Doporučené postupy klinické péče o nosiče patogenních variant v klinicky relevantních genech predisponujících ke vzniku Lynchova syndromu a karcinomu kolorekta definují kroky primární a sekundární prevence, která by měla být osobám ve vysokém riziku vzniku dědičných nádorů v ČR poskytnuta. Tvorba doporučených postupů byla organizována pracovní skupinou onkogenetiky Společnosti lékařské genetiky a genomiky při České lékařské společnosti J. E. Purkyně ve spolupráci se zástupci onkologie, onkogynekologie a gastroenterologie. Doporučené postupy vycházejí z aktuálních doporučení National Comprehensive Cancer Network (NCCN), Evropské společnosti pro klinickou onkologii (ESMO) a zohledňují kapacitní možnosti našeho zdravotnictví.
The guidelines for clinical practice for carriers of pathogenic variants in clinically relevant genes predisposing to Lynch syndrome and colorectal cancer define the steps of primary and secondary prevention that should be provided to the individuals at high risk of developing hereditary cancer in the Czech Republic. The drafting of the guidelines was organized by the Oncogenetics Working Group of the Society for Medical Genetics and Genomics of J. E. Purkyně Czech Medical Society, in cooperation with representatives of oncology, oncogynecology, and gastroenterology. The guidelines are based on the current recommendations of the National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO) and take into account the capacity of the Czech healthcare system.
- MeSH
- Epithelial Cell Adhesion Molecule genetics MeSH
- Colorectal Neoplasms, Hereditary Nonpolyposis genetics MeSH
- Genetic Predisposition to Disease * genetics MeSH
- Colorectal Neoplasms * genetics MeSH
- Mismatch Repair Endonuclease PMS2 genetics MeSH
- MutL Protein Homolog 1 genetics MeSH
- Practice Guidelines as Topic MeSH
- Germ-Line Mutation genetics MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Geographicals
- Czech Republic MeSH
Východiská: Lynchov syndróm (LS) je autozomálne dominantné dedičné ochorenie, ktoré sa prejavuje zvýšením rizika vzniku nádorových ochorení, a to predovšetkým kolorektálneho a endometriálneho karcinómu. Nedávne štúdie preukázali aj asociáciu medzi LS a nádorovým ochorením prsníka. Cieľom tejto štúdie je poukázať na možný výskyt prítomnosti mutácií v génoch asociovaných s LS u pacientov s rakovinou prsníka a na potrebu zahrnúť vyšetrenie Lynch asociovaných génov u pacientov s familiárnym a opakovaným výskytom rakoviny prsníka ako aj s výskytom ďalších Lynch asociovaných nádorových ochorení. Materiál a metódy: Analyzovali sme vzorky nádorového tkaniva od 78 pacientov s primárnym nádorom prsníka. U pacientov sme analyzovali panel génov asociovaný s rizikom vzniku rakoviny prsníka, pričom sme sa v rámci našej štúdie sústredili primárne na výskyt mutácií v mismatch-repair génoch. DNA izolovaná z nádorového tkaniva bola sekvenovaná pomocou metódy sekvenovania novej generácie (next generation sequencing – NGS) a podrobená analýze pomocou nástroja Ingenuity Variant Analysis. Na potvrdenie zárodočnej mutácie sme vyšetrili krvnú vzorku pacientky pomocou NGS. Výsledky: V rámci našej analýzy sa nám v nádorovom tkanive prsníka podarilo identifikovať variant v géne PMS2 u jednej pacientky. Prítomnosť mutácie naznačuje, že vzniknuté nádorové ochorenie môže byť následkom LS. Z hľadiska patogenity sa jednalo o pravdepodobne patogénny variant, nakoľko sme odhalili deléciu v exónovej oblasti, ktorá viedla k frameshift mutácii. Navyše sme identifikovali aj jednonukleotidové patogénne varianty v génoch TP53 a PIK3CA. Pre definitívne stanovenie diagnózy LS u pacientky sme vyšetrili krvnú vzorku, kde sme tiež identifikovali mutáciu génu PMS2. Záver: LS je u mnohých Lynch asociovaných nádorových ochorení poddiagnostikovaný. V prípade familiárneho výskytu rakoviny prsníka a ďalších Lynch asociovaných génov je však dôležité myslieť aj na možnú diagnózu LS a v prípade, že pacient spĺňa diagnostické kritéria, uskutočniť aj genetické vyšetrenie Lynch asociovaných génov.
