Genetic variations in 3'UTRs of SMUG1 and NEIL2 genes modulate breast cancer risk, survival and therapy response.

Breast cancer (BC) is the most frequent malignancy in women accounting for approximately 2 million new cases worldwide annually. Several genetic, epigenetic and environmental factors are known to be involved in BC development and progression, including alterations in post-transcriptional gene regulation mediated by microRNAs (miRNAs). Single nucleotide polymorphisms (SNPs) located in miRNA binding sites (miRSNPs) in 3'-untranslated regions of target genes may affect miRNA-binding affinity and consequently modulate gene expression. We have previously reported a significant association of miRSNPs in the SMUG1 and NEIL2 genes with overall survival in colorectal cancer patients. SMUG1 and NEIL2 are DNA glycosylases involved in base excision DNA repair. Assuming that certain genetic traits are common for solid tumours, we have investigated wherever variations in SMUG1 and NEIL2 genes display an association with BC risk, prognosis, and therapy response in a group of 673 BC patients and 675 healthy female controls. Patients with TC genotype of NEIL2 rs6997097 and receiving only hormonal therapy displayed markedly shorter overall survival (HR = 4.15, 95% CI = 1.7-10.16, P = 0.002) and disease-free survival (HR = 2.56, 95% CI = 1.5-5.7, P = 0.02). Our results suggest that regulation of base excision repair glycosylases operated by miRNAs may modulate the prognosis of hormonally treated BC.

Structural chromosomal aberrations as potential risk markers in incident cancer patients.

Epidemiological prospective studies have shown that increased chromosomal aberrations (CAs) in peripheral blood lymphocytes may predict cancer risk. Here, we report CAs in newly diagnosed 101 colorectal, 87 lung and 158 breast cancer patients and corresponding healthy controls. Strong differences in distributions of aberrant cells (ACs), CAs, chromatid-type aberrations (CTAs) and chromosome-type aberrations (CSAs) were observed in lung and breast cancer patients as compared to healthy controls. In colorectal cancer (CRC) patients, only CTAs were significantly elevated. Binary logistic regression, adjusted for main confounders, indicates that all the analysed cytogenetic parameters along with smoking were significantly associated with breast and lung cancer risks. Significant differences in terminal deletions between breast cancer patients and corresponding female controls were recorded (0.39 vs. 0.18; P ≤ 0.05). We did not find any association of CAs with TNM (tumor nodus metastasis) stages or histopathological grade in either cancer type. CAs were neither associated with additional tumor characteristics-invasivity, ductal and lobular character, estrogene/progesterone receptors in breast tumors nor with non-small/small cell and bronchogenic/pulmonary types of lung tumors. Our study demonstrates that CAs serve as a predictive marker for breast and lung cancer, whereas only CTAs were elevated in incident CRC patients.

The impact of lower induction values of 50 Hz external electromagnetic fields on in vitro T lymphocyte adherence capabilities.

Our research thus far has concerned the impact of external electromagnetic fields (50 Hz) and low (0.01-10 mT) induction on adherence capabilities of T lymphocytes obtained from the blood of patients with head and neck tumors. We know that the in vitro adherence capability of T lymphocytes towards surfaces in cancer patients is less than that of control. Previously, we have found that exposure to electromagnetic fields (50 Hz/0.01-10 mT) increases the capability of T lymphocytes, in larynx/pharynx cancer patients, to adhere in vitro to surfaces, achieving almost physiological values, in not only pre-treatment patients but also those receiving treatment in the course of follow-up. The capability of T lymphocytes in controls (voluntary blood donors) to adhere to surfaces was also increased (50 Hz/0.01-0.5 mT). The present study concentrates on the significance of the level of electromagnetic field induction in order to determine whether low induction values can restore T lymphocytes adherence capabilities. Testing a subset of 20 patients showed a statistically significant difference (p<0.05) in the in vitro adherence capacity of T lymphocytes between both 0.01 and 0.05, and 0.1 mT induction levels. In the control group (patients diagnosed with chronic sensorineural hearing loss) there was even a statistically significant difference between induction values of 0.05 and 0.01 mT. A statistically significant difference (p<0.05) was also achieved with induction levels of 1 and 10 mT compared to 0.5, 0.1, and 0.05 mT, respectively. Therefore, we concluded that lower induction values resulted in a more biologically significant response.

