Lynchův syndrom Dotaz Zobrazit nápovědu
Lynch syndrome (formerly hereditary non-polyposis colorectal cancer) is the most common familial colorectal cancer syndrome with a known molecular genetic background. The syndrome is caused by a germline mutation of one of the genes encoding mismatch repair (MMR) proteins that are responsible for DNA replication errors repair. Impaired function of these proteins leads to microsatellite instability (MSI) and forms a suitable background for the development and progression of tumors, mainly colorectal cancer. Traditionally, Lynch syndrome was regarded to be responsible for 2 % of all cases of colorectal cancer, however recent estimates reach even 5 %. Due to this relatively high frequency, familial occurence, the absence of the premorbid phenotype and the development of malignant tumors during the productive years of life, the correct diagnosis becomes not only a medical, but also a socioeconomical problem. Unfortunately, clinical means of diagnostics of Lynch syndrome (like the Amsterdam criteria and Bethesda guidelines) lack sensitivity. It was shown that predictive models based on histological signs of MSI are more sensitive than the clinical criteria used to detect patients suspicious of Lynch syndrome. Of all MSI-H colorectal cancers, 1/5 is caused by Lynch syndrome, the rest being only sporadic cancers caused by epigenetic inactivation of a MMR protein. To rule out the sporadic cases, molecular genetic investigation of the BRAF gene and methylation analysis of MLH1 is used in the diagnostic workup of Lynch syndrome. The suspicion of Lynch syndrome, based on the results of the assortment of diagnostic methods mentioned above, should be proven by detection of a germline mutation of an MMR gene in peripheral blood, and followed by screening of family members, which is a necessary condition for efficient prevention.
- MeSH
- adaptorové proteiny signální transdukční genetika MeSH
- dědičné nepolypózní kolorektální nádory diagnóza genetika MeSH
- jaderné proteiny genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- MutL homolog 1 MeSH
- oprava chybného párování bází DNA genetika MeSH
- senioři MeSH
- zárodečné mutace MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- adaptorové proteiny signální transdukční MeSH
- jaderné proteiny MeSH
- MLH1 protein, human MeSH Prohlížeč
- MutL homolog 1 MeSH
- MeSH
- dědičné nepolypózní kolorektální nádory diagnóza genetika MeSH
- genetické testování MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Muir-Torre syndrome (MTS) represents an autosomal dominantly inherited condition and is considered a phenotypic variant of the more common hereditary nonpolyposis colorectal cancer syndrome (HNPCC), or Lynch syndrome. MTS combines at least one cutaneous neoplasm with sebaceous differentiation (e.g. sebaceoma, sebaceous adenoma, and sebaceous carcinoma), and at least one visceral malignancy. MTS is a genetic disorder caused by a germline mutation in one of the DNA mismatch repair (MMR) genes. Tumors in MTS patients are characteristically associated with the loss of MMR protein expression and/or microsatellite instability (70%). Patients who are suspected to have MTS/Lynch syndrome are often identified by dermatologists, dermatopathologists/pathologists, gastroenterologists and gynecologists. If MTS is suspected on a clinicopathological ground, necessary additional laboratory investigations should be performed only in specialized pathological departments providing immunohistochemistry and molecular biologic analysis service.
- MeSH
- fenotyp MeSH
- genotyp MeSH
- lidé MeSH
- Lynchův syndrom II diagnóza genetika patologie MeSH
- mikrosatelitní nestabilita MeSH
- nádory kůže diagnóza genetika patologie MeSH
- oprava chybného párování bází DNA genetika MeSH
- Torrého-Muirův syndrom diagnóza genetika patologie MeSH
- zárodečné mutace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- přehledy MeSH
About 5-10 % of cancer diseases may be caused by genetic predisposition, in ovarian cancer it could be almost 20 % of cases. The cause is mostly a pathogenic germline mutation in tumor suppressor genes, DNA repair genes, less frequently in oncogenes. So far, we know more than 200 hereditary cancer syndromes. The most frequently tested are hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer (Lynch syndrome), quite frequent are also hereditary gastrointestinal polyposes. Genetic counseling and testing are routinely available for patients or their relatives. Testing methods are changing; nowadays we use next generation sequencing methods (massive parallel sequencing) with testing of panels of high-risk genes. If the mutation is discovered, we may offer the testing to relatives. Genetic testing is indicated by medical geneticist after the genetic counseling session. High-risk individuals should be followed oncology clinics or by other specialists.