Background: Lynch syndrome (LS) is an autosomal dominant inherited disorder which causes an increased risk of cancer, especially colorectal and endometrial carcinomas. Recent studies have shown an association between LS and breast cancer as well. The aim of our study is to highlight the possible presence of mutations in genes associated with LS in patients with breast cancer and the need to include the examination of Lynch-associated genes in patients with a family history of breast cancer as well as in patients with recurrent breast cancer, as well as with the occurrence of other Lynch-associated cancer. Materials and methods: We analyzed tumor tissue samples from 78 patients with primary breast cancer. Our samples were tested with a gene panel associated with the risk of developing breast cancer, while in our study we focused primarily on the occurrence of mutations in mismatch-repair genes. DNA isolated from tumor tissue was sequenced using next generation sequencing (NGS) and analyzed using the Ingenuity Variant Analysis tool. To confirm the germline mutation, we examined the patient‘s blood sample using NGS sequencing. Results: As a result of our analysis, we managed to identify a mutation in the PMS2 gene in one patient‘s breast tumor tissue. The presence of this mutation indicates that the resulting cancer may be a consequence of LS. As for pathogenicity, this was probably a pathogenic variant, as we detected deletions in the exon region, which led to frameshift mutation. Moreover, we also identified single-nucleotide pathogenic variants in the TP53 and PIK3CA genes. To definitively establish the diagnosis of LS in the patient, we examined a blood sample, where we also identified a mutation of the PMS2 gene. Conclusion: LS is underdiagnosed in many Lynch-associated cancers. However, in the case of a familial occurrence of breast cancer and other Lynch-associated genes, it is important to think about a possible diagnosis of LS and, if the patient meets the diagnostic criteria, to carry out a genetic examination of Lynch-associated genes.
- MeSH
- Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis genetics pathology MeSH
- Genetic Predisposition to Disease MeSH
- Humans MeSH
- Mismatch Repair Endonuclease PMS2 genetics MeSH
- Mutation MeSH
- Breast Neoplasms * genetics MeSH
- Pilot Projects MeSH
- Germ-Line Mutation MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Child MeSH
- Genetic Predisposition to Disease MeSH
- Genetic Testing MeSH
- Humans MeSH
- Mismatch Repair Endonuclease PMS2 genetics MeSH
- Neoplasms * diagnosis genetics MeSH
- DNA Mismatch Repair genetics MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Review MeSH
Upper tract urothelial carcinoma (UTUC) is the third most common malignancy associated with Lynch syndrome (LS). The current European urology guidelines recommend screening for LS in patients with UTUC up to the age of 60 years. In this study, we examined a cohort of patients with UTUC for potential association with LS in order to establish the sensitivity of current guidelines in detecting LS. A total of 180 patients with confirmed diagnosis of UTUC were enrolled in the study during a 12-year period (2010-2022). Loss of DNA-mismatch repair proteins (MMRp) expression was identified in 15/180 patients (8.3%). Germline analysis was eventually performed in 8 patients confirming LS in 5 patients (2.8%), including 4 germline mutations in MSH6 and 1 germline mutation in MSH2. LS-related UTUC included 3 females and 2 males, with a mean age of 66.2 years (median 71 years, range 46-75 years). Four of five LS patients (all with MSH6 mutation) were older than 65 years (mean age 71.3, median 72 years). Our findings indicate that LS-associated UTUCs can occur in patients with LS older than 60 years. In contrast to previous studies which used mainly highly pre-selected populations with already diagnosed LS, the most frequent mutation in our cohort involved MSH6 gene. All MSH6 mutation carriers were > 65 years, and UTUC was the first LS manifestation in 2/4 patients. Using current screening guidelines, a significant proportion of patients with LS-associated UTUC may be missed. We suggest universal immunohistochemical MMRp screening for all UTUCs, regardless of age and clinical history.
