Some aspects of molecular diagnostics in Lynch syndrome

This manuscript is composed of five parts which summarize five publications in succession. Essentially, they are concerned with molecular diagnostics of Lynch syndrome and are based on studies in 238 families. The finding that young age at diagnosis is the key feature in patients with MSH2 and MLH1 mutations (Part 1) has helped to define simple criteria for the preliminary diagnosis of this syndrome. A cheaper method for the detection of mutations has been developed (Part 2) and applied to study the types of mutations and their prevalence in Poland (Part 3) and the Baltic States (Part 4). A specific feature of these mutations, i.e. presence of recurrent mutations in the majority of affected families with mutations, has suggested the feasibility of effective diagnostics with a single test disclosing all of them. An attempt to reveal other causes of familial aggregation of colorectal cancer has ruled out any association with C insertion in the NOD2 gene (Part 5)

The Association of the COMT V158M Polymorphism with Endometrial/Ovarian Cancer in HNPCC Families Adhering to the Amsterdam Criteria

Catechol-O-methyltransferase (COMT) is vital for the conjugation of catechol estrogens that are produced during oestrogen metabolism. The efficiency of this process varies due to a polymorphism in COMT, which changes valine to methionine (V158M). The Met genotypes slow the metabolism of catechol oestrogens, which are agents that are capable of causing DNA damage through the formation of DNA adducts and reactive oxygen species (ROS) production. The slower metabolism of catechol oestrogens results in there being a higher circulating concentration of these oeastrogens and consequently greater probability of DNA damage. To determine whether metabolic inefficiencies of oeastrogen metabolism are associated with the development of malignancy in hereditary non-polyposis colorectal cancer (HNPCC), we studied the V158M polymorphism in COMT in a large cohort of 498 HNPCC patients from Australia and Poland that were either mutation positive (n = 331) or negative (n = 167) for mismatch repair (MMR) gene mutations (hMLH1 or hMSH2). HNPCC is a familial predisposition to colorectal cancer (CRC) and extracolonic cancers that include endometrial cancer

Hereditary Colorectal Cancer (CRC) Program in Latvia

<p>Abstract</p> <p>Introduction</p> <p>The aim of the study is to evaluate the incidence and phenotype - genotype characteristics of hereditary colorectal cancer syndromes in Latvia in order to develop the basis of clinical management for patients and their relatives affected by these syndromes.</p> <p>Materials and methods</p> <p>From 02/1999-09/2002 in several hospitals in Latvia cancer family histories were collected from 865 patients with CRC. In families suspected of having a history consistent with a hereditary colorectal cancer syndrome, DNA testing for MLH1, MSH2 and MSH6 genes was performed. In addition immunohistochemical (IH) examination of the normal and cancer tissue from large bowel tumors for MSH2 and MSH6 protein expression was performed prior to DNA analysis.</p> <p>Results</p> <p>From the 865 CRC cases only 3 (0.35%) pedigrees fulfilled the Amsterdam II criteria of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) and 15 cases (1.73%) were suspected of HNPCC. In 69 cases (8%) with a cancer family aggregation (CFA) were identified. Thus far 27 IH analyses have been performed and in 3 cancers homogenous lack of MSH2 or MSH6 protein expression was found. In one of these cases a mutation in MSH6 was identified. In 18 patients suspected of HNPCC or of matching the Amsterdam II criteria, denaturing high performance liquid chromatography (DHPLC) followed by DNA sequencing of any heteroduplexes of the 35 exons comprising both MLH1 and MSH2 was performed revealing 3 mutations.</p> <p>For all of kindreds diagnosed definitively or with a high probability of being an HNPCC family appropriate recommendations concerning prophylactic measures, surveillance and treatment were provided in written form.</p> <p>Conclusions</p> <p>Existing pedigree/clinical data suggest that in Latvia the frequency of HNPCC is around 2% of consecutive colorectal cancer patients. It is crucial that genetic counseling is an integral part of cancer family syndrome management.</p