- Klíčová slova
- genetic counseling, genetic testing, hereditary cancer syndromes,
- MeSH
- dědičné nádorové syndromy * diagnóza genetika prevence a kontrola MeSH
- dědičné nepolypózní kolorektální nádory * diagnóza genetika prevence a kontrola MeSH
- genetická predispozice k nemoci MeSH
- genetické poradenství MeSH
- genetické testování MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Hereditary tumor syndromes with a possible manifestation in the female internal genital tract represent a heterogeneous group of diseases. The two most common entities are the hereditary breast and ovarian cancer syndrome, and the Lynch syndrome. The less common syndromes include the rhabdoid tumor predisposition syndrome, Cowden syndrome, tuberous sclerosis complex, DICER1 syndrome, nevoid basal cell carcinoma syndrome, Peutz-Jeghers syndrome, von Hippel-Lindau disease, and hereditary leiomyomatosis and renal cell cancer syndrome. The goal of this manuscript is to provide a comprehensive overview of those hereditary tumor syndromes which can manifest in the area of the female genital system, with an emphasis on their summary, the characteristics of the tumors which can develop in association with these syndromes, and the approach to the processing of prophylactically removed tissues and organs. The issue of Lynch syndrome screening is also discussed.
- Klíčová slova
- Lynch syndrome, Peutz-Jeghers syndrome, endometrial stromal tumors, female genital tract, hereditary breast and ovarian cancer syndrome, hereditary cancer predisposition syndromes, hereditary neoplastic syndromes, immunohistochemistry, mesenchymal uterine tumors, molecular classification, smooth muscle tumors, undifferentiated uterine sarcoma,
- MeSH
- DEAD-box RNA-helikasy MeSH
- dědičné nádorové syndromy * genetika MeSH
- dědičné nepolypózní kolorektální nádory * genetika MeSH
- genetická predispozice k nemoci MeSH
- leiomyomatóza * MeSH
- lidé MeSH
- nádory ledvin * MeSH
- ribonukleasa III MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- DEAD-box RNA-helikasy MeSH
- DICER1 protein, human MeSH Prohlížeč
- ribonukleasa III MeSH
Lynch syndrome (formerly known as hereditary non-polyposis colorectal cancer) is the most com-mon hereditary colorectal cancer syndrome. The syndrome is caused by a germline mutation of one of the mismatch repair (MMR) genes responsible for DNA replication error repair. Impaired function of the proteins encoded by these genes leads to microsatellite instability (MSI), which is associated with increased incidence of neoplasms: mainly colorectal cancer. According to recent estimates, up to 5% of all colorectal cancers are associated with Lynch syndrome. Due to this relatively high frequency, familial occurence, absence of premorbid phenotype, and development of malignant tumors at a reproductive age, a correct diagnosis is important not only from an ethical but also from an economical point of view. Unfortunately, clinical means of diagnosis, namely, the revised Bethesda guidelines designed to detect patients suitable for genetic testing for Lynch syndrome, lack sufficient sensitivity. The methods associated with modern pathology are more sensitive than the clinical criteria used to detect patients suspected of having Lynch syndrome. Pathological diagnostics are based on direct or indirect detection of MSI. Indirect methods include analysis of morphological signs associated with MSI in histological samples from colorectal carcinoma patients and immunohistochemical investigation of MMR protein expression. To rule out sporadic cases caused by epigenetic inactivation of an MMR gene, molecular genetic investigation of the BRAF gene and methylation analysis of the MLH1 promoter are performed during diagnostic workup. A suspicion of Lynch syndrome based on the results of the methods mentioned above should be proven by detection of a germline mutation in an MMR gene in peripheral blood leukocytes.
