Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10-17] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE/POLD1; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria.
- Publikační typ
- časopisecké články MeSH
Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates treatment and preventive strategies reducing OC mortality in mutation carriers. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We aimed to analyze 219 genes in 1333 Czech OC patients and 2278 population-matched controls using next-generation sequencing. We revealed germline mutations in 18 OC/BC predisposition genes in 32.0% of patients and in 2.5% of controls. Mutations in BRCA1/BRCA2, RAD51C/RAD51D, BARD1, and mismatch repair genes conferred high OC risk (OR > 5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR = 3.5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Our findings demonstrate the high proportion of patients with hereditary OC in Slavic population justifying genetic testing in all patients with OC, including BTO.
- Publikační typ
- časopisecké články MeSH
Cíl studie: Posoudit možnosti, úspěšnost a výsledky PGD u párů s chromozomální translokací na základě vlastního rozsáhlého souboru pacientů. Typ studie: Retrospektivní analýza. Název a sídlo pracoviště: Sanatorium Pronatal Praha, akreditované pracoviště reprodukční medicíny. Metodika: Do studie bylo zařazeno 94 párů s translokací léčených na našem pracovišti v období 1. 1. 2004 až 31. 5. 2010. U 50 párů byl jeden z partnerů nositelem reciproké translokace, u 44 párů se jednalo o translokaci robertsonskou. Průměrný věk žen v obou skupinách se nelišil (33±4,4 u robertsonských vers. 33±3,9 u reciprokých translokací). Po stimulaci agonisty GnRH s rekombinantním FSH či hMG v „dlouhém“ protokolu a transvaginální punkci folikulů byla provedena biopsie jedné buňky embrya 72 hodin po oplození. Po fixaci blastomery byly vyšetřeny translokované chromozomy a u balancovaných embryí byly vyšetřeny chromozomy 13, 18, 21, X a Y metodou FISH na interfázních jádrech. Do dělohy jsme přenášeli maximálně dvě embrya, případná další euploidní nadpočetná embrya byla kryokonzervována. Výsledky: Z celkového počtu 629 vyšetřených embryí byla u 126 nalezena balancovaná genetická informace (21,9 %) – z toho ve 25,2 % (68/270) u párů s robertsonskou a v 16,4 % (59/359) u párů s reciprokou translokací. Embryotransfer byl v proveden ve 30 cyklech (68,2 %) u robertsonských a ve 27 cyklech (54 %) u reciprokých translokací. Celkem bylo dosaženo 24 těhotenství – 15 u robertsonských translokací (34,1 % na cyklus a 50 % na transfer) a 9 u reciprokých translokací (18 % na cyklus a 33 % na transfer) – tento rozdíl je statisticky významný (p=0,033). Pouze jedno těhotenství v každé skupině skončilo potratem. Závěr: PGD umožňuje vysokému procentu párů s chromozomální translokací, kterým se nepodařilo otěhotnět nebo porodit dítě po spontánní koncepci, v krátkém časovém horizontu otěhotnět a porodit zdravého potomka. S ohledem na biologické aspekty a interchromozomální efekt mají signifikantně lepší prognózu páry s robertsonskou translokací oproti párům s reciprokou translokací.
