Non-diethylstilbestrol exposed vaginal adenocarcinoma in young patients associated with unilateral renal agenesis: two case reports and literature review.

BACKGROUND: Adenocarcinoma, accounts for up to 14% of all vaginal cancer. In young patients, common histological feature is clear cell adenocarcinoma (CCA) while mesonephric adenocarcinoma (MA) is very rare. The authors report two patients in their early twenties with unilateral renal agenesis and vaginal adenocarcinoma not exposed to diethylstilbestrol (DES). CASES: Two patients with vaginal adenocarcinoma were treated, with external beam radiotherapy of pelvis combined with brachytherapy to a radical dose. In 2000, 25-year-old female, was admitted for radiotherapy after incomplete excision of the tumor localized in left vaginal apex and fornix. Histopathology confirmed CCA and classified as clinical Stage II. CT revealed left renal agenesis.The patient is alive and disease-free 15 years after therapy. Vaginal, urethral stenosis, and hydronephrosis occurred and ureteral stent was inserted. In the second patient, 22-year-old, in 2004, after biopsy of bulky tumor of vagina and histology, revealed MA in Stage III and CT scan also confirmed right renal agenesis. Radiotherapy was followed by chemotherapy. After 11 years, patient is disease-free with vaginal stenosis and incipient renal hydronephrosis. CONCLUSION: Radiotherapy is effective treatment in advance vaginal adenocarcinoma, however, with high morbidity. The authors advise rigorous gynecologic exams in young females with renal agenesis as there may be a risk of malignant changes in vagina.

The impact of ultrasound-guided erector spinae plane block on hemodynamic stability and postoperative pain in patients undergoing modified radical mastectomy for breast cancer.

OBJECTIVE: Breast cancer, a prevalent global malignancy in women, necessitates a comprehensive treatment approach, with surgery playing a crucial role. Severe acute pain is common post-radical breast cancer surgery, emphasizing the significance of hemodynamic stability and postoperative pain control for optimal outcomes. This study evaluates the impact of ultrasound-guided erector spinae plane block (ESPB) on these parameters in ASA scores 1-2 patients undergoing modified radical breast cancer surgery with general anesthesia. PATIENTS AND METHODS: Forty-eight patients were divided into two groups: a general anesthesia group, with erector spinae plane block (GA+ESPB), and a control group receiving only general anesthesia (GA). Hemodynamic parameters were continuously monitored, and postoperative pain was assessed using the visual analog scale (VAS) at various time points. RESULTS: Ultrasound-guided ESPB effectively maintained hemodynamic stability and reduced postoperative pain in breast cancer surgery patients. Statistically significant differences were observed in heart rate, systolic and diastolic blood pressure, and mean arterial pressure between the GA and GA+ESPB groups at multiple time points (p < 0.05). VAS scores showed a significant interaction time*group (p < 0.001), with consistent differences between the groups at all time points (p ≤ 0.001). CONCLUSIONS: Ultrasound-guided ESPB application proved effective in preserving hemodynamic stability and managing postoperative pain in modified radical breast cancer surgery. The technique demonstrates promise in minimizing complications related to hemodynamic variations and postoperative pain, contributing to a comprehensive approach to breast cancer surgical treatment.

KRAS and BRAF mutations in Serbian patients with colorectal cancer.

PURPOSE: Mutations of KRAS and BRAF genes represent molecular biomarkers of response to targeted therapy in patients with metastatic colorectal cancer (mCRC). Since these mutations have been shown to exert different biological effects and impacts on patients' outcome, there is a need to determine reliably the frequency and types of KRAS mutations for diagnostic and individual therapeutic purposes. Despite having a wild type (wt) KRAS, some patients fail to respond to treatment. BRAF V600E mutation is an additional molecular determinant of response to the same therapy. In this study we described the KRAS and the BRAF V600E mutation spectra and frequencies in a group of Serbian mCRC specimens. METHODS: KRAS mutations were determined with DxS TheraScreen® K-RAS Mutation Kit and KRAS StripAssay(™), and for the BRAF V600E mutation we applied High Resolution Melting (HRM) analysis. RESULTS: KRAS mutations were present in 34.7% of 190 analyzed samples. The 7 most frequent mutation types observed were: G12D 43.9%, G12V 21.2%, G12A 10.6%, G12C 7.6%, G12S 4.5%, G12R 1.5%, G13D 10.6%. Among the wt KRAS patients, 17.8% carried the BRAF V600E mutation. CONCLUSIONS: We have shown that the spectrum and frequency distribution of the identified KRAS and BRAF mutations in Serbian study population are in good accordance with literature data. We believe that our results are significant concerning aspects related to tumor molecular biology as well as to patient selection in the diagnostic settings.