Chromosomal damage in peripheral blood lymphocytes of newly diagnosed cancer patients and healthy controls.

BACKGROUND: The majority of human cancers arise from cells unable to maintain genomic stability. Recent prospective studies indicated that enhanced chromosomal aberrations (CAs) frequencies are predictive of gastrointestinal and lung cancers. However, studies on incident cancer patients are lacking; thus, we investigated chromosomal damage in newly diagnosed cancer patients and healthy individuals. METHODS: We analyzed chromosomal damage in peripheral blood lymphocytes in a group of 300 incident cancer patients (with different malignancies) in comparison with 300 healthy controls. RESULTS AND CONCLUSIONS: The frequencies of aberrant cells (ACs) and CAs were significantly higher in patients (2.38 +/- 1.56 and 2.53 +/- 1.69, respectively) as compared with controls (1.81 +/- 1.31 and 1.94 +/- 1.47, respectively, P < 0.01). The percentual difference in chromatid-type aberrations (CTAs) between patients and controls was moderately significant (1.37 +/- 1.20 and 1.11 +/- 0.99, respectively, P

Chromosomal damage and telomere length in peripheral blood lymphocytes of cancer patients.

Accumulation of non­specific structural chromosomal aberrations (CAs) and telomere shortening contribute to genome instability, which constitutes as one of the hallmarks of cancer. CAs arise due to direct DNA damage or telomere shortening. CAs in peripheral blood lymphocytes (PBL), which are considered to be markers of exposure, have been previously reported to serve a role in the pathophysiology and progression of cancer through mechanisms that are poorly understood. In addition, the prognostic relevance of telomere length (TL) in patients with cancer remains to be elucidated. In the present study, CAs and TL in PBL isolated from patients with newly diagnosed cancer (151 breast, 96 colorectal, 90 lung) and 335 cancer­free control individuals were investigated. These results were then correlated with clinicopathological factors and follow­up data. The accumulation of CAs in PBL was observed with increased susceptibility to breast and lung cancer (P<0.0001), while individuals with longer TL were found to be at a higher risk of breast cancer (P<0.0001). Increased chromatid­type aberrations were also revealed to be associated with lower overall survival of patients with breast and colorectal cancers using a multivariate model. Compared with control individuals, no association was observed between TL and CAs or age in patients with cancer. In conclusion, the present study demonstrates the association between CAs/TL in PBL and the susceptibility, prognosis and survival of patients with breast, colorectal and lung cancer.

Carcinoid-like pattern in melanoma: report of 4 cases.

Cutaneous melanoma can produce a wide variety of unusual morphological appearances, sometimes mimicking other tumors. We report on 4 cases of melanoma with carcinoid-like features, namely, arrangement of neoplastic cells in trabecules, ribbons, pseudorosettes, rosettes, and/or small round islands. A total of 10 biopsies from 4 patients were available for a histopathological study comprising congenital nevus, a nodule that had developed in this nevus and its persistence/recurrence, 3 primary cutaneous lesions, 3 metastases, and a recurrent/persistent lesion. In 7 of these 10 lesions, the most characteristic finding was a distinctive arrangement of the neoplastic cells as trabecules, ribbons, pseudorosettes, rosettes, or small round insular islands, thus closely resembling cell arrangement in carcinoids of various organs. All these tumors were positive for melanocytic markers. No neuroendocrine differentiation was demonstrated immunohistochemically. We conclude that the carcinoid-like pattern in melanoma, namely, the pattern in which neoplastic cells are arranged in trabecules, ribbons, cords, rosettes, pseudorosettes, and small round insular nests resembling those in carcinoids, is a distinctive pattern, which may rarely occur in primary cutaneous melanoma, its recurrence or metastasis, or in a melanoma associated with a large congenital nevus. This morphological type of melanoma may produce a serious diagnostic pitfall, but despite a confusing microscopic appearance, these tumors seem to demonstrate a conventional immunohistochemical profile.