Heat Capacity of Drained Peat Soils

Soil-specific heat capacity (cp) and volumetric heat capacity (Cv) are recognized as a fundamental soil property essential for the accurate prediction of soil temperature and heat flow. This study presents the analysis of these thermal properties for drained peat soils in Poland. The objectives of this study were to (i) measure and develop a method for determining cp, (ii) analyze the (Cv) data for undisturbed soil samples from surface layers, and (iii) test the applicability of the cp value for calculating Cv of drained peat soils using the mixing model concept. The cp value was measured under laboratory conditions using a modulated differential scanning calorimetry (MDSC) for 18 soil layers sampled in six degraded peat soil profiles. The Cv was estimated for undisturbed triplicate soil samples from the 22 depths (66 samples) by using a dual-needle probe. The cp data for the organic soils were linearly temperature-dependent (MDSC) for the temperature range considered (−20–30 °C). The overall average cp value was equal to 1.202 J g−1 K−1 at a temperature of 0 °C. An increment in temperature of 1 °C corresponded to an increase in cp of 0.0043 J g−1 K−1 on average. Nevertheless, the lowest cp value was obtained for moss samples whereas the highest value represents alder peats. The Cv data measured using the heat thermal probe (HTP) method changed linearly with changes in the soil moisture content (θv) of the moorsh soils. The volumetric heat capacity calculated using the mixing model was comparable to the mean of measured values obtained on the triplicate samples.</jats:p

Nationwide study of clinical and molecular features of hereditary non-polyposis colorectal cancer (HNPCC) in Latvia

Background: The mutational spectrum of mismatch repair (MMR) genes in the Baltic States has been reported to be quite similar to that in Poland; however during a country-wide study considerable differences in the population of Latvia were discovered. This study was undertaken to investigate the clinical and molecular features of HNPCC in Latvia. Materials and Methods: Family cancer histories were collected, from January 2000 until October 2003, for 702 consecutive hospital based colorectal cancer (CRC) cases. In families suspected of having a history consistent with hereditary non-polyposis colorectal cancer (HNPCC), DNA testing for MLH1, MSH2 and MSH6 genes was performed. Immunohistochemical examination of the normal and the cancer tissue from large bowel tumors was undertaken for MSH2 and MSH6 protein expression in 182 out of 702 (26%) of the cases. Results: Among the 702 CRC patients only 1 (0.14%) fulfilled the Amsterdam criteria. Thirteen (1.9%) cases matched the criteria for suspected HNPCC and 10 (1.4%) cases matched the late onset HNPCC criteria. Altogether in 7 out of 702 (1%) cases MMR gene mutations were detected: 2 in MLH1, 3 in MSH2 and 2 in MSH6 gene. Only one out of the seven mutations was registered in the Human Genome Mutation Database and the ICG (International Collaborational Group)-HNPCC mutation data base. Negative MSH2 and MSH6 protein expression was detected in 4 (2.2%) and 18 out of 182 (9.9%) cases respectively. Conclusion: The role of the classical Amsterdam criteria in diagnosing HNPCC in CRC patients from Latvia is very limited and diagnostic criteria for suspected HNPCC are the most effective. The frequency of constitutional mutations within the MMR genes is 1% of all newly diagnosed CRC cases and the spectrum of mutations is potentially characteristic.Peer reviewe

Clinical, Molecular and Geographical Features of Hereditary Breast/Ovarian Cancer in Latvia

Introduction. The aim of the study is to evaluate the incidence and phenotype-genotype characteristics of hereditary breast and ovarian cancer syndromes in Latvia in order to develop the basis of clinical management for patients and their relatives affected by this syndrome. Material and methods. In 2002-2004 in two Latvian oncology hospitals (Liepãja Oncology Hospital and Daugavpils Oncology Hospital) cancer family histories were collected from 287 consecutive patients with breas