TP53 gene status and human papilloma virus infection in response to platinum plus taxane-based chemotherapy of epithelial ovarian carcinomas.

PURPOSE: Lack of symptoms in early stages of disease and resistance to chemotherapy make epithelial ovarian carcinomas one of the most lethal neoplasms among gynaecological malignancies. The aim of this study was to analyse the impact of TP53 mutations, codon 72 polymorphism and human papillomavirus (HPV) infection on the response to platinum-taxane combination chemotherapy in patients with epithelial ovarian carcinomas. METHODS: The study was conducted on 26 ovarian carcinoma patients who received carboplatin plus paclitaxel combination chemotherapy. DNA was isolated by salting-out procedure. Mutations in exons 4-8 of TP53 gene were detected by PCR-SSCP and confirmed by automatic DNA sequencing. Codon 72 polymorphism was assessed by the RFLP method. HPV infection was detected through amplification of one part of L1 viral gene. Genotyping was performed by DNA sequencing. Fisher's exact and log-rank tests were used for statistical analysis. RESULTS: TP53 mutations were present in 5/26 (19.2%) ovarian carcinomas. The distribution of codon 72 TP53 genotypes was: Arg/Arg 38.5%, Arg/Pro 50.0%, Pro/Pro 11.5%. HPV was present in 4/26 (15.4%) ovarian carcinomas. All HPV-positive tumors were HPV16 type. Patients with mutations in TP53 gene, Arg/Arg genotype of codon 72 and absence of HPV infection experienced the highest tumor response rate to platinum-taxane chemotherapy. However, no significant correlation between progression free interval (PFI) and the examined biomarkers was observed. CONCLUSION: Our results indicate that, based on the TP53 gene status and the presence/absence of HPV infection, the subgroups of patients having better initial response to platinum-taxane therapy could be distinguished. This might contribute to more adequate treatment and individual therapeutic approach.

p53 gene mutations and codon 72 polymorphism in ovarian carcinoma patients from Serbia.

PURPOSE: Ovarian cancer is the leading cause of death from gynecological malignancies. The early stages of this disease are asymptomatic and more than 75% of the cases are diagnosed with regional or distant metastases. p53 gene is frequently mutated in some histological subtypes of ovarian carcinomas. The role of p53 mutations and polymorphic variant of codon 72 in the prognosis of disease is still unclear. The aim of this study was to determine the frequency of p53 mutations and polymorphic variants of codon 72 among ovarian carcinoma patients and to correlate them with clinicopathological characteristics of disease. METHODS: 54 ovarian carcinoma patients were included in the study. DNA was isolated from tumor tissue by the salting- out method. p53 mutations in exons 4-8 were detected by PCR-SSCP (polymerase chain reaction - single-stranded conformational polymorphism) electrophoresis. Codon 72 polymorphism was assessed by RFLP (restriction fragment-length polymorphism) method. RESULTS: p53 mutations were present in 11 out of 54 patients (20.4%). Twenty-four patients (44.4%) exhibited Arg/ Arg, 24 patients (44.4%) Arg/Pro and 6 patients (11.2%) Pro/ Pro genotype of 72 codon polymorphism. Correlations between p53 mutations and various clinicopathological characteristics were not found. However, we observed that the frequency of Pro/Pro genotype was increasing with higher histological grade as well as in advanced compared to localized disease, but without statistical significance. Distribution of p53 gene mutations between Pro/Pro genotype and Arg/Pro plus Arg/Arg genotypes was not statistically significant. CONCLUSION: Our study suggests that Pro/Pro genotype of 72 codon polymorphism could be an independent prognostic marker in ovarian carcinomas.

siRNA and miRNA for the treatment of cancer.

In the process of RNA interference (RNAi), small RNAs pair with complementary messenger RNAs preventing their expression. The discovery of RNAi has revolutionized our understanding of gene regulation. Since cancer is a disease of altered genes, RNAi may have tremendous potential as a therapeutic strategy by downregulating altered genes. Just one decade after its discovery, this process is already being used in clinical trials and new technical achievements in delivering small RNAs to the cells are constantly improving the efficiency of this specific cancer treatment.

Therapeutic cancer vaccines in cervical cancer: phase I study of Lovaxin-C.

