In: NEOPLASMA, vol. 54, no. 5
A. Alemayehu - K. Tomkova - K. Zavodna - K. Ventusova - T. Krivulcik - M. Bujalkova - Z. Bartosova - I. Fridrichova
Detaily:
Rok, strany: 2007, 391 - 401
O článku:
Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) represents 1-3% of all diagnosed colorectal cancers
(CRCs). This study aimed to evaluate the benefit of clinical criteria and several molecular assays for diagnosis of this
syndrome. We examined tumors of 104 unrelated clinically characterized colorectal cancer patients for causal mismatch
repair (MMR) deficiency by several methods: microsatellite instability (MSI) and loss of heterozygosity (LOH) presence,
MMR protein absence, hypermethylation of MLH1 promoter and germline mutation presence. Twenty-five (24%) patients
developed CRCs with a high level of MSI (MSI-H). Almost all (96%) had at least one affected relative, while this simple
criterion was satisfied in only 22% (17/79) of individuals with low level MSI or stable cancers (MSI-L, MSS). Using strict
Amsterdam criteria, the relative proportion of complying individuals in both sets of patients (MSI-H vs. MSI-L and MSS)
decreased to 68% and 9%, respectively. The right-sided tumors were located in 54% of MSI-H persons when compared to
14% of cancers found in MSI-L or MSS patients. In 16 MSI positive patients with identified germline mutation by DNA
sequencing, the gene localization of mutation could be indicated beforehand by LOH and/or immunohistochemistry (IHC)
in four (25%) and 14 cases (88%), respectively. The IHC findings in MSI-H cancers with methylation in distal or both
regions of MLH1 promoter have not confirmed the epigenetic silencing of the MLH1 gene. None of the patients with MSIL
or MSS tumors was a carrier of the MLH1 del616 mutation, despite seven of them meeting Amsterdam criteria. The
effective screening algorithm of Lynch-syndrome-suspected patients consists of evaluation of Bethesda or Revised Bethesda
Guidelines fulfilling simultaneous MSI, LOH and IHC analyses before DNA sequencing. Variable methylation “background”
in MLH1 promoter does not affect gene silencing and its role in Lynch-syndrome tumorigenesis is insignificant.
Key words: Lynch-syndrome diagnosis, clinical criteria, microsatellite instability, loss of heterozygosity, MMR protein
expression, MLH1 methylation.
Ako citovať:
ISO 690:
Alemayehu, A., Tomkova, K., Zavodna, K., Ventusova, K., Krivulcik, T., Bujalkova, M., Bartosova, Z., Fridrichova, I. 2007. The role of clinical criteria, genetic and epigenetic alterations in Lynchsyndrome
diagnosis. In NEOPLASMA, vol. 54, no.5, pp. 391-401. 0028-2685.
APA:
Alemayehu, A., Tomkova, K., Zavodna, K., Ventusova, K., Krivulcik, T., Bujalkova, M., Bartosova, Z., Fridrichova, I. (2007). The role of clinical criteria, genetic and epigenetic alterations in Lynchsyndrome
diagnosis. NEOPLASMA, 54(5), 391-401. 0028-2685.