Impaired telomere length (TL) maintenance in ovarian tissue may play a pivotal role in the onset of epithelial ovarian cancer (OvC). TL in either target or surrogate tissue (blood) is currently being investigated for use as a predictor in anti-OvC therapy or as a biomarker of the disease progression, respectively. There is currently an urgent need for an appropriate approach to chemotherapy response prediction. We performed a monochrome multiplex qPCR measurement of TL in peripheral blood leukocytes (PBL) and tumor tissues of 209 OvC patients. The methylation status and gene expression of the shelterin complex and telomerase catalytic subunit (hTERT) were determined within tumor tissues by High-Throughput DNA methylation profiling and RNA sequencing (RNA-Seq) analysis, respectively. The patients sensitive to cancer treatment (n = 46) had shorter telomeres in PBL compared to treatment-resistant patients (n = 93; P = 0.037). In the patients with a different therapy response, transcriptomic analysis showed alterations in the peroxisome proliferator-activated receptor (PPAR) signaling pathway (q = 0.001). Moreover, tumor TL shorter than the median corresponded to better overall survival (OS) (P = 0.006). TPP1 gene expression was positively associated with TL in tumor tissue (P = 0.026). TL measured in PBL could serve as a marker of platinum therapy response in OvC patients. Additionally, TL determined in tumor tissue provides information on OvC patients' OS.
- Klíčová slova
- Ovarian cancer, Shelterin, Telomerase, Telomere length, Therapy response,
- Publikační typ
- časopisecké články MeSH
High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer and is among the most fatal gynecological malignancies worldwide, due to late diagnosis at advanced stages and frequent therapy resistance. In 47 HGSC patients, we assessed somatic and germline genetic variability of a custom panel of 144 known or suspected HGSC-related genes by high-coverage targeted DNA sequencing to identify the genetic determinants associated with resistance to platinum-based therapy. In the germline, the most mutated genes were DNAH14 (17%), RAD51B (17%), CFTR (13%), BRCA1 (11%), and RAD51 (11%). Somatically, the most mutated gene was TP53 (98%), followed by CSMD1/2/3 (19/19/36%), and CFTR (23%). Results were compared with those from whole exome sequencing of a similar set of 35 HGSC patients. Somatic variants in TP53 were also validated using GENIE data of 1287 HGSC samples. Our approach showed increased prevalence of high impact somatic and germline mutations, especially those affecting splice sites of TP53, compared to validation datasets. Furthermore, nonsense TP53 somatic mutations were negatively associated with patient survival. Elevated TP53 transcript levels were associated with platinum resistance and presence of TP53 missense mutations, while decreased TP53 levels were found in tumors carrying mutations with predicted high impact, which was confirmed in The Cancer Genome Atlas data (n = 260). Targeted DNA sequencing of TP53 combined with transcript quantification may contribute to the concept of precision oncology of HGSC. Future studies should explore targeting the p53 pathway based on specific mutation types and co-analyze the expression and mutational profiles of other key cancer genes.