Locally advanced laryngeal cancer: Total laryngectomy or primary non-surgical treatment?

Between January 1997 and December 2013, the Charles University 3rd Medical School and Royal Vinohrady Teaching Hospital Ear, Nose and Throat oncology team treated 185 patients with advanced laryngeal cancer, which, from a surgical perspective, required a total laryngectomy. Overall, ~70% of these patients (n=129) underwent conventional treatment (i.e., total laryngectomy with post-operative radiotherapy), and ~30% (n=56) were treated with larynx preservation protocols (including primary radiotherapy, neoadjuvant chemotherapy followed by radiotherapy or chemoradiotherapy, or primary chemoradiotherapy). Patients treated with laryngeal preservation protocols had a 5-year survival probability of 48%, whereas those treated with total laryngectomy and post-operative radiotherapy had a 5-year survival probability of 63%. This difference was not statistically significant. However, patients who underwent primary surgical treatment survived for a significantly longer period (P<0.010). The sex of the patient did not have a statistically significant impact on patient survival probability. More extensive local disease and more advanced disease stages conferred a lower survival probability, but were not statistically significant; however, a lower survival probability in patients >70 years was identified to be statistically significant (P<0.010). Local disease recurrence and recurrent cervical nodal metastases had a statistically significant impact on the 5-year survival probability (P<0.001). A step wise Cox regression analysis was used to compare the parameters of sex, patient age, tumor extent, disease stage, choice of primary surgery, local recurrence and cervical nodal recurrence. In the first step, local recurrence was selected as the parameter having the greatest effect on survival (P<0.001); patient age >70 years (P<0.001) was selected in the second step; cervical nodal recurrence (P<0.001) in the third step; and disease stage (P<0.010) in the fourth step. Other parameters did not significantly affect survival. The results of the present study confirmed that primary non-surgical treatment is an alternative approach to total laryngectomy, and that an informed patient should determine the treatment approach. The decreased overall survival observed in more extensive tumors suggests that surgical treatment may be a better selection in these cases. Due to increased overall survival, primary non-surgical treatment may be recommended for younger patients. If the patient chooses primary non-surgical treatment, concomitant chemoradiotherapy is recommended. If the patient cannot tolerate cytostatic chemotherapy, radiotherapy alone is recommended.

Complications in the treatment of oropharyngeal carcinoma in patients with systemic sclerosis: A case report.

Systemic sclerosis is a chronic, progressive disease with an extremely poor prognosis. The incidence of malignant tumors in patients with systemic sclerosis is increased when compared with that of the general population. In certain malignancies, systemic sclerosis presents as a paraneoplastic process. The symptoms of sclerosis in the organs of the head and neck often overlap with symptoms of malignant diseases, which may increase the difficulty of a differential diagnosis. Additionally, the presence of sclerosis may complicate standard examination procedures, due to poor access to the oral cavity and oropharynx. When considering treatment options, it is important to evaluate the surgical and oncological risks to soft tissues of the head and neck with regard to both diseases, as well as the relatively poor prognosis for systemic sclerosis and oropharyngeal cancer. The low incidence of patients with systemic sclerosis and oropharyngeal carcinoma together presents a clear case for a casuistic approach. Based upon our own experience, we can attest to the difficulty of treating such patients. However, we have no evidence to indicate that these patients have reduced tolerance to surgical treatments. The current study presents the case of a 47-year-old female with systemic sclerosis, who was diagnosed with oropharyngeal carcinoma. The patient initially tolerated radiotherapy treatment well, however post-radiotherapy complications occurred. Despite many enigmatic indications to the contrary, it appears that the complications in this instance may be due to late toxicity from radiotherapy.

Genotype and Haplotype Analyses of TP53 Gene in Breast Cancer Patients: Association with Risk and Clinical Outcomes.

