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

Pilot study on low penetrance breast and colorectal cancer predisposition markers in Latvia

Introduction: It has not been established whether CHEK2 and NOD2 variants are present in Latvia and whether inherited variation in these genes influences cancer risk in this population. Aim of the study: To evaluate the role of CHEK2 and NOD2 mutations in breast and colorectal cancers in the population of Latvia. Materials and methods: Peripheral venous blood samples were collected from 185 breast cancer and 235 colorectal cancer consecutive hospital-based cases from 11/2003 to 06/2005. The population control group included blood samples from the clamped distal part of the umbilical cord from 978 consecutive anonymous newborns born between 03/2005 and 08/2005. All cases and controls were tested for the presence of NOD2 3020insC mutation and CHEK2 I157T mutation. Results: NOD2 3020insC was present in 7.7% (18/235) of CRC cancers, in 9.2% (17/185) of breast cancers and in 7.7% (75/974) of controls. CHEK2 I157T variant was found in 7.6% (14/185) of breast cancer cases, 10.2% (24/235) of colon cancer cases and in 6.4% (63/978) of population controls. NOD2 3020insC variant was associated with increased risk of breast cancer (OR=2.5, p70 yrs. Conclusions: NOD2 3020insC and CHEK2 I157T variants may be associated with increased risk of colorectal and breast cancers in Latvia.publishersversionPeer reviewe

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

Genotype-phenotype correlations among BRCA1 4153delA and 5382insC mutation carriers from Latvia

<p>Abstract</p> <p>Background</p> <p>Mutations in the high penetrance breast and ovarian cancer susceptibility gene <it>BRCA1 </it>account for a significant percentage of hereditary breast and ovarian cancer cases. Genotype-phenotype correlations of <it>BRCA1 </it>mutations located in different parts of the <it>BRCA1 </it>gene have been described previously; however, phenotypic differences of specific <it>BRCA1 </it>mutations have not yet been fully investigated. In our study, based on the analysis of a population-based series of unselected breast and ovarian cancer cases in Latvia, we show some aspects of the genotype-phenotype correlation among the <it>BRCA1 </it>c.4034delA (4153delA) and c.5266dupC (5382insC) founder mutation carriers.</p> <p>Methods</p> <p>We investigated the prevalence of the <it>BRCA1 </it>founder mutations c.4034delA and c.5266dupC in a population-based series of unselected breast (n = 2546) and ovarian (n = 795) cancer cases. Among the <it>BRCA1 </it>mutation carriers identified in this analysis we compared the overall survival, age at diagnosis and family histories of breast and ovarian cancers.</p> <p>Results</p> <p>We have found that the prevalence of breast and ovarian cancer cases (breast: ovarian cancer ratio) differs significantly among the carriers of the c.5266dupC and c.4034delA founder mutations (OR = 2.98, 95%CI = 1.58 to 5.62, P < 0.001). We have also found a difference in the prevalence of breast and ovarian cancer cases among the 1^stand 2^nddegree relatives of the c.4034delA and c.5266dupC mutation carriers. In addition, among the breast cancer cases the c.4034delA mutation has been associated with a later age of onset and worse clinical outcomes in comparison with the c.5266dupC mutation.</p> <p>Conclusions</p> <p>Our data suggest that the carriers of the c.4034delA and c.5266dupC founder mutations have different risks of breast and ovarian cancer development, different age of onset and prognosis of breast cancer.</p