Producing effective therapeutic vaccines has proved much more difficult and challenging than developing cancer preventive vaccines. Despite huge research in the area of cancer immunology, FDA/EMEA have not approved any type of cancer treatment vaccine so far. More than 99% of cervical cancers have detectable amounts of human papillomavirus (HPV) DNA. Integration of high-risk HPV into the host cell genome is followed by continual expression of HPV E6 and E7 oncoproteins, making them excellent targets for developing vaccines which could be used in high grade precancerous (CIN) lesions or invasive cancer or in the prevention of cancer recurrence. Therapeutic cervical cancer vaccines have been extensively studied. Strategies used were vaccination with HPV peptides or proteins, alone or in pulsed dendritic cells, DNA vaccines, virus-like particles or viral and bacterial vectors. Lovaxin-C is a recombinant live-attenuated Listeria monocytogenes (Lm) that secretes the antigen HPV-16 E7 fused to a non-hemolytic listeriolysin O protein. In a phase I study Lovaxin-C was administered to advanced cervical cancer patients refractory to existing therapies. The dose-limiting toxicity was hypotension and flue-like syndrome. There were no serious adverse events. Specific T-cell response was detected as well as clinical response to Lovaxin-C. Several other therapeutic HPV vaccines are in clinical development and in most of the studies specific immunological and clinical responses were seen. Efficacious therapeutic vaccine for the treatment of cervical cancer should be expected in the near future.

Protective ventilation with high versus low positive end-expiratory pressure during one-lung ventilation for thoracic surgery (PROTHOR): study protocol for a randomized controlled trial.

BACKGROUND: Postoperative pulmonary complications (PPC) may result in longer duration of in-hospital stay and even mortality. Both thoracic surgery and intraoperative mechanical ventilation settings add considerably to the risk of PPC. It is unclear if one-lung ventilation (OLV) for thoracic surgery with a strategy of intraoperative high positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM) reduces PPC, compared to low PEEP without RM. METHODS: PROTHOR is an international, multicenter, randomized, controlled, assessor-blinded, two-arm trial initiated by investigators of the PROtective VEntilation NETwork. In total, 2378 patients will be randomly assigned to one of two different intraoperative mechanical ventilation strategies. Investigators screen patients aged 18 years or older, scheduled for open thoracic or video-assisted thoracoscopic surgery under general anesthesia requiring OLV, with a maximal body mass index of 35 kg/m2, and a planned duration of surgery of more than 60 min. Further, the expected duration of OLV shall be longer than two-lung ventilation, and lung separation is planned with a double lumen tube. Patients will be randomly assigned to PEEP of 10 cmH2O with lung RM, or PEEP of 5 cmH2O without RM. During two-lung ventilation tidal volume is set at 7 mL/kg predicted body weight and, during OLV, it will be decreased to 5 mL/kg. The occurrence of PPC will be recorded as a collapsed composite of single adverse pulmonary events and represents the primary endpoint. DISCUSSION: PROTHOR is the first randomized controlled trial in patients undergoing thoracic surgery with OLV that is adequately powered to compare the effects of intraoperative high PEEP with RM versus low PEEP without RM on PPC. The results of the PROTHOR trial will support anesthesiologists in their decision to set intraoperative PEEP during protective ventilation for OLV in thoracic surgery. TRIAL REGISTRATION: The trial was registered in clinicaltrials.gov ( NCT02963025 ) on 15 November 2016.

Correction to: Protective ventilation with high versus low positive end-expiratory pressure during one-lung ventilation for thoracic surgery (PROTHOR): study protocol for a randomized controlled trial.

After publication of the original article [1], the authors have notified us that two of the collaborator first and last names have been inverted in the "PROTHOR Investigators" table.

TP53 mutations in breast cancer: association with ductal histology and early relapse of disease.

PURPOSE: This study aimed to investigate the incidence of core domain TP53 mutations in Serbian breast cancer patients in view of their possible correlation with prognostic parameters, tumor characteristics and clinical disease course. METHODS: 145 breast cancer patients were included. Data on clinical disease course were available for 100 patients including 30 node-negative and 70 node-positive patients. After surgery, node-positive patients underwent adjuvant chemotherapy, mostly CMF. TP53 mutations were detected by PCR-SSCP. RESULTS: 31 mutations were found in 27/145 patients including 4/59 node-negative patients and 23/83 node-positive patients (4 double mutations). 26/31 TP53 mutations were found in patients with invasive ductal carcinoma and only 2 in patients with invasive lobular carcinoma. The presence of TP53 mutations was correlated with clinical disease course in premenopausal node-positive patients (n=70). 11/20 patients with TP53 mutations relapsed. Within the first 24 months of follow-up, significantly shorter disease-free intervals were observed in TP53-mutated patients. CONCLUSIONS: TP53 mutations correlated only with nodal status and ductal histology. The significance of the predominant distribution of TP53 mutations in tumors with a ductal histology for the aggressive behavior of these tumors has yet to be proved, since the favorable biological features of tumors with a lobular histology do not result in a better prognosis. Early relapse in mutated-TP53 carriers may support data on its predictive value with respect to adjuvant CMF.