- Klíčová slova
- TP53, biomarkers, ovarian carcinoma, platinum resistance, treatment response,
- MeSH
- chemorezistence * genetika MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- nádorový supresorový protein p53 * genetika MeSH
- nádory vaječníků * genetika farmakoterapie patologie MeSH
- platina terapeutické užití farmakologie MeSH
- regulace genové exprese u nádorů MeSH
- sekvenování exomu metody MeSH
- senioři MeSH
- serózní cystadenokarcinom * genetika farmakoterapie patologie MeSH
- zárodečné mutace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- nádorový supresorový protein p53 * MeSH
- platina MeSH
- TP53 protein, human MeSH Prohlížeč
PLAG1 gene fusions were recently identified in a subset of uterine myxoid leiomyosarcomas (M-LMS). However, we have encountered cases of PLAG1-rearranged uterine sarcomas lacking M-LMS-like morphology and/or any expression of smooth muscle markers. To better characterize their clinicopathologic features, we performed a multiinstitutional search that yielded 11 cases. The patients ranged in age from 34 to 72 years (mean, 57 years). All tumors arose in the uterine corpus, ranging in size from 6.5 to 32 cm (mean, 15 cm). The most common stage at presentation was pT1b (n = 6), and 3 cases had stage pT1 (unspecified), and 1 case each presented in stages pT2a and pT3b. Most were treated only with hysterectomy and adnexectomy. The follow-up (range, 7-71 months; median, 39 months) was available for 7 patients. Three cases (7-21 months of follow-up) had no evidence of disease. Three of the 4 remaining patients died of disease within 55 to 71 months, while peritoneal spread developed in the last patient, and the patient was transferred for palliative care at 39 months. Morphologically, the tumors showed a high intertumoral and intratumoral heterogeneity. M-LMS-like and epithelioid leiomyosarcoma-like morphology were present in 3 and 5 primary tumors, respectively, the remaining mostly presented as nondescript ovoid or spindle cell sarcomas. Unusual morphologic findings included prominently hyalinized stroma (n = 3), adipocytic differentiation with areas mimicking myxoid liposarcoma (n = 2), osteosarcomatous differentiation (n = 1), and undifferentiated pleomorphic sarcoma-like areas (n = 1). The mitotic activity ranged from 3 to 24 mitoses per 10 high-power fields (mean, 9); 3 of 10 cases showed necrosis. In 3 of 11 cases, no expression of smooth muscle actin, h-caldesmon, or desmin was noted, whereas 5 of 5 cases expressed PLAG1. By RNA sequencing, the following fusion partners were identified: PUM1, CHCHD7 (each n = 2), C15orf29, CD44, MYOCD, FRMD6, PTK2, and TRPS1 (each n = 1). One case only showed PLAG1 gene break by fluorescence in situ hybridization. Our study documents a much broader morphologic spectrum of PLAG1-rearranged uterine sarcomas than previously reported, encompassing but not limited to M-LMS-like morphology with occasional heterologous (particularly adipocytic) differentiation. As it is currently difficult to precisely define their line of differentiation, for the time being, we suggest using a descriptive name "PLAG1-rearranged uterine sarcoma."
- Klíčová slova
- PLAG1 fusion, adipocytic differentiation, epithelioid, lipoleiomyosarcoma, myxoid leiomyosarcoma, uterine stromal sarcoma,
- Publikační typ
- časopisecké články MeSH
Methylation silencing of certain cellular genes is a sign of carcinogenesis progression and therefore tests that detect methylation could be used in the diagnosis or staging of malignant diseases. In the diagnosis of squamous cell carcinomas of the cervix which are almost 100% caused by long-term infection with highrisk human papillomavirus (HR-HPV), methylation silencing of certain cellular genes is a highly specific marker of advanced dysplastic lesions and appears to result from aberrant activation of the methyltransferase DNMT1 by viral oncoproteins E6 and E7. A methylation test performed on a cervicovaginal cytology specimen allows to increase the diagnostic value of this non-invasive test and to select patients with severe squamous cell lesions for follow-up. Other less frequent anogenital malignancies that are induced by HR-HPV to a lesser extent can also be detected by cytological examination - glandular lesions of various origins, most commonly cervical and endometrial adenocarcinomas and anal carcinoma. The aim of our pilot study was to evaluate the utility of a methylation test for the diagnosis of these malignancies in a cohort of 50 liquid-based cervicovaginal cytologies with glandular lesion and 74 liquid-based anal cytologies from HIV-positive men having sex with men who are at high risk for anal cancer development.