Variations in the TP53 gene have been suggested to play a role in many cancers, including breast. We previously observed an association between TP53 haplotypes based on four polymorphisms (rs17878362, rs1042522, rs12947788, and rs17884306) and the risk of colorectal and pancreatic cancer. Based on these results, in the present study, we have investigated the same polymorphisms and their haplotypes in 705 breast cancer cases and 611 healthy controls in relation to the disease risk, histopathological features of the tumor and clinical outcomes. In comparison to the most common haplotype A1-G-C-G, all the other identified haplotypes were globally associated with a significantly decreased breast cancer risk (P = 0.006). In particular, the A2-G-C-G haplotype was associated with a marked decreased risk of breast cancer when compared with the common haplotype (P = 0.0001). Moreover, rs1042522 in patients carrying the GC genotype and receiving only the anthracycline-based chemotherapy was associated with both overall and disease-free survival (recessive model for overall survival HR = 0.30 95% CI 0.11-0.80, P = 0.02 and for disease-free survival HR = 0.42 95% CI 0.21-0.84, P = 0.01). Present results suggest common genetic features in the susceptibility to breast and gastrointestinal cancers in respect to TP53 variations. In fact, similar haplotype distributions were observed for breast, colorectal, and pancreatic patients in associations with cancer risk. Rs1042522 polymorphism (even after applying the Dunn-Bonferroni correction for multiple testing) appears to be an independent prognostic marker in breast cancer patients.

Non-coding polymorphisms in nucleotide binding domain 1 in ABCC1 gene associate with transcript level and survival of patients with breast cancer.

OBJECTIVES: ATP-Binding Cassette (ABC) transporters may cause treatment failure by transporting of anticancer drugs outside of the tumor cells. Multidrug resistance-associated protein 1 coded by the ABCC1 gene has recently been suggested as a potential prognostic marker in breast cancer patients. This study aimed to explore tagged haplotype covering nucleotide binding domain 1 of ABCC1 in relation with corresponding transcript levels in tissues and clinical phenotype of breast cancer patients. METHODS: The distribution of twelve ABCC1 polymorphisms was assessed by direct sequencing in peripheral blood DNA (n = 540). RESULTS: Tumors from carriers of the wild type genotype in rs35623 or rs35628 exhibited significantly lower levels of ABCC1 transcript than those from carriers of the minor allele (p = 0.003 and p = 0.004, respectively). The ABCC1 transcript levels significantly increased in the order CT-GT>CC-GT>CC-GG for the predicted rs35626-rs4148351 diplotype. Chemotherapy-treated patients carrying the T allele in rs4148353 had longer disease-free survival than those with the GG genotype (p = 0.043). On the other hand, hormonal therapy-treated patients with the AA genotype in rs35628 had significantly longer disease-free survival than carriers of the G allele (p = 0.012). CONCLUSIONS: Taken together, our study shows that genetic variability in the nucleotide binding domain 1 has a significant impact on the ABCC1 transcript level in the target tissue and may modify survival of breast cancer patients.

Cribriform adenocarcinoma of the base of the tongue and low-grade, polymorphic adenocarcinomas of the salivary glands.

Low-grade, polymorphic adenocarcinomas occur mainly in females and are usually associated with the small salivary glands of the palate. The tumors are malignant, but not aggressive. Regional neck as well as distant metastasis is rare and the mortality rate is low. Cribriform adenocarcinoma of the salivary glands is a rare tumor, currently ranked among low-grade, polymorphic adenocarcinomas of the salivary glands. However, it differs from carcinomas in this group as it metastasizes to the cervical lymph nodes and exhibits frequent primary localization in the small salivary glands at the base of the tongue. Despite the tendency to metastasize, patient prognosis remains favorable. A case of a 72-year-old woman with neck metastases of cribriform adenocarcinoma, of unknown primary origin, is reported. The primary tumor origin was ultimately determined using nuclear magnetic resonance, histological verification was difficult due to the presence of an intact mucosal cover over the tumor. Cribriform adenocarcinoma is known to have a number of characteristics in common with a typical low-grade, salivary gland adenocarcinoma. However, in contrast to low-grade adenocarcinomas, the tumor presented with neck lymph node metastasis.