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.

• Klíčová slova
• Immunohistochemistry, Lynch syndrome, MMR, Screening algorithm, Upper urinary tract, Urothelial carcinoma,
• MeSH
• dědičné nepolypózní kolorektální nádory * diagnóza   genetika   patologie   MeSH
• karcinom z přechodných buněk * genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mismatch repair endonukleáza PMS2 genetika   MeSH
• MutL homolog 1 genetika   MeSH
• nádory močového měchýře * MeSH
• oprava chybného párování bází DNA MeSH
• senioři MeSH
• urologie * 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
• Názvy látek
• mismatch repair endonukleáza PMS2 MeSH
• MutL homolog 1 MeSH

Gastrointestinal cancers (GC) are malignancies involving the gastrointestinal (GI) tract and accessory organs of the digestive system, including the pancreas, liver, and gall bladder. GC is one of the most common cancers and contributes to more cancer-related deaths than cancers of any other system in the human body. Causative factors of GC have been consistently attributed to infections, smoking, an unhealthy diet, obesity, diabetes, and genetic factors. More recently, aberrant epigenetic regulation of gene expression has emerged as a new, fundamental pathway in GC pathogenesis. In this review, we summarize the role of the macroH2A histone family in GI cell function and malignant transformation, and highlight how this histone family may open up novel biomarkers for cancer detection, prediction, and response to treatment.

• Klíčová slova
• epigenetics, gastrointestinal cancer, histone variants, macroH2A,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The majority of tumours in patients with hereditary non-polyposis colon cancer (HNPCC) occur in large intestine and endometrium; also, other tissues are at increased risk. We studied expression of hMLH1 and hMSH2 proteins in 148 normal samples of various tissues from non-HNPCC patients and in 14 normal colon tissues from HNPCC patients. Immunohistochemical technique was used. Intensity of nuclear staining, percentage of stained cells and H-scores were calculated. Tissues were divided into groups. Groups A, B and C included tissues with increased risk of cancer in HNPCC A) stomach, small and large bowel; (B) endometrium; (C) ovary, ureter, urinary bladder, kidney and liver. Group D tissues were without increased risk. Expression of the proteins was significantly higher in groups A, B and C compared with group D (P<0.0001, P=0.0004 for hMSH2 in C versus D). The expression was highest in testis. In colons of HNPCC patients, expression of the mutated gene product was significantly lower than in non-HNPCC patients. In conclusion, hMLH1/hMSH2 protein expression is constitutively higher in certain cell types of certain tissues, including the majority of tissues that are at increased risk of cancer in HNPCC. However, association of strong hMLH1/hMSH2 expression with cancer risk is not strictly valid.

• MeSH
• adaptorové proteiny signální transdukční MeSH
• chybné párování bází MeSH
• dědičné nepolypózní kolorektální nádory genetika   MeSH
• DNA vazebné proteiny genetika   MeSH
• endometrium chemie   MeSH
• exprese genu * MeSH
• genetická predispozice k nemoci * MeSH
• homolog 2 proteinu MutS MeSH
• imunohistochemie MeSH
• jaderné proteiny MeSH
• játra chemie   MeSH
• ledviny chemie   MeSH
• lidé MeSH
• messenger RNA analýza   MeSH
• močový měchýř chemie   MeSH
• MutL homolog 1 MeSH
• nádorové proteiny genetika   MeSH
• oprava DNA MeSH
• ovarium chemie   MeSH
• protoonkogenní proteiny genetika   MeSH
• střeva chemie   MeSH
• transportní proteiny MeSH
• ureter chemie   MeSH
• žaludek chemie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• DNA vazebné proteiny MeSH
• homolog 2 proteinu MutS MeSH
• jaderné proteiny MeSH
• messenger RNA MeSH
• MLH1 protein, human MeSH Prohlížeč
• MSH2 protein, human MeSH Prohlížeč
• MutL homolog 1 MeSH
• nádorové proteiny MeSH
• protoonkogenní proteiny MeSH
• transportní proteiny MeSH

Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer-susceptibility condition characterized by early onset colorectal cancer. Germ-line mutations in one of four DNA mismatch repair (MMR) genes, hMSH2, hMLH1, hPMS1, or hPMS2, are known to cause HNPCC. Although many mutations in these genes have been found in HNPCC kindreds complying with the so-called Amsterdam criteria, little is known about the involvement of these genes in families not satisfying these criteria but showing clear-cut familial clustering of colorectal cancer and other cancers. Here, we applied denaturing gradient-gel electrophoresis to screen for hMSH2 and hMLH1 mutations in two sets of HNPCC families, one set comprising families strictly complying with the Amsterdam criteria and another set in which at least one of the criteria was not satisfied. Interestingly, hMSH2 and hMLH1 mutations were found in 49% of the kindreds fully complying with the Amsterdam criteria, whereas a disease-causing mutation could be identified in only 8% of the families in which the criteria were not satisfied fully. In correspondence with these findings, 4 of 6 colorectal tumors from patients belonging to kindreds meeting the criteria showed microsatellite instability, whereas only 3 of 11 tumors from the other set of families demonstrated this instability. Although the number of tumors included in the study admittedly is small, the frequencies of mutations in the MMR genes show obvious differences between the two clinical sets of families. These results also emphasize the practical importance of the Amsterdam criteria, which provide a valid clinical subdivision between families, on the basis of their chance of carrying an hMSH2 or an hMLH1 mutation, and which bear important consequences for genetic testing and counseling and for the management of colorectal cancer families.

• MeSH
• adaptorové proteiny signální transdukční MeSH
• dědičné nepolypózní kolorektální nádory enzymologie   etnologie   genetika   MeSH
• denaturace proteinů MeSH
• DNA vazebné proteiny * MeSH
• elektroforéza v polyakrylamidovém gelu metody   MeSH
• heteroduplexy nukleové kyseliny MeSH
• homolog 2 proteinu MutS MeSH
• jaderné proteiny MeSH
• lidé MeSH
• mikrosatelitní repetice MeSH
• MutL homolog 1 MeSH
• nádorové proteiny genetika   MeSH
• oprava DNA genetika   MeSH
• protoonkogenní proteiny genetika   MeSH
• referenční standardy MeSH
• studie případů a kontrol MeSH
• transportní proteiny MeSH
• zárodečné mutace * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Dánsko MeSH
• Itálie MeSH
• Nizozemsko MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• DNA vazebné proteiny * MeSH
• heteroduplexy nukleové kyseliny MeSH
• homolog 2 proteinu MutS MeSH
• jaderné proteiny MeSH
• MLH1 protein, human MeSH Prohlížeč
• MSH2 protein, human MeSH Prohlížeč
• MutL homolog 1 MeSH
• nádorové proteiny MeSH
• protoonkogenní proteiny MeSH
• transportní proteiny MeSH