p53 gene alterations and human papillomavirus type 16 infection in early stages of cervical carcinoma in Serbia.

PURPOSE: The incidence rate (age-standardized) of cervical carcinoma in Serbia is the highest in Europe. p53 is mainly inactivated at protein level in carcinomas associated with human papillomavirus (HPV) infection, such as cervical carcinomas. These tumors show low rate of p53 mutations. It is not clear if p53 mutations confer additional impact on disease prognosis. The role of polymorphic variant at codon 72 of p53 gene on patient's prognosis is controversial. The aim of this study was to determine the frequency of p53 mutations and to assess polymorphic variants of codon 72 among cervical carcinoma patients. PATIENTS AND METHODS: 53 patients, mainly FIGO stage I (n=50), with squamous cell carcinoma (n=49) were included. 30/32 (94%) patients who received adjuvant radiotherapy were followed-up (median 15 months, range 4-39). DNA was isolated by the salting out method from tumor tissue (n=53) and blood (42/53). p53 mutations were detected by PCR-SSCP (polymerase chain reaction - single-stranded conformational polymorphism) electrophoresis. Codon 72 polymorphism was assessed by the restriction fragment-length polymorphism method. RESULTS: Six p53 mutations were detected in 5/53 (9%) patients with FIGO stage I squamous cell carcinoma (one patient had double mutations). 25/42 (60%) patients exhibited Arg/Arg genotype. HPV16 type was detected in 29/51 (57%) cervical carcinoma samples. Relapse of disease occurred in only 2 patients- both with Arg/Arg genotype and HPV16 positive. One of them exhibited p53 mutation. CONCLUSION: Our results showed low incidence of p53 mutations and prevalence of Arg/Arg genotype polymorphic variant of codon 72 of p53 gene in early stages of cervical carcinoma.

Coagulation status and the presence of postoperative deep vein thrombosis in patients undergoing laparoscopic cholecystectomy.

BACKGROUND: Venous thromboembolism is a relevant social and health care problem because of its high incidence among patients who undergo surgery (20-30% after general surgical operations and 50-75% after orthopedic procedures), its pulmonary embolism-related mortality rate, and its long-term sequelae (postthrombotic syndrome and ulceration), which may be disabling. This study aimed to determine the coagulation status and the presence of postoperative deep vein thrombosis (DVT) in patients undergoing laparoscopic (LC) and open cholecystectomy (OC). METHODS: Prospectively, 114 patients were randomized into two groups. group 1 (58 patients undergoing LC) and group 2 (56 patients who are undergoing OC). The coagulation parameters (prothrombin time [PT], partial thromboplastin time [PTT], D-dimer, prothrombin F1 + 2, antithrombin III, and factor VII) were monitored preoperatively and during the operation, then 24 and 72 h after the operation. The patients in both groups underwent color duplex scan examination preoperatively, then 3 and 7 days after surgery to establish the presence of DVT. None of the patients in either group received thrombosis prophylaxis. RESULTS: In the LC group, postoperative DVT developed in four patients (6.9%; in the calf veins of 3 patients and in the popliteal vein of 1 patient). In the OC group, nine patients (16.07%) had postoperative DVT (in the calf veins of 7 patients and in the popliteal and femoral veins of 2 patients). The plasma levels of monitored parameters in the patients of both groups were altered, but the difference between the groups was not statistically significant. For the patients in both groups who experienced DVT, only the decrease of factor VII had statistical significance (p < 0.05). CONCLUSIONS: The incidence of postoperative DVT among the patients who underwent OC was higher than among the patients who underwent LC (p < 0.05). The decrease in factor VII among the patients who underwent surgery could be a potentially useful parameter indicating the patients at high risk for developing DVT.

Myocardial bridges, neither rare nor isolated-Autopsy study.