- MeSH
- Colorectal Neoplasms, Hereditary Nonpolyposis * diagnosis genetics pathology MeSH
- Carcinoma, Transitional Cell * genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Mismatch Repair Endonuclease PMS2 genetics MeSH
- MutL Protein Homolog 1 genetics MeSH
- Urinary Bladder Neoplasms * MeSH
- DNA Mismatch Repair MeSH
- Aged MeSH
- Urology * MeSH
- Germ-Line Mutation MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Cells with DNA repair defects have increased genomic instability and are more likely to acquire secondary mutations that bring about cellular transformation. We describe the frequency and spectrum of somatic mutations involving several tumor suppressor genes in the rectal carcinoma of a 13-year-old girl harboring biallelic, germline mutations in the DNA mismatch repair gene PMS2. Apart from microsatellite instability, the tumor DNA contained a number of C:G→T:A or G:C→A:T transitions in CpG dinucleotides, which often result through spontaneous deamination of cytosine or 5-methylcytosine. Four DNA glycosylases, UNG2, SMUG1, MBD4 and TDG, are involved in the repair of these deamination events. We identified a heterozygous missense mutation in TDG, which was associated with TDG protein loss in the tumor. The CpGs mutated in this patient's tumor are generally methylated in normal colonic mucosa. Thus, it is highly likely that loss of TDG contributed to the supermutator phenotype and that most of the point mutations were caused by deamination of 5-methylcytosine to thymine, which remained uncorrected owing to the TDG deficiency. This case provides the first in vivo evidence of the key role of TDG in protecting the human genome against the deleterious effects of 5-methylcytosine deamination.
- MeSH
- Adenosine Triphosphatases deficiency genetics MeSH
- DNA-Binding Proteins deficiency genetics MeSH
- DNA Repair Enzymes deficiency genetics MeSH
- Phenotype MeSH
- Heterozygote MeSH
- Homozygote MeSH
- Humans MeSH
- Adolescent MeSH
- Molecular Sequence Data MeSH
- Rectal Neoplasms genetics metabolism MeSH
- Amino Acid Sequence MeSH
- Thymine DNA Glycosylase genetics metabolism MeSH
- Germ-Line Mutation MeSH
- Check Tag
- Humans MeSH
- Adolescent MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients' risk of recurrence based on molecular tumor characteristics. PRIMARY OBJECTIVES: To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy STUDY HYPOTHESIS: Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs. TRIAL DESIGN: A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm). MAJOR INCLUSION/EXCLUSION CRITERIA: Women aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1). ENDPOINTS: The primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs. SAMPLE SIZE: 500 eligible and evaluable patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).
- MeSH
- Radiotherapy, Adjuvant MeSH
- Brachytherapy MeSH
- DNA-Binding Proteins genetics metabolism MeSH
- Carcinoma, Endometrioid genetics radiotherapy therapy MeSH
- MutS Homolog 2 Protein genetics metabolism MeSH
- Clinical Trials, Phase III as Topic MeSH
- Humans MeSH
- Mismatch Repair Endonuclease PMS2 genetics metabolism MeSH
- Multicenter Studies as Topic MeSH
- MutL Protein Homolog 1 genetics metabolism MeSH
- Endometrial Neoplasms genetics radiotherapy therapy MeSH
- Randomized Controlled Trials as Topic MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Clinical Trial Protocol MeSH
- MeSH
- Base Pair Mismatch * genetics MeSH
- Colorectal Neoplasms, Hereditary Nonpolyposis genetics MeSH
- DNA-Binding Proteins MeSH
- Adult MeSH
- MutS Homolog 2 Protein MeSH
- Immunohistochemistry MeSH
- Cohort Studies MeSH
- Colorectal Neoplasms * genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Microsatellite Instability * MeSH
- Mismatch Repair Endonuclease PMS2 MeSH
- MutL Protein Homolog 1 MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.