- Klíčová slova
- HR-HPV, Methylation, anal cancer, anal carcinoma, cytology, glandular lesions,
- MeSH
- cytodiagnostika MeSH
- infekce papilomavirem * komplikace diagnóza patologie MeSH
- lidé MeSH
- metylace MeSH
- onkogenní proteiny virové * genetika MeSH
- Papillomaviridae genetika MeSH
- pilotní projekty MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- onkogenní proteiny virové * MeSH
Epithelial ovarian carcinoma (EOC) is known for high mortality due to diagnosis at advanced stages and frequent therapy resistance. Previous findings suggested that the DNA repair system is involved in the therapeutic response of cancer patients and DNA repair genes are promising targets for novel therapies. This study aimed to address complex inter-relations among gene expression levels, methylation profiles, and somatic mutations in DNA repair genes and EOC prognosis and therapy resistance status. We found significant associations of DUT expression with the presence of peritoneal metastases in EOC patients. The high-grade serous EOC subtype was enriched with TP53 mutations compared to other subtypes. Furthermore, somatic mutations in XPC and PRKDC were significantly associated with worse overall survival of EOC patients, and higher FAAP20 expression in platinum-resistant than platinum-sensitive patients was observed. We found higher methylation of RAD50 in platinum-resistant than in platinum-sensitive patients. Somatic mutations in BRCA1 and RAD9A were significantly associated with higher RBBP8 methylation in platinum-sensitive compared to platinum-resistant EOC patients. In conclusion, we discovered associations of several candidate genes from the DNA repair pathway with the prognosis and platinum resistance status of EOC patients, which deserve further validation as potential predictive biomarkers.
- Klíčová slova
- DNA repair genes, biomarkers, methylome, ovarian carcinoma, resistance, transcriptome, treatment response, whole exome sequencing,
- Publikační typ
- časopisecké články MeSH
Epithelial ovarian carcinoma (EOC) is highly fatal because of the risk of resistance to therapy and recurrence. We performed whole-exome sequencing of blood and tumor tissue pairs of 50 patients with surgically resected EOC. Compared with sensitive patients, platinum-resistant patients had a significantly higher somatic mutational rate in <i>TP53</i> and lower in several genes from the Hippo pathway. We confirmed the pivotal role of somatic mutations in homologous recombination repair genes in platinum sensitivity and favorable prognosis of EOC patients. Implementing the germline homologous recombination repair profile significantly improved the prediction. In addition, distinct mutational signatures, for example, SBS6, and overall mutational load, somatic mutations in <i>PABPC1</i>, <i>PABPC3</i>, and <i>TFAM</i> co-segregated with the resistance status, high-grade serous carcinoma subtype, or overall survival of patients. We generated germline and somatic genetic landscapes of prognostically different subgroups of EOC patients for further follow-up studies focused on utilizing the observed associations in precision oncology.
- MeSH
- epiteliální ovariální karcinom farmakoterapie genetika MeSH
- individualizovaná medicína MeSH
- lidé MeSH
- nádory vaječníků * farmakoterapie genetika MeSH
- platina * farmakologie terapeutické užití MeSH
- sekvenování exomu MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- platina * MeSH
PURPOSE: The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS: GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS: From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL (P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION: Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.
- MeSH
- časové faktory MeSH
- dávka záření * MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfadenektomie * škodlivé účinky mortalita MeSH
- lymfatické metastázy MeSH
- mikrometastázy MeSH
- nádory vulvy mortalita patologie terapie MeSH
- prospektivní studie MeSH
- senioři MeSH
- sentinelová uzlina patologie účinky záření chirurgie MeSH
- staging nádorů MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- webové vysílání MeSH
OBJECTIVE: Currently, it is thought that uterine cervix mucosal samples present a low risk of SARS-CoV-2 exposure. So far, there is no evidence of SARS-CoV-2 detection in Papanicolaou (Pap) smears. Nevertheless, clinicians could be exposed unaware to the coronavirus while performing and handling a Pap smear. We aimed to retrospectively evaluate the presence of SARS-CoV-2 RNA in cervical liquid-based cytology (LBC) samples in women who tested positive for a nasopharyngeal COVID-19 PCR test. METHODS: From our laboratory database, we identified patients with data on a cervical cancer screening LBC sample paired with a positive nasopharyngeal COVID-19 PCR test. Relevant LBC samples taken within an incubation period of 14 days and post-onset RNA shedding interval of 25 days were subsequently tested for SARS-CoV-2 RNA using RT-PCR tests. RESULTS: The study group consisted of 102 women. Of those, 23 LBC samples were tested. SARS-CoV-2 RNA was detected in one LBC sample from a 26-year-old asymptomatic woman taken six days before reporting headaches and knee arthralgia with a positive nasopharyngeal SARS-CoV-2 RT-PCR test. CONCLUSIONS: It is possible to detect SARS-CoV-2 RNA in cervical LBC samples at an early asymptomatic stage of COVID-19. In general, this finding is infrequent in asymptomatic women who tested SARS-CoV-2 positive within an incubation of 14 days and a post-onset RNA shedding period of 25 days. We fully support the current thinking that cervical LBC samples from asymptomatic women pose a low risk of SARS-CoV-2 exposure and can be handled in the frame of good microbiological practice and procedures.
