A molekuláris onkogenezis mechanizmusai gyakori daganatokban = Mechanisms of molecular oncogenesis in common malignancies

Munkacsoportunk két évtizede megkezdett kutatási programját folytatta, amelynek fő célkitűzése új molekuláris rákgenetikai ismeretek szerzése a rák iránti fokozott genetikai fogékonyság molekuláris tényezőinek megismerésére. Vizsgálataink a Magyarországon gyakori daganatos megbetegedésekre (emlőrák, vastagbélrák, ivarszervi daganatok), elsősorban ezek familiáris formáira irányultak. Folytattuk, illetve megkezdtük a daganatszindrómák hajlamosító génjeinek elemzését örökletes emlő- és petefészekrákokban (BRCA1/2, CHEK2), familiáris adenomatozus polyposisban (APC), és herediter, nem a polyposis talaján kialakuló vastagbélrák szindróma (HNPCC) "mutátor gén"-jeiben (MSH2, MLH1). Az emlőrákos családokon, valamint kohorszokon nyert kutatási eredmények adatainak nemzetközi szintű összesítése, molekuláris epidemiológiai kiértékelése révén az örökletes daganatok kialakulására hajlamosító mutációt hordozók rákkockázatáról, a prevenciós tényezőkről és a betegség genetika-klinikai-pathológiai összefüggéseiről szereztünk további új ismereteket. Nemzetközi együttműködésben hozzájárultunk a csírasejtes hererákra hajlamosító első genetikai variánsok azonosításához. Daganatos megbetegedésre hajlamosító gének (BRCA1, STK11) esetében elemeztük az alternatív splicing szerepét a betegség kialakulásában. Újabban megkezdett génexpressziós profilvizsgálatok révén bepillantást nyertünk a molekuláris genetikai útvonalak és a metabolikus útvonalak kölcsönhatásába. | We have extended our molecular cancer genetic studies that were initiated in Hungary two decades ago and were aimed at providing new knowledge on molecular cancer genetics, with a focus on genetic susceptibility to cancer. The studies were conducted on common malignancies in Hungary (breast, colorectal and genitourinary cancers). Extended analysis of the predisposing genes of cancer syndromes was initiated or continued for hereditary breast- and/or ovarian cancer (BRCA1, BRCA2, CHEK2), for familial adenomatous polyposis (APC), for Peutz-Jeghers syndrome (STK11), and for hereditary non-polyposis colorectal carcinoma, HNPCC ("mutator genes" such as MSH2, MLH1). Forwarding the result and data of our molecular genetic analysis on breast cancer families and cancer cohorts for international data integration and molecular epidemiological analysis resulted in generation of new knowledge on cancer risk for the carriers of deleterious germ-line mutations, and on genetic-clinical and pathological correlations in development of breast cancer. Participating in international studies we have contributed to identification of new genetic variants predisposing to germ cell testicular cancer. The role of alternative splicing in development of cancer was investigated in cancer susceptibility genes BRCA1 and STK11. By recent introduction of gene-expression profiling we have gained preliminary insight into the interaction of metabolic and molecular pathways

Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials

In this study we examined the outcome of metastatic renal cell cancer patients with everolimus treatment-related hyperglycemia and hypercholesterolemia. All patients were treated in 2 large, international prospective trials, RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC). Patients who experienced these events might have experienced an improved response to everolimus. Background Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Patients and Methods Adults with vascular endothelial growth factor–refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. Results In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. Conclusion Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies

Characterization of the Rabbit Neonatal Fc Receptor (FcRn) and Analyzing the Immunophenotype of the Transgenic Rabbits That Overexpresses FcRn

The neonatal Fc receptor (FcRn) regulates IgG and albumin homeostasis, mediates maternal IgG transport, takes an active role in phagocytosis, and delivers antigen for presentation. We have previously shown that overexpression of FcRn in transgenic mice significantly improves the humoral immune response. Because rabbits are an important source of polyclonal and monoclonal antibodies, adaptation of our FcRn overexpression technology in this species would bring significant advantages. We cloned the full length cDNA of the rabbit FcRn alpha-chain and found that it is similar to its orthologous analyzed so far. The rabbit FcRn - IgG contact residues are highly conserved, and based on this we predicted pH dependent interaction, which we confirmed by analyzing the pH dependent binding of FcRn to rabbit IgG using yolk sac lysates of rabbit fetuses by Western blot. Using immunohistochemistry, we detected strong FcRn staining in the endodermal cells of the rabbit yolk sac membrane, while the placental trophoblast cells and amnion showed no FcRn staining. Then, using BAC transgenesis we generated transgenic rabbits carrying and overexpressing a 110 kb rabbit genomic fragment encoding the FcRn. These transgenic rabbits – having one extra copy of the FcRn when hemizygous and two extra copies when homozygous - showed improved IgG protection and an augmented humoral immune response when immunized with a variety of different antigens. Our results in these transgenic rabbits demonstrate an increased immune response, similar to what we described in mice, indicating that FcRn overexpression brings significant advantages for the production of polyclonal and monoclonal antibodies

Somatic mutations of KIT in familial testicular germ cell tumours

Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino acid substitutions in exon 17 and one was a 12bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with 3 out 116 unilateral cases (p = 0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes

Palynomorphs of the Normapolles group and related plant mesofossils from the Iharkút vertebrate site, Bakony Mountains (Hungary)

Abstract Palynological and paleobotanical investigation of bonebeds and other strata of the Csehbánya Formation from the vertebrate locality at Iharkút (Bakony Mts, Hungary) reveals well-preserved Santonian palynological assemblages dominated by the Normapolles group, with a minor component consisting of other angiosperm pollen, some gymnosperm pollen, and spores. Eleven species of Normapolles-type pollen grains belonging to seven genera and fruit remains of a new taxon, Sphaeracostata barbackae gen. et sp. nov., are described. The new species is very abundant in the material, represented by ca. 1000 specimens. The genus Caryanthus Friis and an unnamed form previously reported from Haţeg by Lindfors et al. (2010) are also present. Plants producing Normapolles-type pollen grains diversified during the Late Cretaceous, with a bloom in the Santonian. The palynostratigraphy of the Upper Cretaceous terrestrial sediments in the studied region is based on Normapolles-related species. The studied assemblage is assigned to the Oculopollis zaklinskaiae-Tetracolporopollenites (Brecolpites) globosus Zone (or Zone C) indicating a late Santonian age. Comparison of the Iharkút palynoflora with other known Upper Cretaceous palynofloras of Central Europe shows diachronous occurrence of Normapolles taxa at different geographic localities and warrants further investigation. The ecological requirements of the amphibian fauna reflect azonal conditions controlled by the availability of water, which is in agreement with the inferred ecological conditions based on the paleobotanical investigations. The fauna is of entirely non-marine character, further supported by isotope studies, in line with our data showing that the palynological samples contain no marine forms

Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 30 region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.Peer reviewe