PURPOSE: Myocardial bridge is a congenital anomaly with a markedly variable reported incidence on autopsy (4.7%-86%), likely related to geographical regions. Our previous retrospective study showed a prevalence of 0.8%, which we doubted to be the true one in the examined sample of the Serbian population. To assess the importance of the phenomenon we conducted a 2-year prospective study at the same institution. METHODS: Ninety-six cadaver hearts from adult individuals of both genders (51 men, 45 women) who died from natural causes underwent special dissection. Tunneled coronary arteries and myocardium were examined using light microscopy. RESULTS: A total of 14 myocardial bridges were found in 13 (13.54%) hearts. This anomaly was insignificantly more common in men (13.72% vs. 13.33%, p>0.05). In one heart we noted two myocardial bridges (the left anterior interventricular artery and left marginal artery were overbridged). None of the myocardial bridges had been diagnosed during life. The most common causes of death were cardiac related. Myocardial bridges were located in the following areas: left anterior interventricular (50%), left circumflex artery (28.6%), left marginal artery (14.3%), and right coronary artery (7.1%). In 92.3% of cases, the right coronary artery was dominant. The only heart with a balanced-type had two bridges. Most of the myocardial bridges were long and deep. All tunneled coronary arteries, and although surrounded by "coronary cushion," were not protected from atherosclerosis. In 30.8% of hearts with myocardial bridges, we found additional coronary artery anomalies. CONCLUSION: Myocardial bridges were not rare in the examined sample of the Serbian population and were often associated with other coronary artery anomalies, rendering the carriers at higher risk.

Progesterone receptor status of breast cancer metastases.

PURPOSE: The usefulness of steroid receptor content in breast cancer metastases for metastatic disease therapy planning was examined in this study. METHODS: Steroid receptors in primary tumors and corresponding metastases in the same breast cancer patients ( n=23) were determined by five-point DCC assay. We carried out an analysis of the therapeutic response and comparison of the progression-free interval of patients treated with endocrine/chemo-endocrine therapy for metastatic disease according to the positive/negative progesterone receptor status of primary tumors, or of breast cancer metastases. RESULTS AND CONCLUSIONS: It seems that the lack of positive progesterone receptors in metastasis (0/8) and conversion from PR+ primary to PR- metastasis (5/8) may be important in describing the non-responder phenotype. We obtained a similar progression-free interval in patients with progesterone receptor-positive/negative primary tumors, but a longer progression-free interval in the patients with progesterone receptor-positive metastases ( n=9) than with negative ones ( n=14), indicating the possibility of using steroid receptor content from metastases for metastatic disease therapy planning.

Case-control study of female thyroid cancer--menstrual, reproductive and hormonal factors.

A case-control study including 204 histologically verified female thyroid cancer patients and an equal number of hospital controls individually matched with cases by sex, age (+/- 2 years), place of residence and time of hospitalization was performed during the period 1996-2000. In the analysis of data, univariate and multivariate conditional logistic regression, methods were applied. According to multivariate analysis, out of hormonal, menstrual and reproductive characteristics, risk factors for thyroid cancer were spontaneous abortions (odds ratio: OR = 1.89, 95% confidence interval (CI) = 1.03-3.50), oral contraceptives use (OR = 2.34, 95% CI = 1.31-4.18) and thyroid enlargement during pregnancy (OR = 16.44, 95% CI = 3.81-70.80). However, none of these three factors remained independently related to thyroid cancer after adjustment for other factors, which were significantly associated with thyroid cancer in the present study (history of residence in endemic goitre area, history of goitre or thyroid nodule, history of other endocrine diseases, radioactive iodine therapy, occupational exposure to various chemicals, family history of thyroid gland diseases and malignant tumours as well as intake of cruciferous vegetables and other vegetables, and consumption of smoked meat and cheese).

Occult papillary carcinoma of the thyroid gland revealed by cancer pericarditis.

We report a case of hemorrhagic exudative pericarditis in a 41-year-old man which was found to be due to metastatic dissemination of a 4 mm sclerosing carcinoma of the thyroid. Many psammoma bodies were found in the pericardial specimens and malignant cells with folliculoid pattern were observed in the pleural biopsy, arousing suspicion of occult papillary thyroid carcinoma. In the thyroid gland after total thyroidectomy a 4 mm sclerosing carcinoma was found.

PS2 protein in breast carcinomas: cut-off value of estrogen-regulated expression.