- Klíčová slova
- COVID-19, LBC, PAP smear, PCR, SARS-CoV-2, coronavirus,
- MeSH
- COVID-19 * diagnóza genetika metabolismus MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory děložního čípku diagnóza genetika metabolismus virologie MeSH
- Papanicolaouův test * MeSH
- retrospektivní studie MeSH
- SARS-CoV-2 * genetika metabolismus MeSH
- testování na COVID-19 průkazem nukleové kyseliny * MeSH
- vaginální stěr * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: The main objective of the article is to clearly inform healthcare professionals about the newly implemented molecular classification of endometrial cancer into practice. METHODS: Summary of current knowledge, recommendations and new procedures relating to molecular genetic examination of the tissues of patients with endometrial carcinoma. RESULTS: Endometrial cancer is currently dia-gnosed on the base of histopathological morphology. According to the classical Bokhman division, we distinguish between two relatively wide groups of tumors which are different in pathogenesis: type I - estrogen-dependent tumors, clinically usually indolent, and type II - non-endometroid tumors, clinically aggressive, without dependence on estrogen stimulation. This classification fulfills a didactic purpose and provides easy orientation for epidemiological data, but is not suitable for stratification due to the overlap of clinical, pathological and molecular features. The Cancer Genome Atlas project classifies endometrial tumors into 4 groups based on molecular genetic features. CONCLUSION: Integration of the histopathological findings along with molecular classification appears to be the best approach for evaluating each individual tumor. This will help to achieve the ideal stratification of patients for treatment regimens.
- Klíčová slova
- Endometrial carcinoma, POLE mutation –mismatch repair-deficient tumors, TP53 mutation, The Cancer Genome Atlas project, endometrial (endometrioid) carcinoma, molecular classification, non-specific molecular profile,
- MeSH
- endometroidní karcinom * MeSH
- lidé MeSH
- mutace MeSH
- nádory endometria * genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: It is generally acknowledged that interobserver variability for the histological diagnosis of endocervical adenocarcinoma (EA) subtypes is suboptimal. The recently proposed International Endocervical Adenocarcinoma Criteria and Classification (IECC) system is based on the presence of associated human papilloma virus (HPV) infection. It recognises HPV-associated EAs and non-HPV-associated EAs. METHODS: This prospective cytology-histology and molecular genetics-based study investigated the potential effect of IECC being applied to Papanicolaou (Pap) test with regard to the diagnostic accuracy of severe glandular lesions reported at least as adenocarcinoma in situ (AIS). RESULTS: Out of 118 liquid-based cytology Pap tests with AIS+ lesion, complete information on follow-up biopsy and HPV status was available in 51 cases. AIS and EA category correlated with histologically confirmed AIS/EA in 88.5% (23/26) and 70.5% (12/17) of cases, respectively. Interestingly, 93% (40/43) of cases diagnosed as AIS/EA were HPV positive and 7% (3/43) were HPV negative (originating in the cervix, endometrium and adnexa). CONCLUSIONS: Our findings suggest that this approach could possibly divide Pap tests containing severe glandular lesion into two groups: (a) robust diagnosis of HPV-associated EA and (b) non-HPV associated glandular lesions of heterogeneous origin, requiring further clinical preoperative diagnostic workup.
- Klíčová slova
- human papilloma virus, Papanicolaou test, adenocarcinoma, cervix, cytology, endometrioid endometrial adenocarcinoma, liquid-based cytology,
- MeSH
- adenokarcinom klasifikace diagnóza patologie virologie MeSH
- časná detekce nádoru * MeSH
- cytodiagnostika metody MeSH
- dysplazie děložního hrdla klasifikace diagnóza patologie virologie MeSH
- infekce papilomavirem klasifikace diagnóza patologie virologie MeSH
- lidé MeSH
- Papanicolaouův test metody MeSH
- vaginální stěr metody MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
