approach, which is based on differences in melting curves caused by variations in nucleotide sequence. This is the first screening in Croatia on elderly healthy women with no family history of cancer. BRCA1 screening was performed on 220 and BRCA2 screening on 115 samples. Results: In a population well beyond the average age of breast/ovarian cancer onset, 21 different sequence variants in the BRCA1 gene (one novel: c.5193+49_50delTA) and 36 variants in the BRCA2 gene (7 novel: c.459A>C, c.3318C>A, c.4412_ 4414delGAA, c.4790C>A, c.6264T>C, c.9087G>A, and c.9864A>G) were detected. Conclusions: Nine BRCA1 and seven BRCA2 known variants appeared with such high frequencies that they could be declared as harmless in this population. Eight BRCA1 high frequency variants, located further from the promoter region, appear to be strongly correlated. Three novel variants that changed the amino acid sequence of the BRCA2 protein (two missense base substitutions, c.3318C>A and c.4790C>A, and one codon deletion c.4412_4414delGAA), appearing only once, were predicted to have no potential effect on protein structure and function. Clin Chem Lab Med 2008;46:1376–83.
Breast cancer is one of the most frequent tumors in women, and BRCA1 and BRCA2 genes play a major role in the hereditary susceptibility for this disease. Until the age of 70 women carrying a mutation ...in BRCA1 or BRCA2 gene have a 45-85% probability of developing breast cancer, and 11-62% probability of developing ovarian cancer. Mutation carrier's tumors contain nonfunctional BRCA1 or BRCA2 genes, which in healthy cells are involved in DNA repair. These tumors show an increased sensitivity to DNA damaging chemical agents and to PARP (poly(adenosine diphosphate-ribose) polymerase1) inhibitors. New targeted therapies already in use are directed toward tumors of mutation carriers. Successful treatment is most likely to be achieved through cooperation of a pathologist, oncologist and a genetic laboratory performing BRCA genes mutation screening.
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Background and Purpose: BRCA1 and BRCA2 are major hereditary
breast/ovarian cancer predisposing genes and their mutations increase the risk of developing cancer. Genetic testing of these two genes is ...nowadays commonly performed but almost half of found genetics alterations are declared as variants of unknown clinical significance. Interpretation of these unclassified variants is the major concern for BRCA genes. The aim of this study is to investigate potential structural and functional significance of sequence
variants found in 5’ untranslated region (UTR) of BRCA2 gene.
Materials and Methods: Consensus secondary structure of BRCA2 5’
UTR was built based on nucleotide sequences from four different species. We collected all found human BRCA2 5’ UTR variants and explored their potentials effects by folding human BRCA2 5’ UTR including one of each variant, using consensus structure as a constraint. If constrained folding results in a structure that is very different from the consensus one, this may indicate that this particular sequence variant could have potential functional
impact.
Results: Most of the sequence alterations are found near the 3’ end of 5’ UTR, what is in the vicinity of the translation initiation site. Four of them: c.-26G>A, c.-26G>C, c.-26G>T and c.-12T>C most notably disturbed consensus secondary structure by creating substructures with lower minimum free energy, thus less stable.
Conclusions: As previously deduced in the case of variant c.-26G>A,
changes c.-26G>C, c.-26G>T and c.-12T>C could unstabilize the loop
at the vicinity of the translation start site, which could increase the efficiency of the translation and thereby increase the expression of BRCA2. Accordingly, our study suggests this three BRCA2 5’ UTR sequence variants as suitable candidates for further functional characterization and thus potentially clinically significant.
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