Aim of the study: To assess the PGD results in couples with robertsonian and reciprocal translocations. Design: Retrospective study. Setting: Sanatorium Pronatal, Prague, accredited IVF unit. Methods: 94 infertile couples with translocation (44 couples with robertsonian and 50 couples with reciprocal translocations) were included in the study. The mean woman's age was not different: 33±4,4 in robertsonian vers. 33±3,9 in reciprocal translocations. The performance of FISH probes in specific cases was tested on patient's lymfocytes before the treatment was started. After ovarian stimulation (recombinant FSH or hMG + GnRH agonist, „long“ protocol) and transvaginal oocyte pick-up, embryo biopsy of a single cell was performed 72 hours after fertilization. After blastomere fixation, translocated chromosomes + chromosomes 13, 18, 21, X and Y were tested using FISH. The maximum of two embryos euploid for detected chromosomes were transferred, supernumerary euploid embryos were frozen. Results: From the total number of 629 embryos, 126 embryos (21,9%) were detected as normal or with balanced translocation - 25,2% (68/270) in couples with robertsonian and 16,4% (59/359) with reciprocal translocation. Embryotransfer was performed in 30 cycles (68,2%) in robertsonian and 27 (54%) in reciprocal translocations. 24 pregnancies were achieved – 15 (39% per cycle and 50% per ET) for robertsonian and 9 (19% per cycle and 33% per ET) for reciprocal translocation – this diference was statistically significant (p= 0,033). Only one pregnancy in each group ended as abortion. Summary: IVF is a valuable option for couples with infertility problems and translocation. This technique allows in short term a conception and delivery of a healthy baby with general better prognosis for couples with robertsonian translocation.
- Klíčová slova
- robertsonské translokace, ICSI, IVF,
- MeSH
- fertilizace in vitro MeSH
- heterozygot MeSH
- infertilita genetika terapie MeSH
- lidé MeSH
- novorozenec MeSH
- preimplantační diagnóza MeSH
- těhotenství MeSH
- translokace genetická MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
Atopy is a predisposition to hyperproduction of immunoglobulin E (IgE) against common environmental allergens. It is often associated with development of allergic diseases such as asthma, rhinitis, and dermatitis. Production of IgE is influenced by genetic and environmental factors. In spite of progress in the study of heredity of atopy, the genetic mechanisms of IgE regulation have not yet been completely elucidated. The analysis of complex traits can benefit considerably from integration of human and mouse genetics. Previously, we mapped a mouse IgE-controlling locus Lmr9 on chromosome 4 to a segment of <9 Mb. In this study, we tested levels of total IgE and 25 specific IgEs against inhalant and food allergens in 67 Czech atopic families. In the position homologous to Lmr9 on chromosome 8q12 marked by D8S285, we demonstrated a novel human IgE-controlling locus exhibiting suggestive linkage to composite inhalant allergic sensitization (limit of detection, LOD = 2.11, P = 0.0009) and to nine specific IgEs, with maximum LOD (LOD = 2.42, P = 0.0004) to plantain. We also tested 16 markers at previously reported chromosomal regions of atopy. Linkage to plant allergens exceeding the LOD > 2.0 was detected at 5q33 (D5S1507, LOD = 2.11, P = 0.0009) and 13q14 (D13S165, LOD = 2.74, P = 0.0002). The significant association with plant allergens (quantitative and discrete traits) was found at 7p14 (D7S2250, corrected P = 0.026) and 12q13 (D12S1298, corrected P = 0.043). Thus, the finding of linkage on chromosome 8q12 shows precision and predictive power of mouse models in the investigation of complex traits in humans. Our results also confirm the role of loci at 5q33, 7p14, 12q14, and 13q13 in control of IgE.
- MeSH
- alergeny imunologie škodlivé účinky MeSH
- atopická dermatitida etnologie genetika imunologie MeSH
- časná přecitlivělost etnologie genetika MeSH
- dítě MeSH
- dospělí MeSH
- druhová specificita MeSH
- epigeneze genetická genetika MeSH
- etnicita genetika MeSH
- financování organizované MeSH
- genetická predispozice k nemoci MeSH
- imunoglobulin E biosyntéza imunologie krev MeSH
- kvantitativní znak dědičný MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidské chromozomy, pár 8 genetika MeSH
- lod skóre MeSH
- mapování chromozomů MeSH
- mladiství MeSH
- myši genetika imunologie MeSH
- potravinová alergie etnologie genetika imunologie MeSH
- respirační alergie etnologie genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- myši genetika imunologie MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- Geografické názvy
- Česká republika MeSH