- MeSH
- Neoplastic Syndromes, Hereditary diagnosis genetics metabolism MeSH
- DNA-Binding Proteins genetics metabolism MeSH
- DNA Repair Enzymes genetics metabolism MeSH
- Phenotype MeSH
- Genetic Predisposition to Disease MeSH
- Genetic Testing * MeSH
- MutS Homolog 2 Protein genetics metabolism MeSH
- Colorectal Neoplasms diagnosis genetics metabolism MeSH
- Humans MeSH
- Mismatch Repair Endonuclease PMS2 genetics metabolism MeSH
- Mutation * MeSH
- MutL Protein Homolog 1 genetics metabolism MeSH
- Biomarkers, Tumor genetics metabolism MeSH
- Cell Line, Tumor MeSH
- Brain Neoplasms diagnosis genetics metabolism MeSH
- DNA Mismatch Repair * MeSH
- Predictive Value of Tests MeSH
- Case-Control Studies MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
ABSTRACT: Sebaceous neoplasms occur sporadically or in the setting of Muir-Torre syndrome. The data regarding the correlation of pathologic features and DNA mismatch repair (MMR) staining pattern in sebaceous tumors of the skin are very scanty and based on relatively small series of patients. The goal of this study was to correlate MMR staining pattern with selected morphological features in a series of 145 sebaceous neoplasms (sebaceous adenoma, sebaceoma, and extraocular sebaceous carcinoma) from 136 patients. Cystic change, intratumoral mucin deposits, squamous metaplasia in the absence of keratoacanthoma-like changes, ulceration, intratumoral and peritumoral lymphocytes (in cases without epidermal ulceration), and intertumoral heterogeneity proved to be significantly associated with MMR deficiency. Identification of any of these changes, alone or in combination, should prompt further investigation of the patient to exclude Muir-Torre Syndrome. Our study also confirms the previously published observation that the diagnosis and tumor location are significantly associated with MMR deficiency.
- MeSH
- Adenoma metabolism pathology MeSH
- DNA-Binding Proteins metabolism MeSH
- Adult MeSH
- MutS Homolog 2 Protein metabolism MeSH
- Immunohistochemistry MeSH
- Carcinoma metabolism pathology MeSH
- Extremities MeSH
- Middle Aged MeSH
- Humans MeSH
- Mismatch Repair Endonuclease PMS2 metabolism MeSH
- Adolescent MeSH
- Young Adult MeSH
- MutL Protein Homolog 1 metabolism MeSH
- Head and Neck Neoplasms metabolism pathology MeSH
- Sebaceous Gland Neoplasms metabolism pathology MeSH
- Face MeSH
- DNA Mismatch Repair MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Scalp MeSH
- Torso MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Prezentujeme případ 44 leté ženy se sebaceozním adenomem vzniklém ve zralém cystickém teratomu ovária. Nádor lokalizovaný v levém ovariu byl velikosti 125 x 90 x 70 mm. Mikroskopicky se jednalo o nádor tvořený typickými strukturami dermoidní cysty, nicméně s poměrně rozsáhlými oblastmi sebaceozní proliferace. Tyto oblasti byly tvořeny sebaceozními noduly vykazujícími obdobné znaky jako sebaceozní adenom kůže. Imunohistochemicky jsme prokázali „divoký typ“ exprese proteinu p53 a nízkou proliferační aktivitu (Ki-67 index < 5%). K ověření možnosti, že jde o syndrom Muir-Torre, jsme provedli imunohistochemické vyšetření exprese ”DNA mismatch repair“ proteinů. Vyšetření s protilátkami proti všem 4 analyzovaným proteinům (MSH2, MSH6, MLH1, PMS2) vyznělo pozitivně. Sebaceozní adenom vznikající ve zralém teratomu ovaria je vzácný, doposud bylo popsáno pouze 6 takových případů.
We report the case of a 44-year-old female with sebaceous adenoma arising in mature cystic teratoma of the ovary. The patient had a tumor in the left ovary; 125 x 90 x 70 mm. Microscopically, the tumor consisted of structures typical of dermoid cysts. However, large areas of sebaceous proliferation were found. These areas were comprised of sebaceous nodules with features similar to a sebaceous adenoma of the skin. Immunohistochemically, the tumor showed “wild-type” expression of p53 and low proliferative activity (Ki-67 index < 5%). To verify the possibility of Muir-Torre syndrome we performed immunohistochemical examination of DNA mismatch repair proteins expression. However, all four proteins examined (MSH2, MSH6, MLH1, PMS2) were positive. Sebaceous adenoma arising in mature teratoma of the ovary is rare. To the best of our knowledge, only six cases have been reported in the literature to date.
