MOLECULAR BASIS OF BREAST CANCER RELATED TO BRCA 1 AND BRCA2 GENES: CHARACTERISTICS AND TARGETING THERAPY

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.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

In silico analysis of potential structural and functional significance of human breast cancer gene BRCA2 sequence variants found in 5’ untranslated region

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

Polymorphisms in survivin (BIRC5 gene) are associated with age of onset in breast cancer patients

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