BRCA1 and BRCA2 gene mutations confer a high lifetime risk to breast and ovarian cancers. We have screened cancer patients from 13 families with at least three breast and/or ovarian cancers from Lithuania for 5382insC, C61G and 4153delA BRCA1 gene mutations. One of three mutations was found in 9 of the 13 studied families (69%). 4153delA was the most frequently detected and accounted for 56% of all identified mutation. 5382insC and C61G accounted for 33% and 11% of found mutations, respectively. Significantly higher, than in other populations, incidence of 4153delA indicates that this may be founder BRCA1 mutation characteristic for Lithuanians. Our analysis shows that testing of 4153delA, 5382insC, C61G BRCA1 mutations should be extremely effective and inexpensive tool in testing Lithuanian population aimed to identify individuals with high risk of breast and ovarian cancers.
We evaluated the prevalence of BRCA1 founder mutations in unselected cases of breast, ovarian and colon cancer from Lithuania. We identified a founder mutation (4153delA, 5382insC or C61G) in 6% of 235 unselected cases of breast cancer and in 19% of 43 unselected cases of ovarian cancer. Only one patient with a mutation was identified among 178 cases of colon cancer. No mutation was identified among 422 newborn controls. This data indicates that the genetic burden of breast and ovarian cancer attributable to BRCA1 mutations in Lithuania is very high and supports the recommendation that all cases of breast and ovarian cancer in Lithuania be offered genetic testing.
H ereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) is an autosomal dominantly inherited syndrome predisposing to the early development of cancers of the colon, rectum, endometrium, small bowel, and urinary tract and accounts for ∼5% of all colon cancer cases.1 There are at least five genes involved in this cancer predisposition and they include MLH1, 2 MSH2, 3 MSH6, 4 PMS2, and PMS1.5 Currently, more than 300 different mutations have been described in these genes which account for approximately 500 HNPCC kindreds from different parts of the world.6 MLH1 and MSH2 genes show abnormalities in more than 90% of HNPCC families with identified germline mutations 7 (http://www.nfdht.nl). The majority of reported MLH1 and MSH2 mutations are dispersed throughout the 35 exons of these two genes. However, some changes are recurrent and are described as founder mutations in particular populations. [8][9][10][11] In order to develop efficient DNA testing, it is important to describe the nature and frequency of mutations that are characteristic of particular ethnic groups. The MSH2 and MLH1 mutation spectrum has not been investigated in the eastern European region and therefore there is no knowledge about any recurrent mutations which may significantly aid in the mutation screening procedures for this region. Here, we describe the results of DNA/RNA based mutation sequencing of both the MSH2 and MLH1 genes in a series of HNPCC families from Poland (89 cases) and the Baltic States (12 cases). MATERIAL AND METHODS PatientsA total of 101 unrelated patients affected by colorectal cancer or an HNPCC associated cancer (endometrium, small bowel, urinary tract) were from 17 families which fulfilled the Amsterdam II criteria 12 and from 84 families matching our modified criteria of suspected HNPCC, one colorectal cancer patient with a first degree relative affected by an HNPCC associated cancer, one of whom was diagnosed under the age of 50 years. 13 The clinical diagnosis of HNPCC was established or verified at the Hereditary Cancer Centre, Pomeranian Academy of Medicine, Szczecin, Poland. Patients used for this study were ascertained from the following regions: Bydgoszcz (3), Gdańsk (3), Kielce (14), Kraków (3), Legnica (1), Lublin (2), Lódz (1), Olsztyn (13), Poznań (7), Riga (3), Szczecin (33), Tartu (3), Wrocław (5), Vilnius (6), Zielona Góra (4). DNA isolationPeripheral blood samples were collected from the patients after obtaining informed consent. DNA was extracted directly from leucocytes by the classical phenol purification method or as described previously.14 DNA sequencing All exons and exon-intron junctions of MLH1 and MSH2 were amplified using the same protocols as described previously 15 with the same primer sequences as described by Wijnen et al 16 17 for DGGE but without the M13 and GC clamp sequences at the 5′ end. Dye terminator cycle sequencing reactions were performed using the ABI PRISM Dye-terminator Cycle Sequencing Ready Reaction kit (Perkin Elmer) according to the manufacturer's recommended p...
Lynch syndrome (LS) individuals are predisposed to a variety of cancers, most commonly colorectal, uterine, urinary tract, ovarian, small bowel, stomach and biliary tract cancers. The risk of extracolonic manifestations appears to be highest in MSH2 mutations carriers.We present a carrier case with a novel MSH2 gene mutation that clearly demonstrates the broad extent of LS phenotypic expression and highlights several important clinical aspects. Current evidence suggests that colorectal tumors from LS patients tend to have better prognoses than their sporadic counterparts, however survival benefits for other cancers encountered in LS are unclear.In this article we describe a family with a novel protein truncating mutation of c.2388delT in the MSH2 gene, particularly focusing on one individual carrier affected with multiple primary cancers who is surviving 25 years on. Our report of multiple primary tumors occurring in the 12-25 years interval might suggest these patients do not succumb to other extracolonic cancers, provided they are regularly followed-up.
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