The hereditary form of colorectal cancer (Lynch syndrome, cancer family syndrome "nonpolyposis hereditary colorectal cancer"), which is different from familial adenomatous polyposis, represents probably 5-8% of the development of this malignancy. The main characteristics of the syndrome include an autosomal dominant hereditary type, frequent familial occurrence of colorectal cancer (either solely at this site--Lynch variant I--or in combination with other, particularly gynecological sites of cancer-Lynch variant II), younger age at the time of diagnosis, more frequent localization in the right colon and more frequent occurrence of synchronic and metachronic cancer. During the years 1982-1992, we found 339 asymptomatic members of families meeting the criteria of the syndrome. After initial colonoscopy these individuals entered a long-term surveillance system with repeated colonoscopies; intervals between them where organized according to the individual degree of risk and to at the initial finding. Results of initial colonoscopy showed colorectal cancer in 16.2% and adenomas in 32.1% of the whole group. The right colon was affected in 74.5% of the cancers and in 64% of the adenomas; the mean age of the probands with these findings was 46.4% years. The Lynch variant I was found in 34%, the variant II in 66%. Cancer in relatives of the variant II was mostly in the colorectal, followed by the gynecological region. The highest number of cancers detected on initial colonoscopy was found in probands with the highest degree of genetic risk-with 3 or more than 3 direct relatives. On repeated colonoscopies a new cancer was found in 7 further probands. All the cancers were well resectable, mostly DUKES A and B.(ABSTRACT TRUNCATED AT 250 WORDS)
A 76-year-old white male with a history of adenocarcinoma of the rectosigmoideum and multiple colonic polyps removed at the age of 38 and 39 years by an abdominoperitoneal amputation and total colectomy, respectively, presented with multiple whitish and yellowish papules on the face and a verrucous lesion on the trunk. The lesions were surgically removed during the next 3 years and a total of 13 lesions were investigated histologically. The diagnoses included 11 sebaceous adenomas, 1 low-grade sebaceous carcinoma, and 1 squamous cell carcinoma. In some sebaceous lesions, squamous metaplasia, intratumoral heterogeneity, mucinous changes, and peritumoral lymphocytes as sometimes seen in sebaceous lesions in Muir-Torre syndrome were noted. Mutation analysis of the peripheral blood revealed a germline mutation c.692G>A,p.(Arg231His) in exon 9 and c.1145G>A, p.(Gly382Asp) in exon 13 of the MUTYH gene. A KRAS mutation G12C (c.34G>T, p.Gly12Cys) was detected in 1 sebaceous adenoma and a NRAS mutation Q61K (c.181C>A, p.Gln61Lys) was found in 2 other sebaceous adenomas. No germline mutations in MLH1, MSH2, MSH6 and PMS2 genes, no microsatellite instability, no aberrant methylation of MLH1 promoter, and no somatic mutations in MSH2 and MSH6 were found. An identical MUTYH germline mutation was found in the patient's daughter. Despite striking clinicopathological similarities with Muir-Torre syndrome, the molecular biologic testing confirmed the final diagnosis of MUTYH-associated polyposis.
- MeSH
- biopsie MeSH
- dědičné nepolypózní kolorektální nádory enzymologie genetika patologie MeSH
- dědičnost MeSH
- diferenciální diagnóza MeSH
- DNA-glykosylasy genetika MeSH
- exony MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- lidé MeSH
- mutace * MeSH
- mutační analýza DNA MeSH
- nádorové biomarkery genetika MeSH
- nádory mazových žláz enzymologie genetika patologie MeSH
- rodokmen MeSH
- senioři MeSH
- Torrého-Muirův syndrom genetika patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- DNA-glykosylasy MeSH
- mutY adenine glycosylase MeSH Prohlížeč
- nádorové biomarkery MeSH
Pheochromocytoma is a catecholamine-producing neuroendocrine tumor arising from chromaffin cells of the adrenal medulla. The detection of these tumors is extremely important because they are associated with high cardiovascular morbidity and mortality. Progress in molecular genetics has revealed that up to 35% of pheochromocytomas are inhereted. Lynch syndrome (hereditary nonpolypous colorectal cancer - HNPCC) is an autosomal dominant genetic condition that is associated with a high risk of colorectal cancer or other extracolonic tumors (adenocarcinoma of endometrium, stomach, ovarian carcinoma, carcinoma of urinary tract, small intestine, brain tumors and skin cancer). Foreign medical journals are reporting an increasing number of cases on coexistence of HNPCC and neuroendocrine tumors, including pheochromocytoma. It increases the likelihood that this type of tumor could represent an additional extracolonic manifestation of Lynch syndrome.
- Klíčová slova
- Lynch syndrome, extracolonic manifestation, pheochromocytoma,
- MeSH
- dědičné nepolypózní kolorektální nádory * diagnóza genetika MeSH
- dospělí MeSH
- feochromocytom * MeSH
- kolorektální nádory * MeSH
- lidé MeSH
- nádory nadledvin * komplikace MeSH
- náhodný nález MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
The molecular genetics of the hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) is reviewed. Recently, four genes (hMSH2, hMLH1, hPMS1, hPMS2) whose mutations are related to HNPCC were discovered. The products of these genes are homologues of the bacterial mismatch repair (MMR) system proteins MutS and MutL. Dysfunction of MMR system both in bacterial and human cells leads to the microsatellite instability (MI) in repetitive sequences of DNA. These sequences are also present in some tumor suppressor genes (e.g. TGF-beta RII or BAX). Therefore, the MI probably leads to the impairment of the cell cycle regulation and a carcinoma can develop from the clone of such cells with nonregulated growth.
- MeSH
- dědičné nepolypózní kolorektální nádory genetika MeSH
- DNA nádorová genetika MeSH
- lidé MeSH
- mikrosatelitní repetice genetika MeSH
- mutace MeSH
- repetitivní sekvence nukleových kyselin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- DNA nádorová MeSH