This study includes 152 patients with histologically confirmed breast carcinoma. Steroid hormone receptors (SR), estrogen (ER) and progesteron (PR) receptors, and pS2 protein were assayed on the same cytosolic extract in accordance with the recommendation of EORTC. Our results showed menopausal- and histologic grade-related expression of pS2 protein. Unfavorable carcinoma subgroups, in relation to expression of pS2 protein were defined: postmenopausal carcinomas with histologic grade II, and pre-, as well as postmenopausal carcinomas with histologic grade III. There were overlappings of individual pS2 protein values between favorable and unfavorable carcinoma subgroups in relation to the expression of pS2 protein. Otherwise, no overlapping of pS2 protein values was obtained between ER-positive and ER-negative carcinomas within defined unfavorable menopausal - and histologic grade-related expression of pS2 protein subgroups. The highest pS2 protein level observed in ER-negative unfavorable subgroups (15 ng/mg) was considered as the cut-off value which defined estrogen-regulated expression of pS2 protein.

Risk factors for thyroid cancer.

Case-control study comprised 100 histologically verified thyroid cancer patients (23 men, 77 women) and 100 hospital controls matched with cases by sex, age and place of residence. Various risk factors were studied to determine whether they were associated with the occurrence of thyroid cancer. According to the conditional logistic regression analysis, 6 were significantly related to the disease: Cigarette smoking (RR = 7.12 95% CI = 1.53-32.99), family history of any malignant tumors (RR = 5.84 95% CI = 1.76-19.44), history of goiter or thyroid nodules (RR = 27.69 95% CI = 3.11-246.14), long-term occupational exposure to chemicals (RR = 10.07 95% CI = 3.85-26.35), history of second primary tumors (RR = 15.49 95% CI = 3.46-69.30), and diagnostic X-rays exposure (RR = 7.56 95% CI = 2.85-20.07).

pS2 in breast carcinoma: association with steroid hormone receptor status.

AIMS AND BACKGROUND: Knowledge of the steroid hormone receptors has proved to be of significant value in breast cancer. In the present study the possible importance of estrogen-regulated pS2 protein was investigated. Our direct purpose was to answer the question whether the expression of pS2 may be a marker of functional heterogeneity with respect to the steroid hormone receptor status. METHODS AND STUDY DESIGN: The study included 152 patients with primary, operable, histologically confirmed breast carcinomas. Histology specimens were reviewed and classified according to type, nodal status, tumor size and grade. Steroid hormone receptors were assayed by biochemical methods according to the procedures recommended by the EORTC. pS2 protein measurement was performed in breast carcinoma cytosols using an immunoradiometric assay. The results were analyzed by non-parametric statistical methods. RESULTS: A statistically significant inverse correlation between pS2 protein expression and histological tumor grade was found. The expression of pS2 protein was confirmed to be correlated with steroid hormone receptor status. However, it is important to point out that in spite of these statistically significant findings there were no significant biological associations due to overlapping individual pS2 protein values. The baseline level of expression of pS2 protein was obtained in histological grade III carcinomas with a negative steroid hormone receptor status. It was shown that the distribution of carcinomas according to the baseline level of pS2 protein expression was heterogeneous among estrogen receptor-positive carcinomas, and strikingly homogeneous among estrogen and progesterone-negative carcinoma. CONCLUSION: Our study suggested that PR and pS2 protein may identify distinct subsets of estrogen receptor-positive breast carcinomas.

The past and the future of cancer genetics.

Carcinogenesis represents a multistep process associated with accumulation of somatic mutations in the classes of genes that regulate cell proliferation, apoptosis as well as DNA repair. Oncogenes, positive regulators of cell proliferation are activated during carcinogenesis. On the contrary, tumor suppressor genes, negative regulators of cell proliferation have to be inactivated. Mutations in genes that function in the maintenance of genomic stability are manifested by increase in the mutation rate in cancer cells that drive tumor progression. In general, on the basis of malignant transformation lies the abrogation of the balance between cell proliferation and cell apoptosis. The genetic mechanisms included in the transformation of normally acting genes comprise a wide spectrum of events, such as gene mutation, gene and chromosome rearrangement and gene amplification. Besides the role of somatic gene alteration in the development of sporadic cancer, germline mutations are the basis of a substantial number of inherited cancer syndromes. The future decades will be marked with the expansion of data exploiting cancer genetics, epigenetics and genomics into clinical practice. Consequently, translational cancer research should provide the generating of new targeted therapies, since individual molecular profiling of a patient?s tumor should increase efficacy of conventional anticancer therapies such as chemotherapy and radiotherapy.